Methods of treatment of cancer with GSPT1 degraders

Abstract

The present invention relates to methods for treating cancer with a GSPT1 degrader, and particularly, the present invention relates to methods of treating cancer in a patient who is biomarker negative for a gene induced in response to low oxygen levels. In some embodiments, the patient is biomarker positive for a Myc transcription factor. The invention also relates to methods of determining whether a patient is likely to respond to the use of a GSPT1 degrader in the treatment of cancer and thus assess the efficacy of GSPT1 degraders to treat patients with cancer by determining the level of a biomarker in the patient.

Description

METHODS OF TREATMENT OF CANCER WITH GSPT1 DEGRADERSCross reference to related applications

[0001] The application claims the benefit of priority of European application EP 24157729.5, filed on 15th February 2024. The contents of this application are incorporated herein by reference.Field of disclosure

[0002] The present invention relates to methods for treating cancer with a GSPT1 degrader. In particular, the present invention relates to methods of treating cancer in a patient who is biomarker negative for a gene induced in response to low oxygen levels. In some embodiments, the patient is biomarker positive for a Myc transcription factor. The invention also relates to methods of determining whether a patient is likely to respond to the use of a GSPT 1 degrader in the treatment of cancer and thus assess the efficacy of GSPT1 degraders to treat patients with cancer by determining the level of a biomarker in the patient.Background

[0003] The increasing number of cancer cases worldwide and the lack of successful therapies is a major concern. Currently there are only few treatments available for only very specific types of cancer, and even those provide typically no guarantee for a cure. While early detection and thus early intervention increases the chances for a successful treatment, a reliable assessment of the cancer and treatment options is still missing.

[0004] Tumorigenesis in humans is due to genetic alterations that drive the progressive transformation of normal human cells to abnormally high and uncontrollable levels, which ultimately results in the formation of various malignancies. The extent of deregulated expression differs between patients and patient populations and thus the likelihood of a successful therapeutic response may vary broadly and affects the outcome of a specific treatment and the survival chances of a patient. Yet, there is still a need for specific and sensitive methods for predicting patient responsiveness and identifying treatment options targeted to a specific patient and specific patient populations, particularly (but not exclusively) in early stages of the disease. Since early treatment of a specific cancer is absolutely key for survival, biomarkers identifying patients more likely to respond to treatment would be highly beneficial. A reliable assessment of patient status and prediction of patient responsiveness would be highly desirable to be able to select an optimal treatment strategy (and / or tailor an ongoing treatment) and thus increase the chances for survival.

[0005] In addition, the ability to predict the efficacy of a treatment would be beneficial in clinical trials for new cancer treatments, as patients could be stratified according to their responsiveness for a participation. This may allow to reduce the number of patients necessary for a clinical study and / or accelerate the time required to complete a clinical development program and result in more meaningful outcomes of a trial.

[0006] WO 2022152822A1 , the contents of which are incorporated herein by reference, describes the use of biomarkers in methods to predict the responsiveness of cancer patients to GSPT 1 negative modulators and thus determine the of efficacy GSPT1 negative modulators to treat cancer patients by determining the level of a biomarker in samples of the patients.

[0007] In the present application, new specific biomarkers have been identified that allow the improved prediction of responsiveness to treatment of cancer with one or more GSPT 1 degraders and thereby distinguish (before or during a treatment) between patients that are more responsive to such treatment and patients that are less responsive to such treatment. Thus, the use of these biomarkers will aid in devising therapies specifically targeted to those patients who are more likely to benefit from a GSPT1 degrader therapy. This ability to predict the responsiveness to a treatment (with a GSPT1 degrader) is beneficial to both patients that are likely to be more responsive as well as patients that are likely to be less responsive to a GSPT1 degrader.

[0008] In addition to identifying new biomarkers, the applicants have found that the use of biomarkers for more than one type of indicator (e.g. determining the level of a biomarker for a Myc transcription factor and a gene induced in response to low oxygen levels) has proven to be useful in providing further precision while classifying patients. This allows for a more accurate prediction that a patient meeting the specified biomarker criteria will be responsive to a GSPT1 degrader.Summary of invention

[0009] The present invention relates to a method of treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a GSPT1 degrader to the patient, wherein the patient is biomarker negative for a gene induced in response to low oxygen levels. In some embodiments, the patient is biomarker positive for a Myc transcription factor. In some embodiments, the method comprises determining the level of a biomarker in a biological sample obtained from the patient.

[0010] The present invention also relates to a method of determining whether a patient is likely to respond to the use of a GSPT1 degrader in the treatment of cancer, comprising determining the level of a biomarker for a gene induced in response to low oxygen levels in the patient and determining that the patient is likely to be responsive to treatment if the patient is biomarker negative for a gene induced in response to low oxygen levels. In some embodiments, the method further comprises determining the level of a biomarker for a Myc transcription factor in the patient, and determining that the patient is likely to be responsive to treatment if the patient is biomarker positive for a Myc transcription factor and biomarker negative for a gene induced in response to low oxygen levels.

[0011] The present invention also relates to a method of measuring a biomarker in a patient with cancer, comprising determining the level of a biomarker for a gene induced in response to low oxygen levels in the patient. In some embodiments, the method comprises determining the level of a biomarker for a Myc transcription factor in the patient.

[0012] The gene induced in response to low oxygen levels may be NDRG1 . The Myc transcription factor may be N-Myc. Thus, in a preferred embodiment, the present invention relates to a method of treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a GSPT1 degrader to the patient, wherein the patient is biomarker negative for NDRG1 , and wherein the patient is biomarker positive for N-Myc.

[0013] A biomarker negative patient may have a level of that biomarker that is below a reference level, and a biomarker positive patient may have a level of that biomarker that is above a reference level. Preferably, a reference level is determined from a distribution of control subjects.

[0014] In some embodiments, the reference level is the median level of biomarker determined from a distribution of control subjects. A biomarker negative patient may have a level of that biomarker which is below the median determined from a distribution of control subjects. A biomarker positive patient may have a level of that biomarker above the median determined from a distribution of control subjects.

[0015] Preferably, the reference level for a biomarker, such as a biomarker for a gene induced in response to low oxygen levels, is the 20th percentile level of that biomarker determined from a distribution of subjects. Preferably, a reference level for a biomarker, such as a biomarker for a Myc transcription factor, is the 70th percentile level of that biomarker determined from a distribution of subjects.

[0016] Preferably, the cancer is lung cancer. The cancer may be small cell lung cancer (SCLC) or nonsmall cell lung cancer (NSCLC). The cancer may be lung adenocarcinoma (LUAD).

[0017] Preferably, the cancer is prostate cancer. The cancer may be castration resistant prostate cancer or hormone sensitive prostate cancer. The cancer may be neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer.

[0018] Preferably, the cancer is breast cancer. The cancer may be HR-positive, HER2-negative breast cancer or ER-positive breast cancer.

[0019] Preferably, the GSPT1 degrader is a compound, a pharmaceutically acceptable salt, or a stereoisomerthereof of any of Formulae I, II, III, IVa, IVb, V, VI, VII, VIII, or Villa as described herein. In more preferred embodiments, the GSPT1 degrader is a compound, a pharmaceutically acceptable salt, or a stereoisomer thereof of Formula Villa. In the most preferred embodiments, the GSPT1 degrader is compound 145, shown below.

[0020] In preferred embodiments, the gene induced by low oxygen levels is NDRG1 , the Myc transcription factor is N-Myc, the cancer is lung cancer and the GSPT1 degrader is compound 145.

[0021] In preferred embodiments, the gene induced by low oxygen levels is NDRG1 , the Myc transcription factor is N-Myc, the cancer is prostate cancer and the GSPT1 degrader is compound 145.

[0022] In preferred embodiments, the gene induced by low oxygen levels is NDRG1 , the Myc transcription factor is N-Myc, the cancer is breast cancer and the GSPT1 degrader is compound 145.Brief description of the Figures

[0023] Figure 1 shows the mRNA expression of each of NDRG1 , ADM and EGLN3 in the PDX models as described in Example 1. GSPT1 responders were labelled ‘TRUE’ and GSPT1 responders non- responders labelled ‘FALSE’.

[0024] Figure 2 shows the NDRG1 expression and the N-Myc expression measured from the PDX models of Example 1 measured by RNA sequencing and RT-qPCR respectively. The models have been categorised as responders or non-responders. The dashed lines are used to show the reference levels in this experiment for both N-Myc and NDRG1 . The shaded quadrant of the graph corresponds to the PDX models that are above the N-Myc reference level and below the NDRG1 reference level.

[0025] Figure 3 shows a waterfall plot of the tumour volume change from certain PDX models of Example 1 . The N-Myc and NDRG1 status of the PDX models is denoted by a black (high) or white (low) rectangle underneath the bar for the individual PDX model bar.

[0026] Figure 4A shows the median-centred distribution of NDRG1 expression in lung adenocarcinoma patients from the TCGA-LUAD database. The right-hand side y-axis shows the eCDF (empirical cumulative distribution function) and the left-hand side y-axis shows the count of the histogram. The dashed line shows the value that is 0.9 below the median of the dataset.

[0027] Figure 4B shows the median-centred distribution of N-Myc expression in lung adenocarcinoma patients from the TCGA-LUAD database. The right-hand side y-axis shows the eCDF (empirical cumulative distribution function) and the left-hand side y-axis shows the count of the histogram. The dashed line shows the value that is 1 .1 above the median of the dataset.

[0028] Figures 5A and 5B show the NDRG1 expression measured by RNA sequencing and the N-Myc expression, measured by RNA sequencing in Figure 5A and by IHC in Figure 5B, of the PDX models of Example 1 . The models have been categorised as responders or non-responders. The dashed lines areused to show the reference levels in this experiment for both N-Myc and NDRG1 . The shaded quadrant of the graph corresponds to the PDX models that are above the N-Myc reference level and below the NDRG1 reference level.

[0029] Figures 6A, 6B and 6C show the ADM expression measured by RNA sequencing and the N- Myc expression, measured by RTqPCR in Figure 6A, by RNA sequencing in Figure 6B and by IHC in Figure 6C, of the PDX models of Example 1 . The models have been categorised as responders or nonresponders. The dashed lines are used to show the reference levels in this experiment for both N-Myc and ADM. The shaded quadrant of the graph corresponds to the PDX models that are above the N-Myc reference level and below the ADM reference level.

[0030] Figures 7 A, 7B and 7C show the EGLN3 expression measured by RNA sequencing and the N- Myc expression, measured by RT-qPCR in Figure 7A, by RNA sequencing in Figure 7B and by IHC in Figure 7C, of the PDX models of Example 1 . The models have been categorised as responders or nonresponders. The dashed lines are used to show the reference levels in this experiment for both N-Myc and EGLN3. The shaded quadrant of the graph corresponds to the PDX models that are above the N- Myc reference level and below the EGLN3 reference level.

[0031] Figure 8A shows the anti-tumor activity per RECIST v1 .1 in 13 response evaluable patients with Myc high expressing tumors (N-Myc or L-Myc expression or amplification). Figure 8B shows the responses of 10 of these Myc high expression tumor patients responses stratified by NDRG1 expression status (NDRG1-high or NDRG1-low). The following acronyms are used in the figure labels to describe the conditions experienced by the patients: SCLC: small cell lung cancer; NSCLC-A: non-small cell lung cancer. - Adenocarcinoma; SCLC / NSCLC-A: Mixed tumor with SCLC and NSCLC-A pathology; cSCC: cutaneous squamous cell carcinoma; HG NE: high-grade neuroendocrine tumor; CUP: carcinoma of unknown primary. The values in parentheses indicate gene alterations: MYCN: N-Myc over-expression or amplification; RLF-MYC: RLF-L-Myc fusion; EGFR: Activating EFGR mutation.Detailed description

[0032] Unless stated otherwise the following definitions apply throughout the text:

[0033] It is understood that the indication “a” or “the” is not limited to the singular form but also extends to the plural form, e.g. referring to a cell (such as a cancer cell) also includes cells.

[0034] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, i.e. as "including, but not limited to". The term “consist of’ and variations thereof, such as “consists of’ and “consisting of’ are to be construed in a closed sense. For the avoidance of doubt, the open interpretations of the term “comprise” (and variations thereof) include within them the closed interpretations given by “consisting of’ (and variations thereof).

[0035] In the context of the application as filed, it is appreciated that numbers should be considered with error margins corresponding to the significant figure that they are reported to; for example, a value of 5 must be considered to encompass values of less than 5.5 and 4.5 or more. Additionally, as used herein, the term ‘about’ can be considered to refer to + / - up to 10% of the reported value, such as + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1 %.

[0036] The meaning of the term “cancer” or “cancerous” as used herein refers to a physiological condition characterized by cellular hyperproliferation, more particularly pathological hyperproliferation. The term cancer includes a cancer cell (or cancer cell derived therefrom) or a tumor or tumor cell and corresponds to all stages of the disease (precancerous as defined below, early, moderately advanced and advanced). The term “cancerous” when referring to a sample such as a cell or tissue, generally refers to any sample, such as cells or tissues that exhibit, or are predisposed to exhibiting, unregulated growth, including, for example, a neoplastic cell / tissue such as a premalignant cell / tissue or a cancer cell (e.g., carcinoma cell or sarcoma cell).

[0037] The terms “combination” or “used in combination” or “combination therapy” refer the administration of a plurality of therapeutic agents to a subject in need thereof. For instance, these terms may refer to the administration of a GSPT1 degrader described herein with or more therapeutic agents. Therapeutic agents / GSPT1 degraders may be administered simultaneously, sequentially, or separately. Simultaneous administration refers to administration of the one or more therapeutic agents in the same dosage form at the same time. As used herein, separate administration refers to administration of the one or more therapeutic agents in different dosage forms at the same time or one immediately after the other in any order. As used herein, sequential administration refers to administration of the one or more therapeutic agents in different dosage forms at different times. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and / or are administered on different dosing schedules.

[0038] The term “subject” refers to a mammal, including, but not limited to, humans, primates, animals, rodents, preferably a human. A subject includes both a subject suffering from a cancer, as defined herein (also referred to as a patient), as well as a healthy subject.

[0039] The term “patient” or “cancer patient” as used herein refers to subject that has been diagnosed with cancer. A patient also refers to a subject in a precancerous condition, i.e. which is a condition or lesion involving abnormal cells which are associated with an increased risk of developing into cancer, a subject who is afflicted with cancer and is suspected to have a metastatic spread of the primary tumor, a subject who was previously afflicted with cancer and is now in remission, and a subject who was previously afflicted with cancer and is now in remission (and thus has an increased risk for reoccurrence of the cancer, i.e., as a means to monitor for a reoccurrence of the cancer). A patient that is responsive to a specific treatment is also referred to as a responder, while a patient that is non-responsive to a specific treatment is also referred to as a non-responder.

[0040] The term "Myc transcription factor" refers to the myc family of transcription factors, which includes N-Myc (MYCN proto-oncogene; UniProtKB P04198 (MYCN_HUMAN); GenBank Gene ID 4613; Ensembl gene ID: ENSG00000134323), L-Myc (MYCL proto-oncogene; UniProtKB P12524 (MYCL_HUMAN); GenBank Gene ID 4610; Ensembl gene ID: ENSG00000116990) and c-Myc (MYCN proto-oncogene; UniProtKB P01106 (MYC_HUMAN); GeneBank Gene ID 4609). Myc is a member of a family of regulator genes and proto-oncogenes that code for transcription factors, namely the myc transcription factors. Myc leads to the increased expression of many genes, some of which are involved in metabolic reprogramming and cell proliferation, contributing to the formation of cancer. The level of a myc transcription factor may be determined directly, as well as indirectly by determining for example the level of a biomarker such as its mRNA, the level of some posttranslationally modified product of the myc protein, a metabolite of a myc protein or any other form that may be a representative measure for presence and / or level of a myc protein.

[0041] The term "a gene induced in response to low oxygen levels" refers to a group of hypoxia-related genes. In this application, this particularly includes NDRG1 (N-Myc Downstream Regulated 1 ; Ensembl gene ID: ENSG00000104419), EGLN3 (Egl-9 family hypoxia inducible factor 3; Ensembl gene ID: ENSG00000129521), and ADM (Adrenomedullin; Ensembl gene ID: ENSG00000148926). The level of such a gene may be determined directly, as well as indirectly by determining for example the level of a biomarker such as its mRNA, the level of some posttranslationally modified product of the protein associated with the gene, a metabolite of such a protein or any other form that may be a representative measure for presence and / or level of such a protein.

[0042] The term "GSPT1" (G1 To S Phase Transition Protein 1 Homolog) refers to polypeptides (i.e. polypeptides, peptides, proteins) comprising the amino acid sequence of any GSPT1 , such as a human GSPT1 protein (e.g., human GSPT1 isoform 1 , GenBank Accession No. NP_002085.3; or human CRBN isoform 2, GenBank Accession No. NP 001123478.2 and others), and related polypeptides, including SNP variants thereof. Related GSPT 1 polypeptides include allelic variants (e.g., SNP variants), splice variants, fragments, derivatives, substitution variant, deletion variant, insertion variant, fusion polypeptides, and interspecies homologs, which, in certain embodiments, retain GSPT1 activity and / or are sufficient to generate an anti-GSPT1 immune response. GSPT1 is a translation termination factor, which is involved in translation termination in response to the stop termination codons UAA, UAG, and UGA, and facilitates release of a nascent peptide from the ribosome. In addition, GSPT1 is also involved in several other critical cellular processes, such as cell cycle regulation, cytoskeleton organization and apoptosis. GSPT1 stimulates the activity of eRF1 and is a component of the transient SURF complex, which recruits UPF1 to stalled ribosomes in the context of nonsense- mediated decay (NMD) of mRNAs. GSPT1 has been implicated as an oncogenic driver of several different cancer types, including breast cancer (Wang, Shuyang et al, Breast Cancer Res Treat. 2018, 171 , 199-207), lung cancer, leukemia, hepatocellular carcinoma, gastric cancer (Tian, Q-G et al, Eur Rev Med Pharmacol Sci. 2018, 22, 4138- 4145), and prostate cancer. See, e.g., Brito, et al., Carcinogenesis, 2005, 26, 2046-49; Brito, et al., Cane. Genet. Cyto., 2009, 195, 132-42; Tavassoli, et al., Med. Oncol., 2011 , 29, 1581- 85; Wright and Lange,Rev. Urol., 2007, 9, 207-213; Hoshino, et al., Apoptosis, 2012, 17, 1287-99; Liu, et. al., PLOS One, 2014, 9, e8637; Jean-Jean, et al., Mol. Cell. Bio., 2007, 27, 5619-29. GSPT1 may also contribute to glial scar formation and astrogliosis after a central nervous system (CNS) injury (e.g., Ishii et al., J. Biol. Chem., 2017, 292, 1240-50.

[0043] This application relates to the use of a GSPT1 degrader, which is capable of degrading the functional activity of GSPT1 in vivo and / or in vitro. In some embodiments, a GSPT1 degrader is binding to both GSPT1 and an E3 ligase with measurable affinity resulting in the ubiqitination and subsequent degradation of GSPT1 . In some embodiments, a degrader has an DCso of less than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. All of the effects of a degrader can be determined in any suitable manner and / or using any suitable assay known in the art.

[0044] Such degraders are referred to as targeted protein degraders (TPD) and include GSPT1 molecular glue degraders and PROTACs. GSPT1 TPDs act by bringing GSPT1 into proximity with cereblon, leading to ubiquination and subsequent degradation of GSPT1 . GSPT1 degraders that can be used as part of this invention are described herein.

[0045] The term "treat," "treating" or "treatment" refers to a measure to which a cancer patient is subjected to in order to reduce the severity of the cancer, or to slow down the progression of the cancer. These terms are also used herein refer to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition or one or more symptoms of such a disorder or condition. This includes but is not limited to the use of the methods described herein for prophylaxis, or the prevention of disease. The term "prevent”, "preventing”, "prevention”, or "prophylactic treatment” refers to a measure to which a subject is subjected to in order to reducing the probability of developing cancer in a subject, who does not have, but may or may not be at risk of or susceptible to developing cancer.

[0046] The term "therapeutically effective amount" as used herein refers to the amount of a compound (as such or in form of a pharmaceutical composition) of the present disclosure which is effective for producing a therapeutic effect. Such a therapeutic effect may be a treatment effect, as defined above, of a patient with cancer, or a prevention effect, as defined above.

[0047] The term "responsiveness" or “sensitivity” and "responsive" or sensitive” when made in reference to a cancer treatment refers to the degree of effectiveness of a cancer treatment by reducing or decreasing the symptoms of the cancer being treated, which includes cessation or reduction of tumor growth or tumor recurrence, partial or full remission of tumors. Thus, determining the responsiveness of a cancer patient to a particular cancer treatment refers to identifying the cancer patient as having an increased or reduced likelihood of responding to the particular treatment. For example, an increased (or decreased) responsiveness to or an increased (or decreased) likelihood for responding to a cancer treatment provided to a cancer patient refers to an increase (or decrease) of, at least 5 %, at least 10 %, at least 15 %, at least 20 %, at least 50%, at least 100%, at least 200%, at least 300%, at least 400%, atleast 500%, at least 1000% or more, in the effectiveness in reducing or decreasing the symptoms of the cancer when measured using any methods well-known in the art.

[0048] The term "predict", “predictive” or “prediction” refers to the ability to assess the probable course and outcome of a therapeutic intervention, i.e. the likelihood of amelioration of or recovery from the disease, and includes determining or assessing the responsiveness or likelihood of responsiveness of the effectiveness of a cancer treatment in a patient. Predicting the outcome of a treatment or the course of a treatment may be carried out (i) before the treatment has been initiated (or before the treatment period has progressed substantially) to assess the responsiveness of a patient, and / or (ii) during the course of the treatment to monitor responsiveness of a patient and adjust treatment schedules (administered dosages and frequency of administration) should the responsiveness change and / or (iii) after completion of a treatment to assess responsiveness of a patient for further treatments.

[0049] The term "effective (tumor) response" used in reference to a patient or a subject refers to any increase in the therapeutic benefit to the patient. An "effective patient tumor response" can be, for example, about 5 %, about 10 %, about 25 %, about 50 %, about 100 %, about 200%, or more decrease in the rate of progress of the tumor and / or in the physical symptoms of a cancer. An "effective patient tumor response" can also be, for example, about 5 %, about 10 %, about 25 %, about 50 %, about 100 %, about 200 %, or more increase in the response of the patient, as measured by any suitable means, such as gene expression, cell counts, assay results, tumor size, etc. An improvement in the cancer or cancer- related disease can be characterized as a complete or partial response. The term "complete response" refers to an absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements. The term "partial response" refers to at least about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, or about 90 % decrease in all measurable tumor burden (i.e., the number of malignant cells present in the subject, or the measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence of new lesions. The term "treatment" contemplates both a complete and a partial response.

[0050] The terms "determine", "measuring", "evaluate", "assess" and "assay" as used herein with reference to the responsiveness to a specific cancer treatment with a GSPT1 degrader refers to analysing quantitatively and / or qualitatively if a biomarker is present or not in absolute or relative terms (i.e. relative to one or more previous analyses). Thus, assessing the presence of a biomarker can include determining the amount of the biomarker present, as well as determining whether it is present or absent. In any of the methods comprising the measurement of gene expression in a test tissue sample as disclosed herein, however, it should be understood that any step comprising the provision of a test tissue sample obtained from a subject is an optional step. It should also be understood that in certain embodiments, the “measuring” or “assessing” step to determine the expression level, phosphorylation level or gene amplification level includes a transformative method of assaying for gene expression, for example by performing RNA sequencing, a reverse transcriptase-polymerase chain reaction (RT-PCR) assay or an IHC assay. In some cases, the expression level, phosphorylation level or gene amplification level isassessed or determined by, for example, reviewing a report of test results from a laboratory or performed by a different individual or entity. In certain cases, the steps of the methods up to, and including, assessing gene expression provides an intermediate result that can be provided to a physician or other healthcare provider for use in selecting a suitable candidate for treatment with a GSPT1 degrader. In certain embodiments, the steps that provide the intermediate result is performed by a medical practitioner or someone acting under the direction of a medical practitioner. In other embodiments, these steps are performed by an independent laboratory or by an independent person such as a laboratory technician.Methods of treatment

[0051] The present invention relates to methods of treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a GSPT1 degrader to the patient. The methods of treatment provided by the invention may also be expressed in terms of the use of a GSPT1 degrader in these methods. For instance, the invention provides a GSPT1 degrader for use in any method of treating a disease in a subject in need thereof as defined herein. The invention also provides the use of a GSPT1 degrader in the manufacture of a medicament for treating a disease in a subject in need of such treatment according to any method herein.

[0052] In particular, the present invention relates to a method in which the patient is biomarker negative for a gene induced in response to low oxygen levels. In preferred embodiments of the invention, the patient is also biomarker positive for a Myc transcription factor. The use of these two different biomarkers together provides a more accurate prediction versus a prediction using the biomarker status for a Myc transcription factor alone.

[0053] In some embodiments, the patient has been treated with or is being treated with a GSPT1 degrader.

[0054] In some embodiments of the invention, the method comprises determining the level of a biomarker in a biological sample obtained from the patient. In some embodiments of the invention, the level of a biomarker in a biological sample obtained from the patient has been determined. Biomarkers generally may refer to a biomarker for a Myc transcription factor and / or a biomarker for a gene induced in response to low oxygen levels.

[0055] In some embodiments, determining the level of a biomarker in a biological sample comprises obtaining a biological sample and measuring a level of a biomarker or having a biological sample obtained and having a level of a biomarker measured.

[0056] In some embodiments of the invention, the gene induced in response to low oxygen levels is selected from NDRG1 , ADM, EGLN3 or a combination thereof. In preferred embodiments, the gene induced in response to low oxygen levels is NDRG1 .

[0057] In some embodiments of the invention, the Myc transcription factor is selected from N-Myc, L- Myc, c-Myc or a combination thereof. In preferred embodiments of the invention, the Myc transcription factor is N-Myc.

[0058] In some embodiments of the invention, the patient is biomarker negative for a gene induced in response to low oxygen levels, such as EGLN3, ADM or NDRG1 , and biomarker positive for N-Myc.Further methods according to the invention

[0059] The disclosure herein also relates to the following methods. Any embodiments described above may also be considered to relate to methods described below.

[0060] A method of measuring a biomarker in a patient with cancer, comprising determining the level of a biomarker for a gene induced in response to low oxygen levels in the patient. In some embodiments, the method comprises determining the level of a biomarker for a Myc transcription factor in the patient.

[0061] A method of determining whether a patient is likely to respond to the use of a GSPT 1 degrader in the treatment of cancer, comprising determining the level of a biomarker for a gene induced in response to low oxygen levels in the patient and determining that the patient is likely to be responsive to treatment if the patient is biomarker negative for a gene induced in response to low oxygen levels. In some embodiments, the method further comprises determining the level of a biomarker for a Myc transcription factor in the patient and determining that the patient is likely to be responsive to treatment if the patient is biomarker positive for a Myc transcription factor and biomarker negative for a gene induced in response to low oxygen levels.

[0062] A method of determining a treatment regimen for a patient suffering from cancer, comprising determining the level of a biomarker for a gene induced in response to low oxygen levels in the patient; determining that the patient should be administered a therapeutically effective amount of a GSPT1 degrader if the patient is biomarker negative for a gene induced in response to low oxygen levels. In some embodiments, the method further comprises determining the level of a biomarker for a Myc transcription factor in the patient and determining that that the patient should be administered a therapeutically effective amount of a GSPT1 degrader if the patient is biomarker positive for a Myc transcription factor and biomarker negative for a gene induced in response to low oxygen levels.

[0063] In some embodiments the methods comprise comparing the level of a biomarker to a level of the biomarker in a control sample. In some embodiments the method comprises comparing the level of a biomarker to a median level for said biomarker.

[0064] In an alternative aspect, the invention relates to a method of treating cancer in a patient in need thereof, wherein the method comprises administering a therapeutically effective amount of a GSPT1 negative modulator to a patient, wherein the level of a biomarker for a Myc transcription factor in the patient is greater than a reference level, and wherein the reference level is about 4.9 log2(TPM + 1), determined by RNA sequencing. In some embodiments, the reference level is about 5.5 log2(TPM + 1).

[0065] In an alternative aspect, the invention relates to a method of treating cancer in a patient in need thereof, wherein the method comprises administering a therapeutically effective amount of a GSPT1 negative modulator to a patient, wherein the level of a biomarker for a Myc transcription factor in the patient is greater than a reference level, and wherein the reference level is about 6.7 dCQ, determined by RT-qPCR. In some embodiments, the reference level is about 5.5 dCQ.

[0066] In another alternative aspect, the invention relates to a method of treating cancer in a patient in need thereof, wherein the method comprises administering a therapeutically effective amount of a GSPT1 negative modulator to a patient, wherein the level of a biomarker for a Myc transcription factor in the patient is greater than a reference level, and wherein the reference level is about 3 dCQ, determined by RT-qPCR.

[0067] In another alternative aspect, the invention relates to a method of treating cancer in a patient in need thereof, wherein the method comprises administering a therapeutically effective amount of a GSPT1 negative modulator to a patient, wherein the level of a biomarker for a Myc transcription factor in the patient is greater than a reference level, and wherein the reference level is about -1 dCQ, determined by RT-qPCR.

[0068] In an alternative aspect, the invention relates to a method of treating cancer in a patient in need thereof, wherein the method comprises administering a therapeutically effective amount of a GSPT1 negative modulator to a patient, wherein the level of a biomarker for a Myc transcription factor in the patient is greater than a reference level, and wherein the reference level is about 1 logio(TPS), determined by IHC.BiomarkersUse of the term biomarker

[0069] The term “(biological) marker” or "biomarker" used in the context of the present disclosure refers to a measurable entity whose detection indicates a particular biological state, such as, for example, the presence of cancer, or a particular patient characteristic which pre-disposes them to a certain type of therapy. In some embodiments, biomarkers can be determined individually. In some embodiments, several biomarkers can be measured simultaneously.

[0070] A biomarker may be any entity, such as a mRNA, DNA, a polypeptide, a protein including posttranslationally modified forms, such as phosphorylated forms (e.g. mono- or biphosphorylated forms), metabolites and the like, which may be differentially present in a sample taken from a cancer patient (i.e. which may be present at an elevated or decreased level in a sample of a cancer patient) as compared to a control or reference sample as defined herein. Determination of the presence, absence and specific level of a biomarker is carried out by appropriate quantification methods as disclosed herein and known in the art, i.e. by direct measurement of the biomarker, by indirect quantification of the gene expression of the encoding gene of the biomarker, for example by quantification of the expressed mRNA encoding for the respective biomarker. Thus, in some embodiments, a biomarker as used herein indicates a change inthe level of mRNA expression that may correlate with the risk or progression of a cancer, or with the susceptibility of cancer to a given treatment. In some embodiments, the biomarker is a nucleic acid, such as mRNA or cDNA. In some embodiments, a biomarker indicates a change in the level of polypeptide or protein expression that may correlate with the risk or progression of a cancer, or patient' s susceptibility to treatment. In some embodiments, the biomarker can be a polypeptide or protein, or a fragment or a postmodified, e.g. phosphorylated, form thereof. The relative level of specific proteins can be determined by methods known in the art, such as e.g. antibody based methods, such as an immunoblot, enzyme- linked immunosorbent assay (ELISA), copy number variation analysis or other methods.

[0071] Biomarkers for use in the methods of the present invention include biomarkers associated with a Myc transcription factor, and biomarker associated with a gene induced in response to low oxygen levels.

[0072] The biomarker status before, during or after therapy, may be used for assessing the likelihood of response of a cancer to a treatment of a GSPT1 degrader, wherein the biomarker status refers to the altered (absolute or relative) presence or absence of the biomarker as defined herein, in a patient or a clinical subset of patients afflicted with cancer. The present invention is not restricted to any particular method for determining the level of a given biomarker, but encompasses all means that allow for a quantification, or estimation, of the level of said biomarker, either directly or indirectly. The level of a biomarker or the biomarker status may be assessed or confirmed as disclosed herein, such as by, e.g, SMRT (single-molecule real-time sequencing), RNA sequencing, or qPCR (quantitative PCR), overexpression or underexpression of a biomarker nucleic acid (e.g, by ISH (in situ hybridization), Northern Blot, qPCR or NGS (next generation sequencing)), increased or decreased biomarker protein level (e.g, by IHC (immunohistochemistry)), and the like. Preferably, RNA sequencing, RT-qPCR or IHC are used to assess the level of the biomarker(s).

[0073] The term "level" refers to the amount, accumulation, or rate of a biomarker molecule. A level can be represented, for example, by the amount or the rate of synthesis of a messenger RNA (mRNA) encoded by a gene, the amount or the rate of synthesis of a polypeptide or protein encoded by a gene, or the amount or the rate of synthesis of a biological molecule accumulated in a cell or biological fluid. As used herein, the term “level” is a general term to include “expression level” or any other wording used for quantification of a biomolecule such as a gene, a nucleic acid, a protein, a metabolite, and the like.

[0074] In some embodiments, the level of a biomarker, from a patient sample can be higher or “elevated” when compared to the level of the biomarker in a control sample. This increase or elevated level can be about 5 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 90 %, 100 %, 200 %, 300 %, 500 %, 1000 %, 5000 % or more of the comparative control level, which with regards to the present methods would indicate a responsiveness or non-responsiveness to the treatment depending on the nature of the biomarker used. Alternatively, the level of a biomarker may be decreased by for example 99 %, 95 %, 90 %, 80 %, 70 %, 60 %, 50 %, 40 %, 30 %, 20 %, 10 %, 1 % or less of the comparative control level, whichwith regards to the present methods would indicate a responsiveness or non-responsiveness to the treatment depending on the nature of the biomarker used.

[0075] The term “expression profile” (or “profile”) or “expression level” (or “level”) as used in the context of the present methods refers to the extent of expression of one of the biomarkers of the disclosure measured in a sample of a patient afflicted with cancer or in a control sample in accordance with the methods of the present invention.

[0076] Preferably, the biomarker is selected from mRNA, DNA, a polypeptide, a protein, phosphorylated forms of a protein, and metabolites. More preferably, a biomarker comprises, or is, mRNA or a protein.

[0077] In some embodiments, a biomarker for a gene is mRNA that is transcribed by the gene that it is a biomarker for. In some embodiments, a biomarker for a gene is a protein that is expressed by the gene that it is a biomarker for.Biomarker negative patients

[0078] A biomarker negative patient is a patient with a low level of a biomarker for the gene that that particular biomarker is for. For instance, a biomarker negative patient may be “NDRG1-low”, “EGLN3- low”, or “ADM-low”. A biomarker negative patient may be a patient wherein a biomarker, such as a biomarker for a gene induced in response to low oxygen levels, is underexpressed in the patient.

[0079] A patient may be biomarker negative for more than one biomarker, such as a biomarker for a gene induced in response to low oxygen levels. For instance, a patient may be biomarker negative for both NDRG1 and EGLN3, or NDRG1 and ADM, or ADM and EGLN3, or for all three.

[0080] Generally, a low level of a biomarker is a level below a reference level. In some embodiments, the level of the biomarker is below the reference level by an amount greater than the standard error of the measurement method used.

[0081] As used herein, ‘biomarker negative patient’ is merely used as a description of the level of a biomarker. If a patient is biomarker negative, this does not necessarily mean that this is a negative outcome, nor does it mean that they will not respond to treatment with a GSPT1 degrader according to the invention. The responsiveness of a patient to a GSPT1 degrader can be determined by the patient being biomarker negative for certain genes, e.g. NDRG1 , ADM, EGLN3, and, optionally, by the same patient being biomarker positive for a second set of genes, e.g. N-Myc, L-Myc, c-Myc. The term biomarker negative is used herein as defined above and does not have any inherent bearing on the outcome of the treatment.

[0082] In some embodiments, a patient that is biomarker negative for a gene induced in response to low oxygen levels, such as NDRG1 , EGLN3 or ADM may be a patient with a level of a biomarker for agene induced in response to low oxygen levels that is less than a reference level for the biomarker. In preferred embodiments, the patient is biomarker negative for NDRG1 .

[0083] In biomarker negative patients, the level of a biomarker, such as a biomarker for a gene induced in response to low oxygen levels in the patient, may be less than a reference level by at least 5%, for example at least 10%, 15%, 20%, 25%, 30%, 50%, 100%. In some embodiments, the level of a biomarker, such as a biomarker for a gene induced in response to low oxygen levels in the patient may be less than a reference level by between 5% and 5000%, for example at least 10% to 1000%, 15% to 750%, 20% to 500%. In some embodiments, the level of such a biomarker in the patient is less than a reference level by between 10% to 1000%.

[0084] In some embodiments, a reference level for a biomarker, such as a biomarker for a gene induced in response to low oxygen levels, is the 50th, the 45th, the 40th, the 35th, the 30th, the 25th, the 20th, the 15th or the 10th percentile level of the biomarker measured from a distribution of control subjects. In preferred embodiments, a reference level for such a biomarker is the 20th percentile level. A patient that is biomarker negative has a level of a biomarker that is below the reference level.

[0085] In some embodiments, a biomarker negative patient is a patient with a level of a biomarker, such as a biomarker for a gene induced in response to low oxygen levels, that is below the median level of the biomarker in a distribution of control subjects. In some embodiments, the level of such a biomarker is more than one or more than two standard deviations below the median level.Biomarker positive patients

[0086] A biomarker positive patient is a patient with a high level of a biomarker for the gene that that particular biomarker is for. For instance, a biomarker negative patient may be “N-Myc-high”, “L-Myc-high”, or “c-Myc-high”. A biomarker positive patient may be a patient wherein a biomarker, such as a biomarker for a Myc transcription factor, is overexpressed in the patient.

[0087] A patient may be biomarker positive for more than one biomarker, such as a biomarker for a Myc transcription factor. For instance, a patient may be biomarker positive for both N-Myc and L-Myc, or N-Myc and c-Myc, or L-Myc and c-Myc, or for all three.

[0088] Generally, a high level of a biomarker is a level above a reference level. In some embodiments, the level of the biomarker is above the reference level by an amount greater than the standard error of the measurement method used.

[0089] As used herein, ‘biomarker positive patient’ is merely used as a description of the level of a biomarker, particularly in comparison to a reference level. As above discussed with regard to biomarker negative patients, the term biomarker positive is used herein as defined above and does not have any inherent bearing on the outcome of the treatment.

[0090] In some embodiments, a patient that is biomarker positive for a Myc transcription factor, such as L-Myc, c-Myc or N-Myc, is a patient with a level of a biomarker for a Myc transcription factor that is greater than a reference level for the biomarker. In preferred embodiments, the patient is biomarker positive for N-Myc.

[0091] In biomarker positive patients, the level of a biomarker, such as a biomarker for a Myc transcription factor in the patient, may be greater than a reference level by at least 5%, for example at least 10%, 15%, 20%, 25%, 30%, 50%, 100%, 200%, 300%, 400%, 500%. In some embodiments, the level of a biomarker, such as a biomarker for a Myc transcription factor in the patient may be greater than a reference level by between 5% and 5000%, for example at least 10% to 1000%, 15% to 750%, 20% to 500%. In some embodiments, the level of such a biomarker in the patient may be greater than a reference level by between 10% and 1000%.

[0092] In some embodiments, a reference level for a biomarker, such as a biomarker for a Myc transcription factor, is the 50th, the 55th, the 60th, the 65th, the 70th, the 75th, the 80th, or the 85th percentile level of the biomarker measured from a distribution of control subjects. In preferred embodiments, a reference level for such a biomarker is the 70th percentile. A patient that is biomarker positive has a level of a biomarker that is above the reference level.

[0093] In some embodiments, a biomarker positive patient is a patient with a level of a biomarker, such as a biomarker for a Myc transcription factor, that is above the median level of the biomarker in a distribution of control subjects. In some embodiments, the level of such a biomarker is more than one or more than two standard deviations above the median level.Biomarker negative and biomarker positive patients

[0094] In some embodiments, a reference level of a biomarker for NDRG1 that is the 50th, the 45th, the 40th, the 35th, the 30th, the 25th, the 20th, the 15th or the 10th percentile of the level of the biomarker measured from a distribution of control subjects, and a reference level of a biomarker for N-Myc is the 50th, the 55th, the 60th, the 65th, the 75th, the 80th, or the 85th percentile of the level of the biomarker measured from a distribution of control subjects. In preferred embodiments, the reference level of a biomarker for NDRG1 is below the 20th percentile, and the reference level of a biomarker for N-Myc is above the 70th percentile. A patient that is biomarker negative for NDRG1 and biomarker positive for N- Myc has a level of a biomarker for NDRG1 that is below a reference level and a level of a biomarker for N-Myc that is above a reference level.Reference levels

[0095] In some embodiments, the level of the biomarker in the patient is compared to a reference level. Comparison to a reference level may enable determination of biomarker positivity or negativity status. Such a reference level may be defined in any suitable way.

[0096] Where a reference level for a biomarker is disclosed, an accompanying embodiment, wherein the level of such a biomarker in the patient is higher (biomarker positive) or lower (biomarker negative) than the specified reference level, is additionally disclosed.

[0097] When comparing the level of a biomarker to a reference level, the relevant biomarker is compared to a reference level of the same biomarker, i.e. a level of mRNA expression for N-Myc would be compared to a reference level of mRNA expression for N-Myc, not to a reference level of mRNA expression for L-Myc, or a reference level of N-Myc protein expression.Examples of ways to define reference levels

[0098] The term "control" or "reference", when used in combination with a subject, refers to a subject that is suitable for comparison with a patient that is afflicted with a cancer as defined herein. The level of biomarker in such a subject may be determined.

[0099] In some embodiments of the invention, a reference level for a biomarker is the level of the biomarker measured in a control sample.[000100] Control samples may be taken from a control subject or a distribution of control subjects.[000101] In some embodiments, the control subject(s) do not have cancer.[000102] In some embodiments, the control subject(s) have cancer. The control subject(s) may have any type of cancer as described herein. In some embodiments, the cancer of the control subject(s) is in the same part of the body as the patient. In some embodiments, the cancer of the control subjects) is the same type or subtype as the patient.[000103] In some embodiments, the control subject(s) and the patient have lung cancer; optionally, the lung cancer is non-small cell lung cancer, e.g. lung adenocarcinoma (LUAD).[000104] In some embodiments, the control subject(s) and the patient have prostate cancer. Optionally, the prostate cancer is castration resistant prostate cancer or hormone sensitive prostate cancer; alternatively the prostate cancer is neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer.[000105] In some embodiments, the control subject(s) and the patient have breast cancer. Optionally, the breast cancer is HR-positive, HER2-negative breast cancer or ER-positive breast cancer.[000106] In some embodiments, the control subject(s) have similar characteristics. The term “similar characteristics” can mean that the patient and the control subject are at least one of similar age, similar height, similar weight, same stage of disease progression or same categorization of disease severity, same ethnicity, same type of cancer, same underlying condition(s) and / or that they have had the sametreatments. More than one of these characteristics may be shared between the patient and the control subject. Preferably, more of these similar characteristics are shared than not. “Similar”, when used herein to describe quantitative characteristics (e.g. age, weight, height), means that the patient has a value of a characteristic within 10% of the value of the same characteristic in the control subject, for example, within 9% of the value, within 8% of the value, within 7% of the value, within 6% of the value, within 5% of the value, within 4% of the value, within 3% of the value, within 2% of the value, within 1 % of the value.Direct control comparison[000107] In some embodiments, one control sample is taken from or has been taken from a control subject. This allows a direct measurement of a reference level in a single control sample, or direct comparison of the level in a biological sample of the patient to a single control sample. When one control sample has been taken, the reference level of a biomarker is the level of the biomarker determined from the control sample.[000108] In some embodiments, the control subject is a subject without cancer. In some embodiments, the control subject has cancer and the control subject is not responsive to treatment with a GSPT1 degrader. In some embodiments, the control subject has cancer and the subject is responsive to treatment with a GSPT1 degrader.[000109] In some embodiments, the control sample is taken from noncancerous tissue of the patient. In some embodiments such a control sample is a tissue matched, non-cancerous sample. In some embodiments, a control sample may be obtained from the same subject with a cancer as defined herein, of which the test sample is obtained from, but using a sample that is non-cancerous, such as a sample from a site remote of the cancer site.Comparison to a distribution of control subjects[000110] In some embodiments, a reference level for a biomarker is determined from more than one control sample. In some embodiments, a reference level for a biomarker is the median level of the biomarker of more than one control sample. In some embodiments, control samples are each taken from different subjects.[000111] In some embodiments, a reference level for a biomarker is the average or the median of the level of the biomarker, measured from a group of control subjects or a distribution of control subjects.[000112] In some embodiments, the average or the median of the level of the biomarker is determined from more than one control sample, or from a distribution of control subjects. Determining such an average or median level may involve measurement of the level of the biomarker in control samples from control subjects, or may involve calculating the average or median level from data that has been already measured.[000113] A distribution of control subjects refers to a group of more than one control subjects. In some embodiments, a reference level for a biomarker is determined from a distribution of control subjects. Insome embodiments, these control subjects have cancer, preferably cancer of the same type or subtype as the patient.[000114] In some embodiments, the distribution of control subjects includes sufficient data points to allow meaningful calculation of statistical values associated with the distribution. In some embodiments, the distribution of control subjects is representative of the general population of patients with cancer, or representative of the general population of patients with cancer in a specific part of the body or representative of the general population of patients with a type or subtype of cancer.[000115] In some embodiments, the number of control subjects is more than 3, more than 5, more than 10, more than 100, more than 200, more than 300, more than 400, more than 500, or more than 1000. In some embodiments, the number of control subjects is between 3 and 1000, between 5 and 500, between 10 and 250, or between 50 and 300.[000116] In some embodiments, the distribution of control subjects may be taken from a database of cancer patients, preferably a publicly available database. Databases that can be used for this purpose are not particularly limited. In some embodiments, the databases may be taken from the Genomic Data Commons Data Portal, for example The Cancer Genome Atlas Program (TCGA) database, for example TCGA-LUAD. In some embodiments, the database may be taken from the Tempus+ database. In preferred embodiments, the distribution of control subjects is taken from TCGA-LUAD. In embodiments wherein a database of the TCGA is used, the version referred to may be any database accessible before the date of filing of this application, preferably the version available on 25th June 2021 .SamplesBiological sample[000117] The term “sample” or "biological sample" or “test sample” as used herein refers to a cancer- affected or cancerous sample obtained from a subject or patient. This includes a sample of a tissue or of a fluid obtained from e.g. organs, tissues, fractions and cells isolated from a subject, in either healthy state, precancerous state or cancerous state. Exemplary biological samples include but are not limited to a cell lysate, cell culture, cell line, circulating cells, e.g. PBMCs (peripheral blood mononuclear cells), tissue, skin, oral tissue, gastrointestinal tissue, organ, organelle, biological fluid, blood sample, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, or bone marrow, and the like.[000118] A biological sample can include a solid tissue sample (e.g., bone marrow) or a liquid sample (e.g., blood, whole blood, plasma, amniotic fluid, pleural fluid, peritoneal fluid, central spinal fluid, urine, saliva or other body fluid that contains cells). Samples of tissues, cells and the like may be obtained from any part of the body (externally or internally) by a biopsy. A biopsy may be performed either using open surgical techniques or minimally invasive / percutaneous techniques, such as e.g. fine needle aspiration (FNA), transbronchial needle aspiration (TBNA), or core biopsies. In some embodiments biological samples include but are not limited to whole blood, partially purified blood, urine, tissue biopsies,circulating cells, e.g. PBMCs, (including circulating cancer cells, such as circulating tumor cells, circulating stem cells and / or circulating epithelial-mesenchymal transition cells), and the like.[000119] In some embodiments, the biological sample is a solid sample, for example bone marrow. In some embodiments, the biological sample is taken by biopsy.[000120] In some embodiments, the biological sample is taken from tissue of a patient. In some embodiments, the biological sample comprises tissue. In some embodiments, the biological sample is tissue.[000121] In some embodiments, the biological sample is taken from cancerous tissue of a patient. In some embodiments, the biological sample comprises cancerous tissue. In some embodiments, the biological sample is cancerous tissue.[000122] In some embodiments, the biological sample is taken from a cancerous tumour of a patient. In some embodiments, the biological sample comprises tumour tissue or tumour nucleic acid. In some embodiments, the biological sample is tumour tissue or tumour nucleic acid. In some embodiments, the biological sample is tumour DNA or tumour RNA.[000123] In some embodiments, the biological sample is a liquid sample, for example, blood, serum, plasma or urine. In some embodiments, the biological sample comprises blood, serum or plasma. In some embodiments, the biological sample is blood, serum or plasma.Control samples[000124] A control sample is a biological sample taken from a control subject.[000125] In some embodiments, the control sample is a solid sample, for example bone marrow. In some embodiments, the control sample is taken by biopsy.[000126] In some embodiments, the control sample is taken from tissue from a control subject. In some embodiments, the control sample comprises tissue. In some embodiments, the control sample is tissue. In some embodiments, the tissue is cancerous tissue.[000127] In some embodiments, the control sample comprises tumour tissue or tumour nucleic acid. In some embodiments, the control sample is tumour tissue or tumour nucleic acid. In some embodiments, the control sample is tumour DNA or tumour RNA.[000128] In some embodiments, the control sample is a liquid sample, for example, blood, serum, plasma or urine. In some embodiments, the control sample comprises blood, serum or plasma. In some embodiments, the control sample is blood, serum or plasma.[000129] In some embodiments, the control sample is the same type of biological sample as the biological sample taken from the patient, e.g., the biological sample taken from the patient is a solidsample and the control sample is a solid sample. In some embodiments, the control sample is the same biological sample as the biological sample taken from the patient, e.g., the biological sample taken from the patient comprises tumour tissue and the control sample comprises tumour tissue.[000130] In some embodiments, the control sample is a different type of biological sample as the biological sample taken from the patient, e.g., the biological sample taken from the patient is a solid sample and the control sample is a liquid sample. In some embodiments, the control sample is a different biological sample as the biological sample taken from the patient, e.g., the biological sample taken from the patient comprises tumour tissue and the control sample comprises blood.Obtaining sample[000131] The biological or control sample may be obtained before or after the GSPT1 degrader is administered to the patient, or during the time period that the patient is receiving treatment with the GSPT1 degrader.[000132] In some embodiments, the biological sample or control sample is obtained less than 24 hours, 36 hours or 48 hours after the GSPT1 degrader is administered to the patient. In some embodiments, the biological sample is obtained more than 24 hours, 36 hours or 48 hours after the GSPT1 degrader is administered to the patient.[000133] In some embodiments, the biological sample or control sample is obtained more than 24 hours, 36 hours or 48 hours after the GSPT 1 degrader is administered to the patient and less than 1 week, 2 weeks, 3 weeks or 4 weeks after the administration.Embodiments of reference levels[000134] Reference levels according to the invention, defined by any method set out herein, can be determined by any of the methods set out above.[000135] Certain reference levels which can define patient groups according to the invention, are set out below. The level of the biomarker specified in the embodiments below is higher than the specified reference level in biomarker positive patients, and lower than the specified reference level in biomarker negative patients.[000136] Wherein a median level of a biomarker, or a level of a biomarker that is associated with a percentile, is mentioned in relation to the specific reference levels described below, this refers to a level determined from a distribution of control subjects as described herein. Determining such a median or percentile level may involve measurement of the level of the biomarker in control samples from control subjects, or may involve calculating the median or percentile level from data that has been already measured.Reference levels determined through RNA SequencingL-Myc[000137] In some embodiments, the reference level measured by RNA sequencing for a biomarker for L- Myc is about 100%, 105%, 110%, 115%, 120%, 125% or 130% greater (as measured in log2(1+TPM)) than the median biomarker level. In preferred embodiments, the reference level is about 120% greater than the median biomarker level.[000138] In some embodiments, the reference level measured by RNA sequencing for a biomarker for L- Myc is more than about 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7 or 2.8 log2(1 + TPM) above the median biomarker level. In preferred embodiments, the reference level is about 2.3 log2(1 + TPM) above the median biomarker level.[000139] In some embodiments, the reference level measured by RNA sequencing for a biomarker for L- Myc is about 9.6, 9.7, 9.8, 9.9, 10.0, 10.1 , 10.2, 10.3, 10.4, 10.5, or 10.6 log2(1 + TPM). In preferred embodiments, the reference level is about 10 log2(1 + TPM).[000140] In some embodiments, the reference level measured by RNA sequencing for a biomarker for L- Myc is about 3.6, 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, or 4.6 log2(1 + TPM). In preferred embodiments, the the reference level is about 4.1 log2(1 + TPM).N-Myc[000141] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% greater (as measured in log2(1+TPM)) than the median biomarker level. In preferred embodiments, the reference level is about 420% greater than the median biomarker level.[000142] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0 or 2.1 log2(1 + TPM) above the median biomarker level. In preferred embodiments, the reference level is about 1.1 or 1.6 log2(1 + TPM) above the median biomarker level.[000143] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 log2(1 + TPM). In preferred embodiments, the reference level is about 4.9 or 5.5 log2(1 + TPM).[000144] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5 or 2.6 log2(1 + TPM). In preferred embodiments, the reference level is about 1 .6 or 2.2 log2(1 + TPM).NDRG1[000145] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in log2(1 +TPM)) than the median biomarker level.[000146] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 log2(1 + TPM) below the median biomarker level.[000147] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, or 8.4 log2(1 + TPM).[000148] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 1 1 .0, 1 1 .1 , 11 .2, 11.3, 11 .4, 1 1.5, 11.6, 11.7, 11 .8, 1 1.9, 11.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM).[000149] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12% or 15% less (as measured in Iog2(1 +TPM)) than the median biomarker level. In preferred embodiments, the reference level is about 10% less than the median biomarker level.[000150] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, or 1 .4 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the reference level is about 0.9 log2(1 + TPM) below the median biomarker level.[000151] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, or 8.4 log2(1 + TPM). In preferred embodiments, the reference level is about 8 log2(1 + TPM).[000152] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 1 1.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM). In preferred embodiments, the reference level is about 12.3 log2(1 + TPM).[000153] Alternatively, in some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in log2(1 +TPM)) than the median biomarker level. In preferred embodiments, the reference level is about 20% less than the median biomarker level.[000154] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 log2(1 + TPM) below the medianbiomarker level. In preferred embodiments, the reference level is about 1 .8 log2(1 + TPM) below the median biomarker level.[000155] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, or 7.4 log2(1 + TPM). In preferred embodiments, the reference level is about 7 log2(1 + TPM).[000156] In some embodiments, the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 11 .0, 11 .1 , 11 .2, 11 .3, 11 .4, 11 .5, 11 .6, 11 .7, 11 .8, or 11 .9 log2(1 + TPM). In preferred embodiments, the reference level is about 11 .4 log2(1 + TPM).ADM[000157] In some embodiments, the reference level measured by RNA sequencing for a biomarker for ADM is about 10%, 12%, 14%, 16%, 18%, 20%, 22% or 25% less (as measured in log2(1+TPM)) than the median biomarker level. In preferred embodiments, the reference level is about 20% less than the median biomarker level.[000158] In some embodiments, the reference level measured by RNA sequencing for a biomarker for ADM is about 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, or 1 .8 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the reference level is about 1 .3 log2(1 + TPM) below the median biomarker level.[000159] In some embodiments, the reference level measured by RNA sequencing for a biomarker for ADM is about 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 or 4.9 log2(1 + TPM). In preferred embodiments, the reference level is about 4.5 log2(1 + TPM).[000160] In some embodiments, the reference level measured by RNA sequencing for a biomarker for ADM is about 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, or 7.3 log2(1 + TPM). In preferred embodiments, the reference level is about 6.8 log2(1 + TPM).EGLN3[000161] In some embodiments, the reference level measured by RNA sequencing for a biomarker for EGLN3 is about 10%, 15%, 18%, 20%, 25%, 30% or 35% less (as measured in log2(1+TPM)) than the median biomarker level. In preferred embodiments, the reference level is about 25% less than the median biomarker level.[000162] In some embodiments, the reference level measured by RNA sequencing for a biomarker for EGLN3 is about 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3 or 2.4 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the reference level is about 1.6 log2(1 + TPM) below the median biomarker level.[000163] In some embodiments, the reference level measured by RNA sequencing for a biomarker for EGLN3 is about 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 or 4.9 log2(1 + TPM). In preferred embodiments, the reference level is about 4.5 log2(1 + TPM).[000164] In some embodiments, the reference level measured by RNA sequencing for a biomarker for EGLN3 is about 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, or 8.3 log2(1 + TPM). In preferred embodiments, the reference level is about 7.7 log2(1 + TPM).NDRG1 and N-Myc[000165] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% greater (as measured in log2(1 +TPM)) than the median biomarker level, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in log2(1 +TPM)) than the median biomarker level.[000166] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0 or 2.1 log2(1 + TPM) above the median biomarker level, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 log2(1 + TPM) below the median biomarker level.[000167] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 log2(1 + TPM), and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, or 8.4 log2(1 + TPM).[000168] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5 or 2.6 log2(1 + TPM) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 11.0, 11.1 , 11 .2, 1 1.3, 11.4, 11.5, 11.6, 11 .7, 1 1.8, 11.9, 11.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM).[000169] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% greater (as measured in log2(1 +TPM)) than the median biomarker level, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12% or 15% less (as measured in log2(1 +TPM)) than the median biomarker level. Preferably, the N-Myc reference level is about 420% greater than the median N-Myc biomarker level, and the NDRG1 reference level is about 10% less than the median NDRG1 biomarker level.[000170] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0 or 2.1 log2(1 + TPM) above the median biomarker level, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, or 1 .4 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the N-Myc reference level is about 1.1 or 1 .6 log2(1 + TPM) above than the median N-Myc biomarker level and the NDRG1 reference level is about 0.9 log2(1 + TPM) below the median NDRG1 biomarker level.[000171] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 log2(1 + TPM), and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 7.4, 7.5, 7.6, 7.7,7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, or 8.4 log2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 4.9 or 5.5 log2(1 + TPM) and the NDRG1 reference level is about 8 log2(1 + TPM).[000172] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5 or 2.6 log2(1 + TPM) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 11.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 1.6 or 2.2 log2(1 + TPM) and the NDRG1 reference level is about 12.3 log2(1 + TPM).[000173] Alternatively, in some embodiments, the reference level measured by RNA sequencing for a biomarker for N-Myc is about 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% greater (as measured in log2(1+TPM)) than the median biomarker level, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in log2(1+TPM)) than the median biomarker level. Preferably, the N-Myc reference level is about 420% greater than the median N-Myc biomarker level, and the NDRG1 reference level is about 20% less than the median NDRG1 biomarker level.[000174] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0 or 2.1 log2(1 + TPM) above the median biomarker level, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the N-Myc reference level is about 1.1 or 1 .6 log2(1 + TPM) above than the median N-Myc biomarker level and the NDRG1 reference level is about 1 .8 log2(1 + TPM) below the median NDRG1 biomarker level.[000175] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 log2(1 + TPM), and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, or 7.4 log2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 4.9 or 5.5 log2(1 + TPM) and the NDRG1 reference level is about 7 log2(1 + TPM).[000176] In some embodiments, the reference level measured by RNA sequencing for a biomarker for N- Myc is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5 or 2.6 log2(1 + TPM) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 11.0, 11.1 , 11 .2,1 1 .3, 11 .4, 11 .5, 11 .6, 11 .7, 1 1 .8, or 1 1 .9 log2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 1 .6 or 2.2 log2(1 + TPM) and the NDRG1 reference level is about 11 .4 log2(1 + TPM).Reference levels determined using RT-qPCRN-Myc[000177] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9,6.1 . 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ.[000178] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9, 6.1 , 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ. In preferred embodiments, the reference level is about 5.5 or 6.7 dCQ.[000179] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1 .6, 1 .8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2 or 4.4 dCQ. In preferred embodiments, the reference level is about 3 dCQ.L-Myc[000180] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ. In preferred embodiments, the reference level is about -1 dCQ.N-Myc and NDRG1[000181] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1 .6, 1 .8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9,6.1 , 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in log2(1 +TPM)) than the median biomarker level.[000182] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9,6.1 , 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 log2(1 + TPM) below the median biomarker level.[000183] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9,6.1 , 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ, and the reference level measured by RNA sequencing for abiomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,8.1 . 8.2, 8.3, or 8.4 log2(1 + TPM).[000184] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9,6.1 . 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 1 1.0, 1 1.1 , 11.2, 11.3, 11 .4, 1 1.5, 1 1.6, 11.7, 11.8, 11 .9, 1 1.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM).[000185] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9, 6.1 , 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12% or 15% less (as measured in log2(1 +TPM)) than the median biomarker level. In preferred embodiments, the N-Myc reference level is about 5.5 or 6.7 dCQ and the NDRG1 reference level is about 10% less than the median NDRG1 biomarker level.[000186] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9, 6.1 , 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1.1 ,1 .2, 1 .3, or 1 .4 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the N-Myc reference level is about 5.5 or 6.7 dCQ and the NDRG1 reference level is about 0.9 log2(1 + TPM) below the median NDRG1 biomarker level.[000187] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9, 6.1 , 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 ,8.2, 8.3, or 8.4 log2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 5.5 or 6.7 dCQ and the NDRG1 reference level is about 8 log2(1 + TPM).[000188] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9, 6.1 , 6.3, 6.5, 6.7, 6.9, 7.1 or 7.3 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 11 .9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 5.5 or 6.7 dCQ and the NDRG1 reference level is about 12.3 log2(1 + TPM).[000189] Alternatively, in some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1 .6, 1 .8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2 or 4.4 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in log2(1 +TPM)) than the median biomarker level. In preferred embodiments, the N-Myc reference level is about 3 dCQ and the NDRG1 reference level is about 20% less than the median NDRG1 biomarker level.[000190] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1 .6, 1 .8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2 or 4.4 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0,2.1 . 2.2, or 2.3 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the N-Myc reference level is about 3 dCQ and the NDRG1 reference level is about 1 .8 log2(1 + TPM) below the median NDRG1 biomarker level.[000191] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1 .6, 1 .8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2 or 4.4 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 ,7.2, 7.3, or 7.4 log2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 3 dCQ and the NDRG1 reference level is about 7 log2(1 + TPM).[000192] In some embodiments, the reference level measured by RT-qPCR for a biomarker for N-Myc is about 1 .6, 1 .8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2 or 4.4 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 11.0, 11 .1 , 1 1 .2, 11 .3, 11 .4, 11 .5, 1 1 .6, 11 .7, 11 .8, or 11 .9 log2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 3 dCQ and the NDRG1 reference level is about 11 .4 log2(1 + TPM).L-Myc and NDRG1[000193] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in Iog2(1 +TPM)) than the median biomarker level.[000194] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 log2(1 + TPM) below the median biomarker level.[000195] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,7.1 . 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, or 8.4 log2(1 + TPM).[000196] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 11 .0, 1 1.1 , 11 .2, 11.3,1 1.4, 11.5, 11.6, 11.7, 11 .8, 1 1.9, 11.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM).[000197] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12% or 15% less (as measured in log2(1 +TPM)) than the median biomarker level. In preferred embodiments, the L-Myc reference level is about -1 dCQ and the NDRG1 reference level is about 10% less than the median NDRG1 biomarker level.[000198] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, or 1 .4 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the L- Myc reference level is about -1 dCQ and the NDRG1 reference level is about 0.9 log2(1 + TPM) below the median NDRG1 biomarker level.[000199] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, or 8.4 log2(1 + TPM). In preferred embodiments, the L-Myc reference level is about -1 dCQ and the NDRG1 reference level is about 8 log2(1 + TPM).[000200] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 11 .9, 12.0, 12.1 , 12.2, 12.3,12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM). In preferred embodiments, the L-Myc reference level is about -1 dCQ and the NDRG1 reference level is about 12.3 log2(1 + TPM).[000201] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in log2(1 +TPM)) than the median biomarker level. In preferred embodiments, the L-Myc reference level is about -1 dCQ and the NDRG1 reference level is about 20% less than the median NDRG1 biomarker level.[000202] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 log2(1 + TPM) below the median biomarker level. In preferred embodiments, the L-Myc reference level is about -1 dCQ and the NDRG1 reference level is about 1 .8 log2(1 + TPM) below the median NDRG1 biomarker level.[000203] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, or 7.4 log2(1 + TPM). In preferred embodiments, the L-Myc reference level is about -1 dCQ and the NDRG1 reference level is about 7 log2(1 + TPM).[000204] In some embodiments, the reference level measured by RT-qPCR for a biomarker for L-Myc is about -2.2, -2.0, -1 .8, -1 .6, -1 .4, -1 .2, -1 .0, -0.8, -0.6, -0.4, -0.2, 0.0, 0.2, 0.4 or 0.6 dCQ, and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 11 .0, 1 1.1 , 11 .2, 11.3, 11 .4, 11 .5, 1 1 .6, 1 1 .7, 11 .8, or 11 .9 log2(1 + TPM). In preferred embodiments, the L-Myc reference level is about -1 dCQ and the NDRG1 reference level is about 11 .4 log2(1 + TPM).Reference levels determined using IHCN-Myc[000205] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS). In preferred embodiments, the reference level is about 1 logio(TPS).N-Myc and NDRG1[000206] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in Iog2(1 +TPM)) than the median biomarker level.[000207] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4,1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 log2(1 + TPM) below the median biomarker level.[000208] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4,7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, or 8.4 log2(1 + TPM).[000209] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 1 1.0, 11.1 , 11.2, 11.3, 11 .4, 1 1.5, 11.6, 11.7, 11 .8, 1 1.9, 11.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 log2(1 + TPM).[000210] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 2%, 4%, 5%, 6%, 8%, 10%, 12% or 15% less (as measured in Iog2(1 +TPM)) than the median biomarker level. In preferred embodiments, the N-Myc reference level is about 1 logio(TPS) and the NDRG1 reference level is about 10% less than the median NDRG1 biomarker level.[000211] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2, 1 .3, or 1 .4 Iog2(1 + TPM) below the median biomarker level. In preferred embodiments, the N-Myc reference level is about 1 logio(TPS) and the NDRG1 reference level is about 0.9 Iog2(1 + TPM) below the median NDRG1 biomarker level.[000212] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, or 8.4 Iog2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 1 logio(TPS) and the NDRG1 reference level is about 8 Iog2(1 + TPM).[000213] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 11.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, or 12.9 Iog2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 1 logio(TPS) and the NDRG1 reference level is about 12.3 Iog2(1 + TPM).[000214] Alternatively, in some embodiments, the reference level measured by IHC for a biomarker for N- Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25% less (as measured in Iog2(1+TPM)) than the median biomarker level. In preferred embodiments, the N-Myc reference level is about 1 logio(TPS) and the NDRG1 reference level is about 20% less than the median NDRG1 biomarker level.[000215] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, or 2.3 Iog2(1 + TPM) below the median biomarker level. In preferred embodiments, the N-Myc reference level is about 1 logio(TPS) and the NDRG1 reference level is about 1 .8 Iog2(1 + TPM) below the median NDRG1 biomarker level.[000216] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, or 7.4 Iog2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 1 logio(TPS) and the NDRG1 reference level is about 7 Iog2(1 + TPM).[000217] In some embodiments, the reference level measured by IHC for a biomarker for N-Myc is about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .1 , 1 .2 or 1 .3 logio(TPS) and the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 10.9, 11.0, 11.1 , 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11 .8, or 11 .9 Iog2(1 + TPM). In preferred embodiments, the N-Myc reference level is about 1 logio(TPS) and the NDRG1 reference level is about 11 .4 Iog2(1 + TPM).Methods of measurement[000218] Reference levels and levels of a biomarker in a patient may be measured by any suitable method available. Specific methods of measurement that may be used are described in more detail below.[000219] The reference level of the biomarker and the level of the same biomarker in the patient should be measured by the same method. They can be measured by RNA sequencing, RT-qPCR or IHC. In some embodiments, the reference level of the biomarker and / or the level of a biomarker in the patient is measured by or has been measured by RNA sequencing, RT-qPCR or IHC.[000220] In some embodiments, a patient has been determined to be biomarker positive for a Myc transcription factor and / or has been determined to be biomarker negative for a gene induced in response to low oxygen levels, through measurement by RNA sequencing, RT-qPCR or IHC. In some embodiments, the method includes determining whether a patient is biomarker positive for a Myc transcription factor and / or determining whether a patient is biomarker negative for a gene induced in response to low oxygen levels through measurement by RNA sequencing, RT-qPCR or IHC.[000221] Wherein the patient is biomarker positive for a Myc transcription factor and biomarker negative for a gene that is induced in response to low oxygen levels, the biomarkers may be measured by the same method or by different methods.RNA-Seq[000222] In some embodiments, RNA sequencing is used or has been used to determine the level of a biomarker, e.g., as a reference level and / or in the patient. RNA sequencing is usually used to determine mRNA expression associated with or expressed by a particular gene.[000223] In some embodiments, the reference level of a biomarker for a Myc transcription factor and / or the reference level of a biomarker for a gene that is induced in response to low oxygen levels is measured by or has been measured by RNA sequencing.[000224] The reference level may be the median level for each biomarker from a distribution of control subjects, determined as described herein. The reference level of a biomarker, measured by RNA sequencing, may be above or below such a median level. The level of such a biomarker in the patient may be above (biomarker positive) or below (biomarker negative) such a reference level.[000225] In some embodiments, the level of a biomarker in a patient that is biomarker positive for a Myc transcription factor and / or the level of a biomarker in a patient that is biomarker negative for a gene that is induced in response to low oxygen levels is measured by or has been measured by RNA sequencing.Description of RNA sequencing measurement method[000226] RNA sequencing may be performed on extracted total RNA. Total RNA may be extracted by any means known in the art, for example, using an appropriate kit, such as the Qiagen Cat#74106 kit. The integrity of the total RNA may be determined and quantified by any means known in the art, for example, the total RNA may be determined by an automated electrophoresis tool, such as the 2100 Bioanalyser (Agilent), and quantified using a spectrophotometer, such as the NanoDrop (Thermo Scientific). Once the integrity has been determined, only high-quality RNA samples (OD260 / 280=1 ,8~2.2, OD260 / 230>2.0, RIN >7, >500 ng) should be used to construct a sequencing library.[000227] The RNA should be further purified before sequencing. PolyA mRNA may be purified from total RNA using any suitable method known in the art, such as using oligo-dTattached magnetic beads, and then the RNA is fragmented by any suitable method, such as through use of a fragmentation buffer.[000228] Taking these short fragments as templates, first stranded cDNA may be synthesized using any suitable method such as reverse transcriptase and random primers, followed by second stranded cDNA synthesis by any suitable method. Then the synthesized cDNA may be subjected to end-repair, phosphorylation and 'A' base addition through any suitable method, according to an appropriate library construction protocol. Then sequencing adapters may be added to both sides of the cDNA fragments. After PCR amplification for cDNA fragments, the targets of 250-350 bp may be cleaned up by any suitable method.[000229] After library construction, any suitable method, such as a flurometer, such as a Qubit 2.0 fluorometer dsDNA HS Assay (Thermo Fisher Scientific), may be used to quantify the concentration of the resulting sequencing libraries, while the size distribution may be analyzed by any suitable method, such as through automated electrophoresis, for example by using the BioAnalyzer 2100 (Agilent). After library validation, any suitable method, such as the Illumina cBOT cluster generation system with HiSeq PE Cluster Kits (Illumina), may be used to generate clusters.[000230] Paired-end sequencing may be performed using an appropriate system known in the art, such as an Illumina system, following Illumina-provided protocols for 2 x150 paired-end sequencing RNAseq raw data analysis. The quality of RNAseq raw data may be checked by any suitable method, such as by the FastQC software. The adapter and low-quality sequences may be trimmed by any suitable method, such as through using software, such as Trimmomatic software. The clean data after trimming may be used for analysis.RT-qPCR[000231] In some embodiments, quantitative reverse transcription polymerase chain reaction (RT-qPCR) is used or has been used to determine the level of a biomarker, e.g., as a reference level and / or in the patient.[000232] RT-qPCR produces lower values for higher biomarker levels, and so a lower value from RT- qPCR will mean that a higher level has been measured, and vice versa. Therefore, for the level of a biomarker measured by RT-qPCR to be higher than a reference level, the value measured by RT-qPCR must be lower than the reference level. Similarly, for the level of a biomarker measured by RT-qPCR to be lower than a reference level, the value measured by RT-qPCR must be higher than the reference level.[000233] In some embodiments, the reference level of a biomarker for a Myc transcription factor and / or the reference level of a biomarker for a gene that is induced in response to low oxygen levels is measured by or has been measured by RT-qPCR.[000234] The reference level, measured by RT-qPCR, may be the median level for each biomarker from a distribution of control subjects, determined as described herein. The reference level of a biomarker may be above or below such a median level. The level of such a biomarker in the patient may be above (biomarker positive) or below (biomarker negative) such a reference level.[000235] In some embodiments, the level of a biomarker in a patient that is biomarker positive for a Myc transcription factor and / or the level of a biomarker in a patient that is biomarker negative for a gene that is induced in response to low oxygen levels is measured by or has been measured by RT-qPCR.Description of RT-qPCR measurement method[000236] RT-qPCR may be carried out on a biological sample taken from a subject.[000237] RT-qPCR may include stages of RNA isolation, genomic DNA (gDNA) removal and copy DNA (cDNA) synthesis, followed by qPCR analysis.[000238] RNA isolation may be carried out using formalin-fixed paraffin-embedded (FFPE) slides as starting material. RNA may be extracted using an isolation kit, or any other such method known in the art,such as using the High Pure FFPET RNA isolation kit (Roche, cat. no. 06650775001). RNA may be eluted using a 30 pl elution buffer. Such a buffer may be any such buffer known in the art.[000239] RNA samples may then be treated with DNase to remove gDNA. The gDNA may be removed with a removal kit, or any other such method known in the art, such as the Heat&Run gDNA removal reagents: ArcticZymes Technologies, cat. no. 66001 , 70800-201.[000240] Synthesis of cDNA is performed using random primers, using any such method to do so; for example, the iScriptTM Advanced cDNA Synthesis Kit for RT-qPCR (Bio-Rad, cat. no. 1725038). 15 pL RNA sample may be mixed with 4 pL of 5x iScript Advanced reaction mix and 1 pL iScript Advanced Reverse transcriptase. The mixture may be incubated for 20 min at 46 °C, 1 min at 95 °C.[000241] After the stages above, qPCR analysis may be performed in order to quantify the transcript abundance of each gene of interest in the FFPE tissue samples.[000242] For each qPCR reaction, 20 pL PCR reaction volume may be used, which contains 10 pL SsoAdvanced Universal Probes Supermix (Bio-Rad, cat. no. 1725284), 2 pL primer probe mix (including either target of interest primers and probes or reference gene primers and probes) and 8 pL of cDNA. Samples are analyzed in triplicate.[000243] PCR cycling on the LightCycler480 II System (Cat. No. 05 015 278 001 , Roche) is performed as follows: 2 min at 95 °C followed by 45 rounds of 5 s at 95°C and 30 s at 60 °C. Read-out is performed using the LightCycler® 480 software, version 1 .5.1 .[000244] Primers that may be used in such a method of RT-qPCR are set out below.[000245] Primers (forward and reverse) and probe for each target of interest L-MYC and N-MYC and reference gene GUSB and SDHA, may be used to PCR amplify their respective transcripts (Table 1). A concentration of 160 nM per primer and 50 nM per probe is used per reaction.Table 1 : Oligonucleotide overview and sequences for the target of interest (TOI) and reference genes (REF) included in the RT-qPCR assay.IHC[000246] In some embodiments, immunohistochemistry (IHC) is used or has been used to determine the level of a biomarker (e.g. the mRNA expression), e.g., as a reference level and / or in the patient.[000247] In some embodiments, the reference level of a biomarker for a Myc transcription factor and / or the reference level of a biomarker for a gene that is induced in response to low oxygen levels is measured by or has been measured by IHC.[000248] The reference level, measured by IHC, may be the median level for each biomarker from a distribution of control subjects. The reference level of a biomarker may be above or below such a median level. The level of such a biomarker in the patient may be above (biomarker positive) or below (biomarker negative) such a reference level.[000249] In some embodiments, the level of a biomarker in a patient that is biomarker positive for a Myc transcription factor and / or the level of a biomarker in a patient that is biomarker negative for a gene that is induced in response to low oxygen levels is measured by or has been measured by IHC.Description of IHC measurement method[000250] IHC methods may involve a stage of preparing a biological sample, and then staining such a biological sample so that the intensity may be determined.[000251] Tissue specimens to be analysed by IHC may be stored in FFPE blocks and sectioned into 4 pm thick slides; 2h baking at 60°C ±2°C. Slides may be either used immediately or stored for a maximum of 12 weeks at 2-8°C.[000252] Slides may be deparaffinized by any method known in the art, for example by using a tissue stainer, such as a Tissue-Tek Prisma® Automated slide Stainer (Sakura), to immerse the slides repeatedly in xylene, ethanol and to rehydrate with ultrapure water. Tissue slides may then be pretreatedwith a suitable solution, such as Envision™ Flex Target retrieval Solution High pH (Dako, cat. no. K8004), for 40 min at 97°C using a suitable method, such as the DAKO PT Module (Agilent), before proceeding with the staining procedure.[000253] Using a suitable apparatus, such as Dako Autostainer LINK 48 (Agilent), tissue slides may be first blocked with a suitable reagent, such as EnVision Flex Peroxidase-Blocking reagent (Dako, cat. no. SM801) for 5 min. Concentrated research grade (RUO) N-MYC and L-MYC antibodies may be diluted in a suitable diluent, such as Dako Antibody Diluent with background reducing components (S3022, Agilent), to the appropriate working concentration.[000254] Diluted primary antibody may then be added for a 30 min incubation period. Primary antibody binding may be detected by incubating with suitable agents, such as EnVision FLEX+ Rabbit Linker (Dako, cat. no. K8009) and EnVision + System-HRP Labelled Polymer Anti-mouse (Dako, cat. no.K4001). Chromogenic visualization may be achieved with a suitable method, such as by using the Dako Liquid DAB+ Substrate Chromogen System (Dako, cat. no. K3468), after two 5 min incubations. A suitable buffer, such as EnVision™ Flex wash buffer (Dako, cat. no. K8007) may be used to rinse the slides after each staining step, followed by a final rinse with ultrapure water. Slides may be counterstained with a suitable reagent, such as Hematoxylin (Dako, cat. no. S3301) and Ammonium hydroxide and rinsed with phosphate buffered saline (PBS).[000255] Following this, tissue slides may be dehydrated by repeated immersion in ethanol and xylene, and coverslipped using a suitable coverslipper, such as Tissue-Tek Prisma® Automated slide Stainer and Coverslipper (Sakura).[000256] Determination of the N-MYC and L-MYC tumor proportional positivity at any intensity (>1+) may be done by an anatomical pathologist using an inverted light microscope. Intensity grading and tumor annotation is guided by HE staining and IgG isotype control staining of matched tissue slides to control for non-specific staining.[000257] Examples of suitable antibodies for the use in an IHC assay are described below.[000258] Target specific rabbit IgG antibodies may be used for the detection and staining of nuclear proteins of interest N-MYC and L-MYC in an IHC assay. A non-binding matching isotype control may be included to control for non-specific staining. The primary antibodies are further diluted in antibody diluent with background reducing components (Dako, cat. no. S3022), as detailed in Table 2.Table 2: Details of primary antibodies and matching isotype control used in the IHC Assay.Embodiments of GSPT1 degraders[000259] Examples of GSPT1 degraders that may be used as part of the invention are disclosed in WO 2022 / 152821 , the contents of which are incorporated herein by reference.[000260] In some embodiments, the GSPT1 degrader is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of formula I:wherein:X1is linear or branched C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, -OC(0)-Ci-4alkylamino, -C(O)O-Ci- salkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkoxy, C1-4 alkylhydroxy, -CH2F, - N(H)C(O)-O-CI-6 alkyl, and C(OH)(CF3); orX1together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, - C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy;X2is H, C3-6 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and C1-4 alkylhydroxy;L1is a covalent bond, linear or branched C1-6 alkyl; L2is a covalent bond, linear or branched C1-6 alkyl; and L3is a covalent bond, linear or branched C1-6 alkyl, -O-, or -C1-4 alkoxy, wherein linear or branched C1-6 alkyl is unsubstituted or substituted with one or more of halogen.[000261] In some embodiments, the GSPT1 degrader is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X1is linear or branched -C1-6 alkyl, -C3-6 cycloalkyl, -C6-10 aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched -C1-4 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2- OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy; or X1together with the N atom of the carbamate forms a 5-6 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-4 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2- OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy.[000262] In some embodiments, the GSPT1 degrader is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X2is H, C3-6 cycloalkyl, Ce aryl, 5-6 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-4 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and -C1-4 alkylhydroxy.[000263] In some embodiments, the GSPT1 degrader is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L1is -CH2- or -CH(CH3)- and / or L2is a covalent bond, - CH2- or -CH(CH3)- and / or L3is a -CH2-, -O-, -CH2-O-, -CH2-CH2-O-.[000264] In some embodiments, the GSPT1 degrader is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of formula II:wherein:X1is linear or branched C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, -OC(0)-Ci-4alkylamino, -C(O)O-Ci- salkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkoxy and C1-4 alkylhydroxy; orX1together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, - C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy;X2is H, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and C1-4 alkylhydroxy;L2is a covalent bond, linear or branched C1-6 alkyl;L3is a covalent bond, linear or branched C1-6 alkyl, -O-, -C1-4 alkoxy;Rais H or linear or branched C1-4 alkyl, such as methyl or ethyl, n is 1 or 2.[000265] In some embodiments, the GSPT1 degrader is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1 and Rais H or methyl. In some embodiments, the GSPT1 degrader is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 0. In some embodiments, the GSPT1 degrader is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 1 and Rb, Rcare H or wherein p is 1 , Rbis methyl and Rcis H. In some embodiments, the GSPT1 degrader is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L2is a covalent bond, -CH2- or - CH(CH3)- and / or L3is a -CH2-, -O-, -CH2-O-, -CH2-CH2-O-.[000266] In some embodiments, the GSPT1 degrader is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of formula III, such as IVa or IVb:wherein:X1is linear or branched C1-6 alkyl, C3-6 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-ealkyl, -OC(O)-Ci-ealkyl, -OC(0)-Ci-4alkylamino, -C(O)O-Ci- salkyl, -COOH, -Ci-ealkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkoxy and C1-4 alkylhydroxy; orX1together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6 alkyl, CF3, CHF2,CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, - C(O)O-Ci-6alkyl, -COOH, -Ci-ealkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy;X2is H, C3-6 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and C1-4 alkylhydroxy;L3is a covalent bond, linear or branched C1-6 alkyl, -O-, -C1-4 alkoxy;Ra, Rb, Rcare independently of each other H, linear or branched C1-4 alkyl, such as methyl; p is 0 or 1 .[000267] In some embodiments, the GSPT1 degrader is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of formula III, IVa, or IVb, wherein p is 0.[000268] In some embodiments, the GSPT1 degrader is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of formula III, IVa, or IVb, wherein p is 1 and Rb, Rcare H or wherein p is 1 , Rbis methyl and Rcis H.[000269] In some embodiments, the GSPT1 degrader is a compound, or pharmaceutically acceptable salts or stereoisomers thereof, of formula V, VI or VII:wherein: one or two of w1, w2, w3, w4, w5are independently of each other selected from C, N, S, and O, and the remaining of w1, w2, w3, w4, w5are C;one or two of w6, w7, w8, w9are selected from C and O and the remaining of w6, w7, w8, w9are C; w10, w11are independently of each other selected from C and N;L1is a covalent bond, linear or branched C1-6 alkyl;L2is a covalent bond, linear or branched C1-6 alkyl;R1, R2, R3, R4are independently of each other selected from H, linear or branched -C1-6 alkyl, linear or branched C1-6 heteroalkyl, - C1-4 alkoxy, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, -C1-6 alkylamino, -CN, -OC(O)-Ci-6alkyl, -N(H)C(O)-Ci-6alkyl, -C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -C1- 6alkylC(O)O-Ci-6alkyl, NH2, -C1-4 alkylhydroxy, and halogen, such as F, Cl or Br, e.g. F or Cl, or a group of formula -L3-X2, wherein L3is a covalent bond, linear or branched C1-6 alkyl, -O-, -C1-4 alkoxy and X2is C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and -C1-4 alkylhydroxy;R5, R6, R7R8are independently of each other selected from H, linear or branched C1-4 alkyl, such as methyl, and halogen, such as F or Cl, e.g. F;Z is linear or branched -C1-6 alkyl, -C3-6 cycloalkyl, 4-8 membered heterocycloalkyl, wherein Z is unsubstituted or substituted with C1-4 alkyl, Ce aryl, Ce aryloxy, 6 membered heteroaryl or CFs; or Z together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with C1-4 alkyl, Ce aryl, Ce aryloxy, 6 membered heteroaryl or CFs; q is 0, 1.[000270] In some embodiments, the GSPT1 degrader is a compound, or pharmaceutically acceptable salts or stereoisomers thereof, of formula VIII or VillaVIII Villa wherein Rais H or methyl and W1and W2are selected from:[000271] Embodiments of the invention include the administration of a GSPT1 degrader that is a compound selected from the group consisting of compounds 1-240 from Table 3 below.Table 3and pharmaceutically acceptable salts and stereoisomers thereof.[000272] In some embodiments, the GSPT1 degrader is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from any of:and pharmaceutically acceptable salts thereof.[000273] In preferred embodiments, the GSPT1 degrader is compound 145, or a pharmaceutically acceptable salt or stereoisomer thereof.Compound 145:[000274] The following definitions are understood to apply to the disclosure of any compound disclosed above.[000275] It is understood that “independently of each other” means that when a group is occurring more than one time in any compound, its definition on each occurrence is independent from any other occurrence.[000276] It is further understood that a dashed line (or a wave being transverse to a bond) or a solid line without attachment, such as -C1-4 alkyl, depicts the site of attachment of a residue (i.e. a partial formula).[000277] It is further understood that the abbreviations “C” and “N” are representative for all possible degrees of saturation, which typically do not result in radicals, nitrenes or carbenes, i.e. N includes -NH- and -N=, C includes -CH2- and =CH- In addition, “C” as an atom in an aromatic or heteroaromatic ring which has a substituent Rxat any suitable position, includes =CH- as well as =CRX-.[000278] The term "saturated" in reference to ring systems refers to a ring having no double or triple bonds. The term "partially unsaturated" in reference to ring systems refers to a ring that includes at least one double or triple bond, but does not include aromatic systems.[000279] The term “aromatic” refers to monocyclic or multicyclic (e.g. bicyclic) ring systems, which show some or complete conjugation or delocalization of their electrons. Aromatic monocyclic rings, such as aryl or heteroaryl rings as defined herein, include phenyl, pyridinyl, furyl and the like. Aromatic multicyclic rings, such as aryl or heteroaryl rings as defined herein, refer to ring systems, wherein at least one ring is an aromatic ring, and thus include (i) aromatic ring systems, wherein an aromatic ring is fused to one or more aromatic rings, such as in e.g. naphthyl, indolyl, benzimidazolyl, and the like (also referred to as fully aromatic ring systems), and (ii) aromatic ring systems, wherein an aromatic ring is fused to one or more non-aromatic rings, such as in e.g. indanyl, indenyl, phthalimidyl, naphthimidyl, phenanthridinyl, tetrahydronaphthyl, 1 ,4-dihydronapthyl, and the like (also referred to as partially aromatic ring systems).[000280] The term “non-aromatic” refers to (i) fully saturated rings such as monocyclic rings, e.g. cyclohexyl, and bicyclic rings, e.g. tetrahydronaphthyl, and (ii) partially unsaturated rings such as monocyclic rings, e.g. cyclohexenyl, and bicyclic rings, e.g. 1 ,4-dihydronapthyl.[000281] The term “C6-10 aryl” includes both fully aromatic C6-10 aryl and partially aromatic C6-10 aryl having 6, 7, 8, 9, or 10 ring atoms and includes monocycles and fused bicycles. Examples of fully aromatic C6-10 aryl include e.g. phenyl (fully aromatic Ce aryl), naphthyl (fully aromatic Cio aryl). Examples of partially aromatic C6-10 aryl include e.g. indenyl (partially aromatic C9 aryl), 2,3-dihydroindenyl (partially aromatic C9 aryl), 1 , 2, 3, 4-tetrahydronaphthyl (partially aromatic C10 aryl). In some embodiments for group X1, C6-10 aryl is phenyl, 2,3-dihydroindenyl. In some embodiments for group X2, C6-10 aryl is phenyl. The term “-C1-6 alkyl-Cs-io aryl” refers to -L2-X1- or L3-X2- with L2, L3being a C1-6 alkyl group and X1, X2being a C6-10 aryl, and thus refers to a C6-10 aryl, which is linked through a C1-6 alkyl group as defined herein to its neighbouring group. The term “-C1-6 alkoxy-Ce -io aryl” refers to -L2-X1- or L3-X2- with L2, L3being a C1-6 alkoxy group and X1, X2being a C6-10 aryl, and thus refers to a C6-10 aryl, which is linked through a C1-6 alkoxy group as defined herein to its neighbouring group. The term “-O-C6-10 aryl” or “C6-10 aryloxy” refers to -L2-X1- or L3-X2- with L2, L3being -O- and X1, X2being a C6-10 aryl, and thus refers to a C6-10 aryl, which is linked through a -O- group to its neighbouring group. The C6-10 aryl group may be unsubstituted or substituted with C1-4 alkyl, such as methyl, ethyl, t-butyl, fluorinated C1-4 alkyl, such as -CF3, -C(CH3)F2, C1-4 alkoxy, such as methoxy, ethoxy, fluorinated C1-4 alkoxy, such as -OCF3, -OCHF2, CN, -N(Me)2, halogen, such as F, Cl, or Br, such as F or Cl.[000282] In some embodiments for X1, a C6-10 aryl group refers to a fully aromatic ring system, e.g. phenyl, which is unsubstituted or substituted with C1-4 alkyl, such as methyl, ethyl, t-butyl, fluorinated C1-4 alkyl, such as -C(CH3)F2, C1-4 alkoxy, such as methoxy, ethoxy, fluorinated C1-4 alkoxy, such as -OCF3, - OCHF2, CN, halogen, such as F or Cl, In some embodiments for X1, a C6-10 aryl group refers to a partially aromatic ring system, e.g. 2,3-dihydroindenyl, which is unsubstituted or substituted with C1-4 alkyl, such as methyl, ethyl, t-butyl, or halogen, such as F or Cl.[000283] In some embodiments for X2, a C6-10 aryl group refers to a fully aromatic ring system, e.g. phenyl, which is unsubstituted or substituted with C1-4 alkyl, such as methyl, ethyl, C1-4 alkoxy, such as methoxy, ethoxy, halogen, such as F, Cl, or Br, such as F or Cl, e.g. F.[000284] The term “5-10 membered heteroaryl” refers to a fully or partially aromatic ring system in form of monocycles or fused bicycles having 5, 6, 7, 8, 9, 10 ring atoms selected from C, N, O, and S, such as C, N, and O, or C, N, and S, with the number of N atoms being e.g. 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2. In some embodiments a 5-10 membered heteroaryl refers to a fully aromatic ring system having 5, 6, 7, 8, 9, 10, such as 5 or 6, e.g. 6 ring atoms selected from C and N, with the number of N atoms being 1 , 2 or 3, such as 1 or 2. In some embodiments a 5-10 membered heteroaryl refers to a fully aromatic ring system having 5, 6, 7, 8, 9, 10, such as 5 or 6, e.g. 5 ring atoms selected from C, N, O, S with the number of N, S and O atoms each being independently 0, 1 or 2. In some embodiments the total number of N, S and O atoms is 2. In some embodiments a 5-10 membered heteroaryl refers to a fully aromatic ring system having 5 ring atoms selected from C, N, S with the number of N and S atoms each being independently 0 or 1 . In some embodiments the total number of N and S atoms is 2. In some embodiments a 5-10 membered heteroaryl refers to a fully aromatic ring system having 6 ring atoms selected from C and N, with the number of N atoms being 1 or 2. In other embodiments a 5-10 membered heteroaryl refers to a partially aromatic ring system having 9 or 10 ring atoms selected from C, N and O, with the number of O atoms being 1 , 2 or 3, such as 1 or 2, and the number of N atoms being 1 or 2, such as 1 . In some embodiments, examples of “5-10 membered heteroaryl” include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiophenyl, thiazolyl, thienyl, indolyl, quinazolinyl, oxazolinyl, isoxazolinyl, indazolinyl, isothiazolyl, 1 ,3-benzodioxolyl, 2,2-difluoro-1 ,3-benzodioxolyl, 2,3-dihydrobenzofuryl, 2- methyl-2,3-dihydrobenzofuryl, 3-methyl-2,3-dihydrobenzofuryl, 3,3-dimethyl-2,3-dihydrobenzofuryl, 2,3- dimethyl-2,3-dihydrobenzofuryl, benzodihydropyrane, 1 ,2,3,4-tetrahydronaphthyl, 2,3-dihydroindenyl and the like. In some embodiments, examples of “5-10 membered heteroaryl” include 5-membered heteroaryl, such as isothiazole, 6-membered heteroaryl, such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 9- membered heteroaryl, such as 2, 2-difluoro-1 ,3-benzodioxolyl, 2,3-dihydrobenzofuryl, 2-methyl-2,3- dihydrobenzofuryl, 3-methyl-2,3-dihydrobenzofuryl, 3,3-dimethyl-2,3-dihydrobenzofuryl, 2,3-dimethyl-2,3- dihydrobenzofuryl, cyclopentenopyridine, and 10-membered heteroaryl, such as benzodihydropyrane (chromane), dihydropyrano-pyridine. The term “-C1-6 alkyl 5-10 membered heteroaryl” refers to -L2-X1- orL3-X2- with L2, L3being a C1-6 alkyl group and X1, X2being a 5-10 membered heteroaryl, and thus refers to a 5-10 membered heteroaryl, which is linked through a C1-6 alkyl group as defined herein to its neighbouring group. The term “-C1-6 alkoxy 5-10 membered heteroaryl” refers to -L2-X1- or L3-X2- with L2, L3being a C1-6 alkoxy group and X1, X2being a 5-10 membered heteroaryl, and thus refers to a 5-10 membered heteroaryl, which is linked through a C1-6 alkoxy group as defined herein to its neighbouring group. The term “-O-5-10 membered heteroaryl” refers to -L2-X1- or L3-X2- with L2, L3being -O- and X1, X2being a 5-10 membered heteroaryl, and thus refers to a 5-10 membered heteroaryl, which is linked through a -O- group to its neighbouring group. The 5-10 membered heteroaryl group may be unsubstituted or substituted with C1-4 alkyl, such as methyl, ethyl, t-butyl, fluorinated C1-4 alkyl, such as - CF3, -C(CH3)F2, C1- alkoxy, such as methoxy, ethoxy, fluorinated C1-4 alkoxy, such as -OCF3, -OCHF2, CN, -N(Me)2, halogen, such as F, Cl, or Br, such as F or Cl. In some embodiments, the 5-10 membered heteroaryl group may be unsubstituted or substituted with C1-4 alkyl, such as methyl, ethyl, t-butyl, fluorinated C1-4 alkyl, such as -CF3, C1-4 alkoxy, such as methoxy, ethoxy, halogen, such as F or Cl.[000285] In some embodiments for X1, a 5-10 membered heteroaryl refers to a fully aromatic ring system having 5 ring atoms selected from C, N and S with the number of N and S atoms being independently of each other 0 or 1 , e.g. 1 or a fully aromatic ring system having 6 ring atoms selected from C and N, with the number of N atoms being 1 or 2 or a partially aromatic ring system having 9 or 10 ring atoms selected from C, N and O, with the number of O atoms being 1 or 2 and the number of N atoms being 1 . In some embodiments for X1, a 5-10 membered heteroaryl refers to isothiazole, phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, 2,2-difluoro-1 ,3-benzodioxolyl, 2,3-dihydrobenzofuryl, 2-methyl-2,3- dihydrobenzofuryl, 3-methyl-2,3-dihydrobenzofuryl, 3,3-dimethyl-2,3-dihydrobenzofuryl, 2,3-dimethyl-2,3- dihydrobenzofuryl, cyclopentenopyridine, benzodihydropyrane, dihydropyrano-pyridine.[000286] In some embodiments for X2a 5-10 membered heteroaryl refers to a fully aromatic ring system having 6 ring atoms selected from C and N, with the number of N atoms being 1 or 2, such as 1 . In some embodiments for X2a 5-10 membered heteroaryl refers to pyridinyl.[000287] The term “C3-8 cycloalkyl” refers to a non-aromatic, i.e. saturated or partially unsaturated alkyl ring system, such as monocycles, fused bicycles, bridged bicycles or spirobicycles, containing 3, 4, 5 6, 7, or 8 carbon atoms. The term “C3-6 cycloalkyl” refers to a non-aromatic, i.e. saturated or partially unsaturated alkyl ring system, such as monocycles, fused bicycles, bridged bicycles or spirobicycles, containing 3, 4, 5, or 6 carbon atoms. Examples of “C3-8 cycloalkyl” include monocycles, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bridged bicycles, such as bicyclo[1 .1 .1]pentyl, bicyclo[2.1 ,1]hexyl, fused bicycles, such as bicyclo[3.1 .0]hexyl. The C3-6 cycloalkyl group may be unsubstituted or substituted with C1-4 alkyl, such as methyl, ethyl, t-butyl, fluorinated C1-4 alkyl, such as - CF3, -C(CH3)F2, C1- alkoxy, such as methoxy, ethoxy, fluorinated C1-4 alkoxy, such as -OCF3, -OCHF2, CN, -N(Me)2, halogen, such as F, Cl, or Br, such as F or Cl. In some embodiments the C3-6 cycloalkyl group may be unsubstituted or substituted by e.g. one or more of C1-4 alkyl, such as methyl and halogen, such as F. The term “-C1-4 alkyl-C3-6 cycloalkyl” refers to -L2-X1- or L3-X2- with L2, L3being a C1-4 alkyl group and X1, X2being C3-6 cycloalkyl as defined herein and refers to a C3-6 cycloalkyl, which is linkedthrough a C1-6 alkyl group as defined herein to its neighbouring group. The term “-O-C3-6 cycloalkyl” refers to -L2- X1- or L3-X2- with L2, L3being -O- and X1, X2being C3-6 cycloalkyl as defined herein and refers to a C3-6 cycloalkyl, which is linked through -O- to its neighbouring group. The term “-C1-4 alkoxy-C3-6 cycloalkyl” refers to -L2-X1- or L3-X2- with L2, L3being a C1-4 alkoxy group and X1, X2being C3-6 cycloalkyl as defined herein and refers to a C3-6 cycloalkyl, which is linked through a C1-6 alkoxy group as defined herein to its neighbouring group. In some embodiments for X1, a C3-6 cycloalkyl refers to cyclopropyl, cyclopentyl, cyclohexyl. In some embodiments for X2, a C3-6 cycloalkyl refers to cyclopropyl, cyclobutyl.[000288] The term “4-8 membered heterocycloalkyl” refers to a non-aromatic, i.e. saturated or partially unsaturated ring system having 4, 5, 6, 7 or 8 ring atoms (of which at least one is a heteroatom), which ring atoms are selected from C, N, O, and S, such as C, N, and O, the number of N atoms being 0, 1 , or 2 and the number of O and S atoms each being 0, 1 , or 2. In some embodiments the term “4-8 membered heterocycloalkyl” comprises saturated or partially unsaturated monocycles, fused bicycles, bridged bicycles or spirobicycles. In some embodiments the term “4-8 membered heterocycloalkyl” comprises fully saturated or partially unsaturated monocycles and bridged bicycles. Examples of 4-8 membered heterocycloalkyl groups include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, 1 ,4-oxathianyl 1 ,4-dithianyl, 1 ,3-dioxanyl, 1 ,3-dithianyl, piperazinyl, thiomorpholinyl, piperidinyl, morpholinyl, azabicyclo[2.2.1]heptan-5-yl, 8-oxa-3- azabicyclo[3.2.1]octan-3-yl and the like.. The 4-8 membered heterocycloalkyl group may be unsubstituted or substituted with C1-4 alkyl, such as methyl, ethyl, C1-4 alkoxy, such as methoxy, ethoxy, halogen, such as F, Cl or Br, e.g. F or Cl.[000289] In some embodiments, the 4-8 membered heterocycloalkyl representing group X1is a non- aromatic ring system having 5 or 6 ring atoms of which at least one is a heteroatom selected from N and O, the number of N atoms being 1 or 2 and the number of O being 0, 1 , or 2, such as a non-aromatic 6 membered ring system having 1 or 2 N-atoms, such as piperidine, lin some embodiments, the 4-8 membered heterocycloalkyl formed by groups X1together with the N atom of the carbamate forms is a non-aromatic ring system having 5 or 6 ring atoms of which at least one is a heteroatom selected from N and O, the number of N atoms being 1 or 2 and the number of O being 0, 1 , or 2, e.g. a non-aromatic ring system having 5 or 6 ring atoms comprising one or two N-atoms. Examples include pyrrolidinyl, piperdinyl, morpholinyl, piperazinyl, N-methyl piperazinyl. In some embodiments, the 4-8 membered heterocycloalkyl representing X2is a non-aromatic ring system having 4, 5, 6, 7 or 8 ring atoms of which at least one is a heteroatom selected from N and O, the number of N atoms being 1 or 2 and the number of O being 0, 1 , or 2. In some embodiments, 4-8 membered heterocycloalkyl include 4-membered heterocycloalkyl having at least one heteroatom selected from N and O, the number of N atoms being 1 or 2 and the number of O being 0 or 1 , such as azetidinyl, oxetanyl, unsubstituted or substituted by e.g. Ci-4alkyl, such as methyl; 5-membered heterocycloalkyl having 1 or 2 N-atoms, such as pyrrolidinyl, unsubstituted or substituted by e.g. one or more of Ci-4alkyl, such as methyl; 6-membered heterocycloalkyl having N and O-atoms, such as morpholinyl, piperazinyl, piperidinyl, dioxanyl, unsubstituted or substituted by e.g. one or more of Ci-4alkyl, such as methyl, halogen, e.g. F; 7-membered heterocycloalkyl having N and O-atoms, such as 1 N- and 1 O-atom, such as 2-oxa-5- azabicyclo[2.2.1]heptan-5-yl, 1 ,4-diazabicyclo[3.2.1]octan-4-yl, 3-methyl-3-azabicyclo[3.1 ,0]hexan-1-yl; 8- membered heterocycloalkyl having N and O-atoms, such as 1 N- and 1 O-atom, such as 8-oxa-3- azabicyclo[3.2.1 ]octan-3-yl.[000290] The term “C1-4 alkyl 4-8 membered heterocycloalkyl” refers to -L2-X1- or L3-X2- with L2, L3being C1 -4 alkyl and X1, X2being 4-8 membered heterocycloalkyl as defined herein. Thus, the 4-8 membered hetereocycloalkyl is linked through a C1-4 alkyl group as defined to the neighbouring group. In some embodiments, the alkyl may be Ci, resulting in -(CH2)-(4-8 membered heterocycloalkyl) or C2, resulting in -(CH2)2-(4-8 membered heterocycloalkyl) or C3, resulting in -(CH2)3-(4-8 membered heterocycloalkyl) or C , resulting in -(CH2) -(4-8 membered heterocycloalkyl). Examples include -(CH2)-morpholinyl, -(CH2)2- morpholinyl, -(CH2)3-morpholinyl, -(CH2)4-morpholinyl, -(CH2)-piperazinyl, -(CH2)2-N-methyl-piperazinyl, -(CH2)3-piperazinyl or -(CH2)4-piperazinyl.[000291] The term “-C1-4 alkoxy 4-8 membered heterocycloalkyl” refers to -L2-X1- or L3-X2- with L2, L3being C1-4 alkoxy and X1, X2being 4-8 membered heterocycloalkyl as defined herein. Thus, the 4-8 membered hetereocycloalkyl is linked via a C1-4 alkoxy group as defined herein to its neighbouring group. In some embodiments, the C1-4 alkoxy may be Ci, resulting in -(O-CH2)-(4-8 membered heterocycloalkyl) or C2, resulting in -(O-CH2)2-(4-8 membered heterocycloalkyl) or C3, resulting in -(O-CH2)3-(4-8 membered heterocycloalkyl). Examples include -(0-CH2)-(N-morpholinyl), -(0-CH2)2-(N-morpholinyl).[000292] The term “-O-(4-8 membered heterocycloalkyl)” refers to -L2-X1- or L3-X2- with L2, L3being -O- and X1, X2being 4-8 membered heterocycloalkyl as defined herein. Thus, the 4-8 membered hetereocycloalkyl is linked through an -O-atom to the neighbouring group. Examples include -O- morpholinyl, -O-piperazinyl, -O-pyrrolidinyl and the like.[000293] The term "halogen" or "hal" as used herein may be fluoro, chloro, bromo or iodo such as fluoro, chloro or bromo, e.g. fluoro or chloro.[000294] The term "C1-4 alkyl" and "Ci-ealkyl" refer to a fully saturated branched or unbranched hydrocarbon moiety having 1 , 2, 3 or 4 and 1 , 2, 3, 4, 5 or 6 carbon atoms, respectively. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl or neohexyl.[000295] The term “C1-6 heteroalkyl” refers to an alkyl as defined with 1 , 2, 3, 4, 5 or 6 carbon atoms in which at least one carbon atom is replaced with a heteroatom, such as N, O, or S, e.g. N, O. It is understood that the heteroatom may further be substituted with one or two C1-6 alkyl. Examples include - (CH2)2-O-Me, -(CH2)3-O-Me, -(CH2)2-O-CH2Me, -(CH2)2-NMe2, -(CH2)-NMe2, -(CH2)2-NEt2, -(CH2)-NEt2and the like.[000296] The term “Ci-4alkylamino” refers to a fully saturated branched or unbranched C1-4 alkyl, which is substituted with at least one, such as only one, amino group, alkylamino group or dialkylaminogroup,such as NH2, HN(Ci-4alkyl) or N(Ci-4alkyl)2. Thus, a Ci-4alkylamino refers to Ci-4alkylamino, Ci-4alkyl-(Ci- 4alkyl)amino, Ci-4alkyl-(Ci-4dialkyl)amino. Examples include but are not limited to methylaminomethyl, dimethylamonimethyl, aminomethyl, dimethylaminoethyl, aminoethyl, methylaminoethyl, n-propylamino, iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino, tert-butylamino.[000297] The term “C1-4 alkoxy” refers to an unsubstituted or substituted alkyl chain linked to the remainder of the molecule through an oxygen atom, and in particular to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, and t-butoxy.[000298] Based on the definitions given throughout the application the skilled person knows which combinations are synthetically feasible and realistic, e.g. typically combinations of groups leading to some heteroatoms directly linked to each other, e.g. -O-O-, are not contemplated, however synthetically feasible combinations, such as -S-N= in aisothiazole are contemplated.[000299] The compounds may contain one or more asymmetric centers in the molecule. A compound without designation of the stereochemistry is to be understood to include all the optical isomers (e.g., diastereomers, enantiomers, etc.) in pure or substantially pure form, as well as mixtures thereof (e.g. a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (e.g. by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods).[000300] Compounds described herein having one enantiomeric form may epimerise into the other enantiomeric form if the chiral center is in a position susceptible to epimerization. Thus, unless it is specifically stated or the context indicates otherwise, disclosure of one stereoisomer with a chiral centre encompasses the isolated stereoisomer and a mixture, such as a racemic mixture, of the (R) and (S) stereoisomers if the stereoisomers epimerise. For example, a disclosure of a compoundencompasses isolated, so a e[000301] The compounds may be isotopically-labeled compounds, for example, compounds including various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, or chlorine. The disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism.[000302] The compounds of the disclosure include the free form as well as the pharmaceutically acceptable salts and stereoisomers thereof. The pharmaceutically acceptable salts include all the typical pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present compounds can be synthesized from the compounds of this disclosure which contain a basic or acidic moiety by conventional chemical methods, see e.g. Berge et al, "Pharmaceutical Salts," J. Pharm. ScL, 1977:66:1- 19. Furthermore, the compounds of the disclosure also include lyophilized and polymorphs of the free form.[000303] For example, conventional pharmaceutically acceptable salts for a basic compound include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. Conventional pharmaceutically acceptable salts for an acidic compound include those derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.[000304] The compounds of the disclosure may exist in solid, i.e. crystalline (e.g., polymorphs, i.e., different crystalline structures that have the same chemical composition but differ in packing, geometricalarrangement) or noncrystalline form (optionally as solvates) or liquid form. In the solid state, it may exist in, or as a mixture thereof. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. The formation of solvates may include non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or aqueous solvents such as water (also called “hydrates”). Different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents.Diseases[000305] The method of the invention provides treatment of cancer with a GSPT1 degrader. The cancer may be associated with GSPT1 .[000306] The cancer may be a solid cancer including but not limited to cancers of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx and salivary glands), neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, uterus, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castrationresistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu-NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy -insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma; and blood bourne (liquid) or hematological cancers, including but not limited to leukemias, lymphomas, and myelomas, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia,myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM).[000307] In some embodiments, the cancer is a myc-driven cancer. In some embodiments, the cancer is a solid tumor cancer, such as breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu-NETs), liver cancer, stomach cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, skin cancer, brain cancer, cervical cancer, ovarian cancer, melanoma and head and neck cancer.[000308] Preferably, the cancer may be lung cancer, for example a non-small cell lung cancer, such as squamous cell lung cancer, lung adenocarcinoma, or small cell lung cancer.[000309] Preferably, the cancer is prostate cancer. The cancer may be castration resistant prostate cancer or hormone sensitive prostate cancer. The cancer may be neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer.[000310] Preferably, the cancer is breast cancer. The cancer may be HR-positive, HER2-negative breast cancer or ER-positive breast cancer.[000311] The cancer may be a solid tumour with Myc amplification, e.g. L-Myc or N-Myc amplification. L- Myc or N-Myc amplification can be measured from a sample taken from a subject, e.g. a tumour sample, according to any suitable commercially available assay. Subjects with Myc amplification, e.g. L-Myc or N- Myc, amplification may be particularly suited to the methods of treatment described herein.[000312] Assays for determining Myc amplification include the FoundationOne CDx (F1CDx) assay or the Tempus xT assay, to detect the copy number alterations and therefore the alterations. Copy number variations are a deviation from the normal number of copies of a gene, which is typically 2. They are reported either as a Copy Number Gain (amplification) or a Copy Number Loss (deletion).[000313] The FoundationOne assay detects copy number alterations (CNAs) using a comparative genomic hybridization (CGH)-like method. First, a log-ratio profile of the sample is acquired by normalizing the sequence coverage obtained at all exons and genome-wide SNPs (~3,500) against a process-matched normal control. This profile is segmented and interpreted using allele frequencies of sequenced SNPs to estimate tumor purity and copy number at each segment. Amplifications are called at segments with > 6 copies (or > 7 for triploid / > 8 for tetrapioid tumors) and homozygous deletions at 0 copies, in samples with tumor purity > 20%. In the Tempus xT assay, a Copy Number Gain is reported when > 8 copies are detected, and a Copy Number Loss is reported when 2 copies are lost.[000314] The method of the invention may comprise treating a Myc-driven cancer in a subject, comprising administering the subject a therapeutically effective amount of the compound or a composition as described herein.[000315] The method of the invention may comprise degrading GSPT1 in a subject suffering from cancer, comprising administering the subject a therapeutically effective amount of a compound or a composition as described herein.[000316] The method of the invention may comprise reducing the level of GSPT1 in a subject suffering from cancer, comprising administering the subject a therapeutically effective amount of a compound or a composition as described herein.Combinations[000317] For the avoidance of doubt, the methods described are not necessarily limited to the administration of the GSPT1 degrader only. For any given embodiment above, the GSPT1 degrader may be administered in combination with any other suitable therapeutic agent, for example another anti-cancer agent. The GSPT1 degrader may be administered simultaneously, sequentially or separately with the other suitable therapeutic agent.[000318] In some embodiments, at least one other suitable therapeutic agent is administered with the GSPT 1 degrader for the treatment of cancer.[000319] In some embodiments, the at least one other suitable therapeutic agent is a known treatment for cancer. In some embodiments, the at least one other suitable therapeutic agent is the standard of care treatment for the cancer.[000320] In some embodiments, the at least one suitable therapeutic agent is a treatment for prostate cancer. The prostate cancer may be castration resistant prostate cancer or hormone sensitive prostate cancer. The prostate cancer may be neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer. In some embodiments, the at least one other suitable therapeutic agent is an anti-androgen agent, for example an androgen receptor (AR) antagonist. In some embodiments, the AR antagonist is enzalutamide. In some embodiments, enzalutamide is administered at a dose of 160 mg daily. Enzalutamide may be administered through any appropriate method, such as orally. In these embodiments, the invention may be used for the treatment of prostate cancer as described herein.[000321] In some embodiments, the at least one suitable therapeutic agent is a treatment for breast cancer. The cancer may be HR-positive, HER2-negative breast cancer or ER-positive breast cancer. In some embodiments, the at least one other suitable therapeutic agent is a selective estrogen receptor degrader (SERD). In some embodiments, the SERD is fulvestrant. In some embodiments, fulvestrant isadministered as a dose of 500 mg per month. In some embodiments, a further dose of 500 mg is given 2 weeks after the initial dose of fulvestrant. Fulvestrant may be administered through any appropriate method, such as by intramuscular injection. In these embodiments, the invention may be used for the treatment of breast cancer as described herein.Numbered embodiments[000322] The following numbered embodiments also describe embodiments of the invention, which may be combined with each other.1 . A method of treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a GSPT1 degrader to the patient, wherein the patient is biomarker negative for a gene induced in response to low oxygen levels.2. The method according to embodiment 1 , wherein the method comprises determining the level of a biomarker for a gene induced in response to low oxygen levels in a biological sample obtained from the patient.3. A method of determining whether a patient is likely to respond to the use of a GSPT 1 degrader in the treatment of cancer, comprising determining the level of a biomarker for a gene induced in response to low oxygen levels in the patient and determining that the patient is likely to be responsive to treatment if the patient is biomarker negative for a gene induced in response to low oxygen levels.4. A method of determining a treatment regimen for a patient suffering from cancer, comprising determining the level of a biomarker for a gene induced in response to low oxygen levels in the patient; determining that the patient should be administered a therapeutically effective amount of a GSPT1 degrader if the patient is biomarker negative for a gene induced in response to low oxygen levels.5. The method according to embodiment 1 or embodiment 2, wherein the patient is biomarker positive for a Myc transcription factor.6. The method according to embodiment 5, wherein the method comprises determining the level of a biomarker for a Myc transcription factor in a biological sample obtained from the patient.7. The method according to embodiment 3 wherein the method further comprises determining the level of a biomarker for a Myc transcription factor in the patient and determining that the patient is likely to be responsive to treatment if the patient is biomarker positive for a Myc transcription factor and biomarker negative for a gene induced in response to low oxygen levels.The method according to embodiment 4 wherein the method further comprises determining the level of a biomarker for a Myc transcription factor in the patient and determining that that the patient should be administered a therapeutically effective amount of a GSPT1 degrader if the patient is biomarker positive for a Myc transcription factor and biomarker negative for a gene induced in response to low oxygen levels. The method according to any one of embodiments 5 to 9 wherein the Myc transcription factor is selected from: N-Myc, L-Myc, c-Myc or a combination thereof. The method according to embodiment 10 wherein the Myc transcription factor is N-Myc. The method according to any previous embodiment wherein the gene induced in response to low oxygen levels is selected from: NDRG1 , ADM, EGLN3 or a combination thereof. The method according to embodiment 12 wherein the gene induced in response to low oxygen levels is NDRG1 . The method according to any previous embodiment wherein biomarker negative refers to a patient that has a level of a biomarker that is less than a reference level for the biomarker. The method according to any one of embodiments 3 to 13 wherein biomarker positive refers to a patient that has a level of a biomarker that is more than a reference level for the biomarker. The method according to embodiment 14 wherein the reference level for a biomarker for a Myc transcription factor is the median level of the biomarker of a distribution of control subjects. The method according to embodiment 14 wherein the reference level for a biomarker for a Myc transcription factor is the 70th percentile level of the biomarker of a distribution of control subjects. The method according to embodiment 14 wherein the reference level measured by RNA sequencing for a biomarker for N-Myc is about 1 .1 Iog2(1 +TPM) above the median of a distribution of control subjects. The method according to embodiment 14 wherein the reference level measured by RNA sequencing for a biomarker for N-Myc is about 1 .6 Iog2(1 +TPM) above the median of a distribution of control subjects. The method according to embodiment 14 wherein the reference level measured by RNA sequencing for a biomarker for N-Myc is about 4.9 Iog2(1 +TPM).The method according to embodiment 14 wherein the reference level measured by RNA sequencing for a biomarker for N-Myc is about 5.5 Iog2(1 +TPM). The method according to embodiment 14 wherein the reference level measured by RNA sequencing for a biomarker for N-Myc is about 1 .6 Iog2(1 +TPM). The method according to embodiment 14 wherein the reference level measured by RNA sequencing for a biomarker for N-Myc is about 2.2 Iog2(1 +TPM). The method according to embodiment 14 wherein a reference level measured by RT-qPCR for a biomarker for N-Myc is about 6.7 dcQ. The method according to embodiment 14 wherein a reference level measured by RT-qPCR for a biomarker for N-Myc is about 5.5 dcQ. The method according to embodiment 14 wherein a reference level measured by RT-qPCR for a biomarker for N-Myc is about 3 dcQ. The method according to embodiment 14 wherein a reference level measured by RT-qPCR for a biomarker for L-Myc is about -1 dcQ. The method according to embodiment 14 wherein the reference level measured by IHC for a biomarker for N-Myc is about 1 logio(TPS). The method according to any one of embodiments 13-27 wherein the reference level for a biomarker for a gene induced in response to low oxygen levels is the median level of the biomarker of a distribution of control subjects. The method according to embodiments 13-27 wherein the reference level for a biomarker for a gene induced in response to low oxygen levels is the 20th percentile level of the biomarker of a distribution of control subjects. The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 0.9 Iog2(1 +TPM) below the median of a distribution of control subjects. The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 1 .8 Iog2(1 +TPM) below the median of a distribution of control subjects.The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for ADM is about 1 .3 Iog2(1 +TPM) below the median of a distribution of control subjects. The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for EGLN3 is about 1 .6 Iog2(1 +TPM) below the median of a distribution of control subjects. The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 8 Iog2(1 +TPM). The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 12.3 Iog2(1 +TPM). The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 7 Iog2(1 +TPM). The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for NDRG1 is about 11 .4 Iog2(1 +TPM). The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for ADM is about 4.5 Iog2(1 +TPM). The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for ADM is about 6.8 Iog2(1 +TPM). The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for EGLN3 is about 4.5 Iog2(1 +TPM). The method according to any one of embodiments 13-27 wherein the reference level measured by RNA sequencing for a biomarker for EGLN3 is about 7.7 Iog2(1 +TPM). The method according to any one of embodiments 15-18 or 28-33 wherein the control subjects have cancer. The method according to embodiment 42 wherein the cancer of the control subjects is the same type as the cancer of the patient. The method according to embodiment 42 or embodiment 43 wherein the cancer of the control subjects is lung cancer.The method according to embodiment 44 wherein the lung cancer is non-small cell lung cancer (NSCLC). The method according to embodiment 45 wherein the non-small cell lung cancer is lung adenocarcinoma (LUAD). The method according to embodiment 42 or embodiment 43 wherein the cancer of the control subjects is prostate cancer. The method according to embodiment 47 wherein the prostate cancer is castration resistant prostate cancer or hormone sensitive prostate cancer. The method according to embodiment 47 wherein the prostate cancer is neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer. The method according to embodiment 42 or embodiment 43 wherein the cancer of the control subjects is breast cancer. The method according to embodiment 50 wherein the breast cancer is HR-positive, HER2-negative breast cancer or ER-positive breast cancer. The method according to any one of embodiments 37 to 46 wherein the distribution of control subjects is from The Cancer Genome Atlas Program (TCGA) database. The method according to embodiment 52 wherein the median level is determined from the TCGA- LUAD database. The method according to any one of embodiments 15 to 53 wherein a reference level of a biomarker is measured by RNA sequencing, RT-qPCR or IHC. The method according to any previous embodiment wherein the level of a biomarker in the patient is measured by RNA sequencing, RT-qPCR or IHC. A method of measuring a biomarker in a patient with cancer, comprising determining the level of a biomarker for a gene induced in response to low oxygen levels in the patient.The method according to embodiment 56 wherein the method comprises determining the level of a biomarker for a Myc transcription factor in the patient. The method according to embodiment 56 or embodiment 57, wherein the method comprises comparing the level of a biomarker to a level of the biomarker in a control sample. The method according to embodiment 56 or embodiment 57, wherein the method comprises comparing the level of a biomarker to a reference level as defined in any one of embodiments 15 to 54. The method according to any previous embodiment wherein the biomarker is selected from: mRNA, DNA, a polypeptide, a protein, phosphorylated forms of a protein and metabolites. The method according to any previous embodiment wherein the biomarker comprises mRNA or a protein. The method according to any previous embodiment wherein the cancer of the patient is a solid cancer including but not limited to cancers of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx and salivary glands), neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, uterus, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castration-resistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu- NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy -insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma; and blood bourne (liquid) or hematological cancers, including but not limited to leukemias, lymphomas, and myelomas, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantlecell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T- cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virustype 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM). The method according to embodiment 62 wherein the cancer is breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu-NETs), liver cancer, stomach cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, skin cancer, brain cancer, cervical cancer, ovarian cancer, melanoma and head and neck cancer. The method according to embodiment 63, wherein the cancer is lung cancer. The method according to embodiment 64 wherein the cancer is non-small cell lung cancer, squamous cell lung cancer, or small cell lung cancer. The method according to embodiment 65 wherein the cancer is non-small cell lung cancer. The method according to embodiment 66 wherein the cancer is lung adenocarcinoma (LUAD). The method according to embodiment 63, wherein the cancer is prostate cancer. The method according to embodiment 68, wherein the prostate cancer is castration resistant prostate cancer or hormone sensitive prostate cancer. The method according to embodiment 68, wherein the prostate cancer is neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer. The method according to embodiment 63, wherein the cancer is breast cancer.The method according to embodiment 71 , wherein the breast cancer is HR-positive, HER2- negative breast cancer or ER-positive breast cancer. The method according to embodiment 62 wherein the cancer is diffuse large B Cell lymphoma. The method according to any previous embodiment where the GSPT 1 degrader is a compound or pharmaceutically acceptable salt or stereoisomer thereof of formula I:I whereinX1is linear or branched C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, -O- CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, -OC(O)- Ci-4alkylamino, -C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkoxy, C1-4 alkylhydroxy, -CH2F, -N(H)C(O)-O-CI-6alkyl, and C(OH)(CF3); or X1together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci- ealkyl, -C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy;X2is H, C3-6 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and C1-4 alkylhydroxy;L1is a covalent bond, linear or branched C1-6 alkyl;L2is a covalent bond, linear or branched C1-6 alkyl; andL3is a covalent bond, linear or branched C1-6 alkyl, -O-, or -C1-4 alkoxy, wherein linear or branchedC1-6 alkyl is unsubstituted or substituted with one or more of halogen. The method according to embodiment 74, wherein the GSPT 1 degrader is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X1is linear or branched - C1-6 alkyl, -C3-6 cycloalkyl, -Ce-io aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched -C1-4 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy; or X1together with the N atom of the carbamate forms a 5-6membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-4 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, - CN, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy. The method according to embodiment 74, wherein the GSPT 1 degrader is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X2is H, C3-6 cycloalkyl, Ce aryl, 5-6 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-4 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and -C1-4 alkylhydroxy. The method according to embodiment 74, wherein the GSPT 1 degrader is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L1is -CH2- or -CH(CH3)- and / or L2is a covalent bond, -CH2- or -CH(CH3)- and / or L3is a -CH2-, -O-, -CH2-O-, -CH2-CH2-O-. The method according to embodiment 74, wherein the GSPT1 degrader is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof of formula II:whereinX1is linear or branched C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, -O- CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, -OC(O)- Ci-4alkylamino, -C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkoxy and C1-4 alkylhydroxy; or X1together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci- ealkyl, -C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy;X2is H, C3-6 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and C1-4 alkylhydroxy;L2is a covalent bond, linear or branched C1-6 alkyl;L3is a covalent bond, linear or branched C1-6 alkyl, -O-, -C1-4 alkoxy;Rais H or linear or branched C1-4 alkyl, such as methyl or ethyl, n is 1 or 2.The method according to embodiment 78, wherein the GSPT 1 degrader is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1 and Rais H or methyl. The method according to embodiment 78, wherein the GSPT 1 degrader is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 0. The method according to embodiment 78, wherein the GSPT 1 degrader is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 1 and Rb, Rcare H or wherein p is 1 , Rbis methyl and Rcis H. The method according to embodiment 78, wherein the GSPT 1 degrader is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L2is a covalent bond, - CH2- or -CH(CH3)- and / or L3is a -CH2-, -O-, -CH2-O-, -CH2-CH2-O-. The method according to embodiment 74, wherein the GSPT 1 degrader is a compound or a pharmaceutically acceptable salt or stereoisomer thereof, of formula III, such as IVa or IVb:whereinX1is linear or branched C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, -O- CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, -OC(O)- Ci-4alkylamino, -C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkoxy and C1-4 alkylhydroxy; or X1together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci- ealkyl, -C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy;X2is H, C3-6 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and C1-4 alkylhydroxy;L3is a covalent bond, linear or branched C1-6 alkyl, -O-, -C1-4 alkoxy;Ra, Rb, Rcare independently of each other H, linear or branched C1-4 alkyl, such as methyl; p is 0 or 1 . The method according to embodiment 83, wherein the GSPT 1 degrader is a compound or a pharmaceutically acceptable salt or stereoisomer thereof, of formula III, IVa, or IVb, wherein p is 0. The method according to embodiment 83, wherein the GSPT 1 degrader is a compound or a pharmaceutically acceptable salt or stereoisomer thereof, of formula III, IVa, or IVb, wherein p is 1 and Rb, Rcare H or wherein p is 1 , Rbis methyl and Rcis H. The method according to embodiment 74, wherein the GSPT1 degrader is a compound or pharmaceutically acceptable salts or stereoisomers thereof, of formula V, VI or VII:wherein one or two of w1, w2, w3, w4, w5are independently of each other selected from C, N, S, and O, and the remaining of w1, w2, w3, w4, w5are C; one or two of w6, w7, w8, w9are selected from C and O and the remaining of w6, w7, w8, w9are C; w10, w11are independently of each other selected from C and N;L1is a covalent bond, linear or branched C1-6 alkyl;L2is a covalent bond, linear or branched C1-6 alkyl;R1, R2, R3, R4are independently of each other selected from H, linear or branched -C1-6 alkyl, linear or branched C1-6 heteroalkyl, - C1-4 alkoxy, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, -C1-6 alkylamino, -CN, -OC(O)-Ci-6alkyl, -N(H)C(O)-Ci-6alkyl, -C(O)O-Ci-6alkyl, -COOH, - Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, -C1-4 alkylhydroxy, and halogen, such as F, Cl or Br, e.g. F or Cl, or a group of formula -L3-X2, wherein L3is a covalent bond, linear or branched C1-6alkyl, -O-, -C1-4 alkoxy and X2is C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and -C1-4 alkylhydroxy;R5, R6, R7R8are independently of each other selected from H, linear or branched C1-4 alkyl, such as methyl, and halogen, such as F or Cl, e.g. F;Z is linear or branched -C1-6 alkyl, -C3-6 cycloalkyl, 4-8 membered heterocycloalkyl, wherein Z is unsubstituted or substituted with C1-4 alkyl, Ce aryl, Ce aryloxy, 6 membered heteroaryl or CF3; or Z together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with C1-4 alkyl, Ce aryl, Ce aryloxy, 6 membered heteroaryl or CF3; q is 0, 1. The method according to embodiment 74, wherein the GSPT1 degrader is a compound or pharmaceutically acceptable salt or stereoisomer thereof, of formula VIII or VillaVIII Villa wherein Rais H or methyl and W1and W2are selected from:The method according to any one of embodiments 1 to 73 wherein the compound is selected from compounds 1-240 of Table 3.The method according to any one of embodiments 1 to 73, wherein the compound, pharmaceutically acceptable salt and stereoisomer thereof is selected from the group consisting of:The method of any one of embodiments 1 to 73, wherein the GSPT1 degrader is compound 145(shown below),or a pharmaceutically acceptable salt or stereoisomer thereof. The method according to embodiment 90 wherein Compound 145 is administered in combination with at least one further therapeutic agent. The method according to embodiment 91 wherein the cancer is prostate cancer and the further therapeutic agent is an anti-androgen agent, such as an AR antagonist, for example, enzalutamide.93. The method according to embodiment 92 wherein the prostate cancer is castration resistant prostate cancer or hormone sensitive prostate cancer.94. The method according to embodiment 92 wherein the prostate cancer is neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer.95. The method according to any of embodiments 91 to 94 wherein enzalutamide is administered at a dose of 160 mg daily.96. The method according to embodiment 91 wherein the cancer is breast cancer and the further therapeutic agent is a selective estrogen receptor degrader (SERD), for example, fulvestrant.97. The method according to embodiment 96 wherein the breast cancer is HR-positive, HER2-negative breast cancer or ER-positive breast cancer.98. The method according to embodiment 96 or embodiment 97 wherein fulvestrant is administered at a dose of 500 mg monthly.Additional embodimentsThe embodiments set out below also form part of the invention and may be combined with each other. The embodiments set out below also form part of the invention.1 . A GSPT 1 degrader for use in a method of treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of the GSPT1 degrader to the patient, wherein the patient is biomarker negative for a gene induced in response to low oxygen levels.2. The GSPT 1 degrader for use according to embodiment 1 , wherein the gene induced in response to low oxygen levels is selected from: NDRG1 , ADM, EGLN3 or a combination thereof, for example, wherein the gene induced in response to low oxygen levels is NDRG1 .3. The GSPT 1 degrader for use according to embodiment 1 or embodiment 2, wherein the patient is biomarker positive for a Myc transcription factor, for example, wherein the Myc transcription factor is selected from: N-Myc, L-Myc, c-Myc or a combination thereof, or wherein the Myc transcription factor is N-Myc.4. The GSPT1 degrader for use according to any one of embodiments 1-3, wherein the method comprises determining the level of a biomarker for a gene induced in response to low oxygen levels in abiological sample obtained from the patient, and / or wherein the method comprises determining the level of a biomarker for a Myc transcription factor in a biological sample obtained from the patient.5. The GSPT1 degrader for use according to any previous embodiment, wherein biomarker negative refers to a patient that has a level of a biomarker that is less than a reference level for the biomarker, and / or wherein biomarker positive refers to a patient that has a level of a biomarker that is more than a reference level for the biomarker.6. The GSPT1 degrader for use according to embodiment 5, wherein the reference level for a biomarker for a Myc transcription factor is:(i) the median level of the biomarker of a distribution of control subjects; or(ii) the 70th percentile level of the biomarker of a distribution of control subjects.7. The GSPT1 degrader for use according to embodiment 5, wherein the Myc transcription factor is N-Myc and wherein:(a) the reference level for N-Myc measured by RNA sequencing is:(i) about 1.1 Iog2(1 +TPM) above the median of a distribution of control subjects, or(ii) about 1 .6 Iog2(1 +TPM) above the median of a distribution of control subjects, or(iii) about 4.9 Iog2(1 +TPM), or(iv) about 5.5 Iog2(1 +TPM); and / or(b) the reference level for N-Myc measured by RT-qPCR is:(i) about 6.7 dCQ, or(ii) about 5.5 dCQ, or(iii) about 3 dCQ; and / or(c) the reference level for N-Myc measured by IHC is about 1 log10(TPS); or wherein the Myc transcription factor is L-Myc and wherein the reference level for L-Myc measured by RT- qPCR is about -1 dCQ.8. The GSPT1 degrader for use according to any one of embodiments 5-7, wherein the reference level for a biomarker for a gene induced in response to low oxygen levels is:(i) the median level of the biomarker of a distribution of control subjects; or(ii) the 20th percentile level of the biomarker of a distribution of control subjects.9. The GSPT1 degrader for use according to any one of embodiments 5-7, wherein:(a) the gene induced in response to low oxygen levels is NDRG1 , and the reference level measured by RNA sequencing is:(i) about 0.9 Iog2(1 +TPM) below the median of a distribution of control subjects, or(ii) about 1 .8 Iog2(1 +TPM) below the median of a distribution of control subjects, or(iii) about 12.3 Iog2(1 +TPM), or(iv) about 11 .4 Iog2(1 +TPM); and / or(b) the gene induced in response to low oxygen levels is ADM, and the reference level measured by RNA sequencing is:(i) about 1 .3 Iog2(1 +TPM) below the median of a distribution of control subjects, or(ii) about 6.8 Iog2(1 +TPM); and / or(c) the gene induced in response to low oxygen levels is EGLN3, and the reference level measured by RNA sequencing is:(i) about 1 .6 Iog2(1 +TPM) below the median of a distribution of control subjects, or(ii) about 7.7 log2(1 +TPM).10. The GSPT1 degrader for use according to any one of embodiments 6-9, wherein, where the reference level is determined from a distribution of control subjects, the control subjects have cancer, optionally wherein:(i) the cancer of the control subjects is the same type as the cancer of the patient and optionally wherein the control subjects are taken from The Cancer Genome Atlas Program (TCGA) database; and / or(ii) the cancer of the control subjects is:(A) lung cancer, for example, non-small cell lung cancer (NSCLC), for example, lung adenocarcinoma (LUAD), and optionally wherein the control subjects are taken from The Cancer Genome Atlas Program (TCGA) database, or(B) prostate cancer, for example, castration resistant prostate cancer or hormone sensitive prostate cancer, or alternatively for example, neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer, or(C) breast cancer, for example, HR-positive, HER2-negative breast cancer or ER-positive breast cancer.11 . The GSPT 1 degrader for use according to any previous embodiment, wherein the level of a biomarker in the patient is measured by RNA sequencing, RT-qPCR or IHC, and / or wherein, where a reference level of a biomarker is used, the reference level of a biomarker is measured by RNA sequencing, RT-qPCR or IHC.12. The GSPT1 degrader for use according to any previous embodiment, wherein the biomarker is selected from: mRNA, DNA, a polypeptide, a protein, phosphorylated forms of a protein and metabolites, for example, wherein the biomarker comprises mRNA or a protein.13. The GSPT1 degrader for use according to any previous embodiment, wherein the cancer of the patient is a solid cancer including but not limited to cancers of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx and salivary glands), neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, uterus, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castrationresistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu-NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy -insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma; and blood bourne (liquid) or hematological cancers, including but not limited to leukemias, lymphomas, and myelomas, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM), for example, wherein the cancer is breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu-NETs), liver cancer, stomach cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, skin cancer, brain cancer, cervical cancer, ovarian cancer, melanoma and head and neck cancer, for example, wherein:(A) the cancer is lung cancer, such as non-small cell lung cancer, squamous cell lung cancer, small cell lung cancer, or lung adenocarcinoma (LUAD), or(B) prostate cancer, for example, castration resistant prostate cancer or hormone sensitive prostate cancer, or alternatively for example, neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer, or(C) breast cancer, for example, HR-positive, HER2-negative breast cancer or ER-positive breast cancer, or(D) the cancer is diffuse large B-cell lympohoma.14. The GSPT1 degrader for use according to any previous embodiment, wherein the GSPT-1 degrader is a compound or pharmaceutically acceptable salt or stereoisomer thereof of formula I:I whereinX1is linear or branched C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, -OC(0)-Ci-4alkylamino, -C(O)O-Ci- salkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkoxy, C1-4 alkylhydroxy, -CH2F, - N(H)C(O)-O-CI-6 alkyl, and C(OH)(CF3); or X1together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, - C(O)O-Ci-6alkyl, -COOH, -Ci-6alkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy;X2is H, C3-6 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and C1-4 alkylhydroxy;L1is a covalent bond, linear or branched C1-6 alkyl;L2is a covalent bond, linear or branched C1-6 alkyl; andL3is a covalent bond, linear or branched C1-6 alkyl, -O-, or -C1-4 alkoxy, wherein linear or branched C1-6 alkyl is unsubstituted or substituted with one or more of halogen, for example, wherein:(i) X1is linear or branched -C1-6 alkyl, -C3-6 cycloalkyl, -C6-10 aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched -C1-4 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy; or X1together with the N atom of the carbamate forms a 5-6 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-4 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy; or(ii) X2is H, C3-6 cycloalkyl, Ce aryl, 5-6 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-4 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and -C1-4 alkylhydroxy; or(iii) L1is -CH2- or -CH(CH3)- and / or L2is a covalent bond, -CH2- or -CH(CH3)- and / or L3is a -CH2- , -O-, -CH2-O-, -CH2-CH2-O-.15. The GSPTI degrader for use of any one of embodiments 1 to 14, wherein the GSPT-1 degrader is compound 145 (shown below)or a pharmaceutically acceptable salt or stereoisomer thereof.EXAMPLESExample 1[000323] A PDX experiment was performed on mice bearing tumors, in order to determine the anti-tumor activity of the GSPT1 degrader, MRT-2359 (identified herein as compound 145), against a panel of 80 lung cancer PDX models representing three lung cancer subtypes: NSCLC without NE phenotype (N = 47), NSCLC with NE phenotype (N = 7) and SCLC (N =26).[000324] In brief, fresh tumor tissues from tumor bearing mice were harvested and cut into small pieces(approximately 2-3 mm in diameter). PDX tumor fragments were inoculated subcutaneously at the upper right flank of mice for tumor development. The randomization was started when the mean tumor size reached around 90-150 mm3. Total 12 mice were enrolled in each model, and were randomly allocated to 4 study groups as shown in the table below. Body weight and tumor volume were measured twice per week. Volume was expressed in mm3using the formula: V = (L x W x W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L).MC, methyl cellulose; SDD, spray-dried dispersion; ROA, route of administration; PO, oral (per os); QD,oncedafy (guaque die)Anti-tumor efficacy[000325] Efficacy was summarized for each model and dose regimen based on tumor volumes measurements as follows:Definitions[000326] mean tumor volume = mean of the three replicate tumor volume measurements for a given dose regimen[000327] nitiai = mean tumor volume of the drug-treated group before initiation of dosing of drug[000328] Tn= mean tumor volume of the drug-treated group on a given day Dn[000329] DTn= Tn- Tinitiai; mean tumor volume of drug treated group on Dn- mean tumor volume of the drug treated group before initiation of dosing of drug[000330] Cinitiai = mean tumor volume of the vehicle control group before initiation of dosing of vehicle[000331] Cn= mean tumor volume of vehicle control group on a given day Dn[000332] DCn= Cn- Cinitiai; mean tumor volume of vehicle control group on Dn- mean tumor volume of the vehicle control group before initiation of dosing of vehicleCalculations[000333] Best percent tumor volume changes were calculated as detailed below using the tumor volume values on the day n, on which the strongest anti-tumor activity (i.e. minimum tumor volume) was observed.[000334] If DTn> 0: Best percent tumor volume change = 100 * DTnI DCn[000335] This value is also known as “percent treatment / control (T / C)”.[000336] If DTn 0: Best percent tumor volume change = 100 * DTn / Tinitiai[000337] This value is also known as “percent regression”.Example 2[000338] Secondary gene expression markers that complement the use of a Myc transcription factor such as N-Myc were further investigated to further improve predictive performance and specificity to a response to a GSPT1 degrader using the information from the PDX models of Example 1 .[000339] High N-Myc mRNA expression is predictive of sensitivity to GSPT1 degrader, in NSCLC patient- derived xenograft (PDX) models and is a potential biomarker for patient selection in an ongoing clinical trial with GSPT1 degrader. In NSCLC PDX data, samples with high N-Myc mRNA expression had better response rates compared to those with low expression.[000340] Analysis of real-world lung cancer data suggested an N-Myc reference level of > 5.5 RNASeq Iog2(transcripts per million + 1) units (in TCGA median adjusted units) could be used to define N-Myc high expressors.[000341] In this context, TCGA median adjusted units means that the N-Myc expression of the PDX data has had the median N-Myc expression measured by RNA sequencing of the PDX models subtracted from it, and then had the median value of the N-Myc expression measured by RNA sequencing from the TCGAdata set added to it. In non-median adjusted units, the RNASeq reference level is 1 .6 Iog2(transcripts per million + 1) units.[000342] Based on regression analysis with RT-qPCR PDX data this corresponds to a value of roughly < 5.4 dCQ [95% Cl 4.9-5.9], RNA sequencing and RTqPCR analysis was performed as detailed in the description above.[000343] Subsequent ROC analysis of N-Myc expression and PDX response to GSPT1 degrader showed that a RT-qPCR cutoff of <6.7 dCQ yielded the best predictive performance with an AUC 0.64. At the optimal cutoff the true positive rate was 80% (12 / 15), the false positive rate was 50%, with 43% (12 / 28) response in the N-Myc high vs 16% (3 / 19) response in the N-Myc low models. Selecting samples based solely on N-Myc high expression includes several non-responders which results in higher false positive rates and lower specificity. Therefore, there is a need to identify other genes that can be used to categorise patients.Predictive biomarker analysis[000344] Differential expression analysis of RNASeq profiles from 28 N-Myc-high expressing NSCLC PDX samples (RT-qPCR dCq < 6.7) was performed by comparing the gene expression levels in responders with non-responders to GSPT1 degrader treatment. Here responders refer to the PDX models that showed tumor shrinkage upon treatment with GSPT1 degrader at the 10 mg / kg QD regimen (i.e. a negative best % tumor volume change). The RNAseq data were filtered to include 12,043 genes that were expressed in most of the samples (i.e. with an expression >0.5 Iog2(1+TPM) in at least 70% of the samples). Differential expression analysis comparing 12 responders to 16 non-responders was run using the limma package (version 3.56.2) [1] in the R statistical language (version 4.3.1) [2], Gene set enrichment analysis (GSEA) of the pre-ranked list of differentially expressed genes was performed with the Broad GSEA software v4.3.2 [3] using Msigdb Hallmark gene sets representing 50 well-characterized biological pathways [4].TCGA (The Cancer Genome Atlas) analysis[000345] In order to assess biomarker gene expression levels in patient lung adenocarcinoma (LUAD) tumor data from TCGA the cutoffs derived from the PDX NSCLC data were converted to median-centered values i.e. the change in expression relative to the median expression of each marker gene within the PDX NSCLC dataset (n=275). The cutoff for N-Myc high expression (RT-qPCR < 6.7 dCQ) corresponds to a median-centered value of > 1.1. The corresponding cutoff for NDRG1 low expression (RNASeq < 8 Iog2(1+TPM)) was < -0.9.Results[000346] Differential gene-expression analysis of N-Myc-high expressing NSCLC PDX samples comparing RNASeq profiles of responders with non-responders to GSPT 1 degrader treatment identifiedgenes predictive of sensitivity. Pathway enrichment analysis identified a set of genes induced in response to low oxygen levels (hypoxia) as the most negatively enriched set amongst the pathways tested (Hallmark Hypoxia, 164 genes, NES = -2.3, FDR q-value < 1e-6). The genes NDRG1 (N-Myc downstream regulated gene 1), ADM (adrenomedullin) and EGLN3 (EGL-9 family hypoxia inducible factor 3) were amongst the most differentially-expressed genes belonging to this gene set [Figure 1] Similar differential expression and pathway results were obtained when a more stringent N-Myc cutoff of < 5.5 dCQ was applied indicating that the results were robust to the precise definition of the N-Myc high population.[000347] The best predictive performance based on a ROC analysis of NDRG1 expression and PDX response was observed at a cutoff value < 8 Iog2(1 +TPM). Analysis of N-Myc and NDRG1 gene expression levels of 47 NSCLC PDX models in the study showed that the combination of high N-Myc and low NDRG1 expression specifically selected for responders to GSPT1 degrader treatment [Figure 2],[000348] Within the subset of high N-Myc expressing samples, low NDRG1 expression had high predictive value (PPV=100%, 8 / 8 and NPV = 80%, 16 / 20) selecting 8 / 12 (67%) of responders and excluding all non-responders (specificity = 100%, 16 / 16) [Figure 3]Biomarker expression in Lung adenocarcinoma patient tumors from TCGA[000349] The distribution and proportion of NDRG1 low and N-Myc high patient tumors were examined in TCGA lung adenocarcinoma samples (LUAD) using median-centered cutoff values derived from the PDX NSCLC data (see Methods). Based on this analysis 29% (169 / 576) of samples had N-Myc high expression (with a median centered expression > 1.1) and 17% (98 / 576) had NDRG1 low expression (with a median-centered expression < -0.9) [Figures 4A and 4B],RNA sequencing and IHC[000350] Similar analysis was performed with RNA sequencing and IHC as the tool to quantify the level of N-Myc. Both methods were performed as described in the description of the invention above.[000351] As shown in Figures 5A and 5B, both reference levels of 1 .6 Iog2(1+TPM) (in non-median adjusted units) for RNA sequencing and logic 1 TPS for IHC, alongside a NDRG1 reference level of 8 Iog2(1+TPM)), provide similar levels of specificity and sensitivity to the values for RT-qPCR.ADM and EGLN3[000352] Similar analysis was performed for ADM and EGLN3, which led to the determination of reference levels for each of these genes as 4.5 Iog2(1+TPM). As can be seen in Figs 6A-6C and Figs 7A- 7C, similar levels of specificity and sensitivity are achieved by these reference levels, using any of the three methods described.[000353] References:1 . Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015). “limma powers differential expression analyses for RNA-sequencing and microarray studies.” Nucleic Acids Research, 43(7), e47. doi:10.1093 / nar / qkv007.2. R Core Team (2023). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. <https: / / www.R-project.org / >.3. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005;102:15545-504. Arthur Liberzon, Aravind Subramanian, Reid Pinchback, Helga Thorvaldsdottir, Pablo Tamayo, Jill P. Mesirov, Molecular signatures database (MSigDB) 3.0, Bioinformatics, Volume 27, Issue 12, June 2011 , Pages 1739-1740, https: / / doi.org / 10.1093 / bioinformatics / btr260Example 3[000354] To confirm that low NDRG1 expression enriches for activity of MRT-2359 in MYCh'9htumors in patients, biomarker expression was analyzed in patient biopsy samples obtained from an ongoing clinical study of MRT-2359 titled “A Phase 1 / 2, Open-label, Multicenter Study of Oral MRT-2359 in Patients with MYC-driven and Other Selected Solid Tumors Including Lung Cancer and Diffuse Large B-cell Lymphoma”. This study included cohorts of patients with previously treated selected solid tumors, including lung cancer, high-grade neuroendocrine cancer of any primary site, diffuse large B-cell lymphoma (DLBCL), and tumors with L-MYC or N-MYC amplification.[000355] Inclusion criteria:Patients must have met all the following criteria to have been eligible for enrolment in the study:• Have a selected advanced solid tumor or DLBCL (listed above) for which there are no further standard therapeutic options available• Be age > 18 years and willing to voluntarily complete the informed consent process• A predicted life expectancy of > 3 months• An ECOG performance status < 2• Have measurable disease by RECIST 1 .1 (Eisenhauer et al., 2009) in case of solid tumors or Revised Response Criteria for Malignant Lymphoma (Phase 1 only) (Cheson et al., 2014) in case of DLBCLHave adequate organ function defined by the selected laboratory parameters:Abbreviations: ALT = alanine aminotransferase: ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time: AST = aspartate aminotransferase: INR = international normalized ratio: PT = prothrombin time; ULN = upper limit of normal.Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.Patients may be retested more than once during the screening period.• Have serum calcium and phosphate levels within normal limits, no worse than Grade 1 if abnormal, or correctable with supplements or other therapies. Hypercalcemia with serum calcium corrected for albumin < 13.5 mg / dL is allowed.• Have vitamin D levels of > 12 ng / mL, confirmed using a serum 25-hydroxy vitamin D test.• Have magnesium levels of Grade < 1 .• If female of childbearing potential, avoid becoming pregnant and agree to use acceptable methods of contraception after informed consent, throughout the study, and for 90 days after the last dose of MRT-2359• Male of reproductive potential must use an approved method of contraception from informed consent until 90 days after study discharge[000356] Exclusion Criteria:• Have received prior chemotherapy, definitive radiation, biological cancer therapy or any investigational agent within 21 days before the first dose of study treatment, or have any AEs that have failed to recover to baseline.• Have received bisphosphonates or denosumab within 14 days before the first administration of the study drug unless they were given for acute hypercalcemia.• Inability to swallow oral medication.• Be unable to take oral calcium and calcitriol.• Have received prior therapy with a GSPT1 degrader that was discontinued due to an AE• Have systolic blood pressure < 100 mmHg.• Have received prior auto-HCT and not fully recovered from effects of the last transplant• Have received prior allogeneic hematopoietic stem cell transplantation within past 6 months and / or have symptoms of graft-versus-host disease. Patients requiring minimal intervention such as topical steroids are eligible.• Have received a live vaccine within 90 days before the first dose of study treatment• COVID-19 immunization within 14 days of receiving the first dose of MRT-2359.• Current use of chronic systemic steroid therapy in excess of replacement doses (prednisone < 10 mg / day is acceptable).• Have clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug• Have anticipated requirement of any other form of antineoplastic therapy while on study.• Have a history of a second malignancy, unless controlled not requiring therapy• Have clinically active central nervous system involvement and / or carcinomatous meningitis. Patients with treated and stable brain metastases (not progressing for at least 4 weeks prior to enrollment) not requiring steroids are eligible.• Have a confirmed history of (non-infectious) pneumonitis that required steroids• Have known human immunodeficiency virus (HIV) unless the patient is on antiviral therapy with undetectable HIV RNA levels.• Have known hepatitis B or C infection(s) unless treated with undetectable hepatitis B DNA or hepatitis C RNA levels.• Have active infection requiring systemic intravenous therapy.• Have significant detectable infection or failure to fully recover from the effects of major surgery.• Clinically significant cardiac disease.• Have a history or current evidence of any other condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the fullduration of the study, or not be in the best interest of the participant to participate, in the opinion of the treating Investigator.• Be pregnant or breastfeeding.[000357] Patients enrolled in the study received doses between 0.5 mg and 2 mg of MRT-2359. In this analysis, patient response was measured in % change in target lesions per RECIST 1 .1 . Tumor biopsies were collected from 44 patients pre-treatment and analysed using RNA-sequencing and RT-qPCR.MethodsRNASeq Profiling[000358] RNA Seq profiling was performed on Formalin-Fixed Paraffin-Embedded (FFPE) tissue biopsies obtained from the clinical study of MRT-2359. Tumor RNA Seq profiling was performed on Formalin-Fixed Paraffin-Embedded (FFPE) tissue biopsies (extracted RNA). Sequencing coverage was at least 50 million paired-end reads, 2x150bp fragments on the Illumina NovaSeq sequencing system. For all samples, wet lab and sequencing quality control metrics were assessed and samples that did not reach a minimal acceptable level were excluded from downstream analysis. The raw reads were processed via a standard RNASeq pipeline using Salmon v1 .4 for pseudo-alignment and Gencode release 37 as the reference transcriptome.RT-qPCR method[000359] Real-time polymerase chain reaction (RT-qPCR) for determination of L-MYC and N-MYC mRNA expressions was performed on Formalin-Fixed Paraffin-Embedded (FFPE) tissue biopsies using LightCycler® 480 II System (Roche). Genomic DNA removed RNA was used to synthesize cDNA. LightCycler® 480 II System software was used to collect and analyze raw data. MYC expression level was reported as delta Cq normalized to two reference genes (SDH, and GUSB) for each sample.Biomarker Status[000360] The N / L Myc expression status of each sample was determined by mRNA expression via RT- qPCR. The cutoffs to define Myc-high samples were N-Myc < 3 dCQ or L-Myc < -1 dCQ. NDRG1 expression status was determined by RNASeq quantification with NDRG1-low samples defined as < 7 Iog2(1+TPM) which corresponds to a relative change of -1 .8 from the median value (8.8) across n=35 evaluated patients.Results[000361] Analysis of Myc expression levels of the pre-treatment biopsy samples from 44 patients, showed that 13 patients had high N / L-Myc expressing tumors as determined by mRNA expression viaRT-qPCR or DNA amplification by sequencing. These patients showed a range of responses to MRT- 2359 treatment (Figure 8A).[000362] The types of tumors seen in these 13 patients are set out below.[000363] NDRG1 gene expression levels were quantified via RNA-Seq profiling for 10 of the Myc-high patients. When the clinical responses to MRT-2359 were stratified by the NDRG1 expression levels, patients with Myc-high and NDRG1-low expressing tumors showed significantly better response than those with Myc-high and NDRG1-high expressing tumors (p=0.017, Wilcox test) (Figure 8B). Two of the patients that were classified as low NDRG1 Myc-high had SCLC and one patient had high-grade neuroendocrine bladder cancer.[000364] The impact of relaxing the N-Myc and NDRG1 cutoffs to match the pre-clinical values was evaluated. Lowering the N-Myc threshold to < 5.5 dCQ increased the number of Myc-high cases by six, all of which were non-responders with high NDRG1 expression levels. The difference in activity continued to be significant when the NDRG1 threshold was lowered from <7 Iog2(1+TPM) to <7.5. At a cutoff <8, the NDRG1-low group continued to show moderately better performance, however the difference was not statistically significant. Taken together, these results suggest that the results are robust to relaxing the thresholds.

Claims

CLAIMS1 . A GSPT1 degrader for use in a method of treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of the GSPT1 degrader to the patient, wherein the patient is biomarker negative for a gene induced in response to low oxygen levels selected from NDRG1 , ADM, EGLN3, or a combination thereof, wherein a biomarker negative patient is a patient with a level of that biomarker below a reference level, wherein the patient is biomarker positive for a Myc transcription factor selected from: N-Myc, L-Myc, c- Myc or a combination thereof, and wherein a biomarker positive patient is a patient with a level of that biomarker that is above a reference level.

2. The GSPT1 degrader for use according to claim 1 , wherein the gene induced in response to low oxygen levels is NDRG1.

3. The GSPT 1 degrader for use according to claim 1 or claim 2, wherein the Myc transcription factor is N-Myc.

4. The GSPT1 degrader for use according to any one of claims 1-3, wherein the method comprises determining the level of a biomarker for a gene induced in response to low oxygen levels in a biological sample obtained from the patient, and / or wherein the method comprises determining the level of a biomarker for a Myc transcription factor in a biological sample obtained from the patient.

5. The GSPT1 degrader for use according to any previous claim, wherein biomarker negative refers to a patient that has a level of a biomarker that is less than a reference level for the biomarker, and / or wherein biomarker positive refers to a patient that has a level of a biomarker that is more than a reference level for the biomarker.

6. The GSPT1 degrader for use according to claim 5, wherein the reference level for a biomarker for a Myc transcription factor is:(i) the median level of the biomarker of a distribution of control subjects; or(ii) the 70th percentile level of the biomarker of a distribution of control subjects.

7. The GSPT1 degrader for use according to claim 5, wherein the Myc transcription factor is N-Myc and wherein:(a) the reference level for N-Myc measured by RNA sequencing is:(i) about 1.1 Iog2(1 +TPM) above the median of a distribution of control subjects, or(ii) about 1 .6 Iog2(1 +TPM) above the median of a distribution of control subjects, or(iii) about 4.9 Iog2(1 +TPM), or(iv) about 5.5 Iog2(1 +TPM); and / or(b) the reference level for N-Myc measured by RT-qPCR is:(i) about 6.7 dCQ, or(ii) about 5.5 dCQ.or(iii) about 3 dCQ; and / or(c) the reference level for N-Myc measured by IHC is about 1 logl O(TPS); or wherein the Myc transcription factor is L-Myc and wherein the reference level for L-Myc measured by RT- qPCR is about -1 dCQ.

8. The GSPT1 degrader for use according to any one of claims 5-7, wherein the reference level for a biomarker for a gene induced in response to low oxygen levels is:(i) the median level of the biomarker of a distribution of control subjects; or(ii) the 20th percentile level of the biomarker of a distribution of control subjects.

9. The GSPTI degrader for use according to any one of claims 5-7, wherein:(a) the gene induced in response to low oxygen levels is NDRG1 , and the reference level measured by RNA sequencing is:(i) about 0.9 Iog2(1 +TPM) below the median of a distribution of control subjects, or(ii) about 1 .8 Iog2(1 +TPM) below the median of a distribution of control subjects, or(iii) about 12.3 Iog2(1 +TPM), or(iv) about 11 .4 Iog2(1 +TPM); and / or(b) the gene induced in response to low oxygen levels is ADM, and the reference level measured by RNA sequencing is:(i) about 1 .3 Iog2(1 +TPM) below the median of a distribution of control subjects, or(ii) about 6.8 Iog2(1 +TPM); and / or(c) the gene induced in response to low oxygen levels is EGLN3, and the reference level measured by RNA sequencing is:(i) about 1 .6 Iog2(1 +TPM) below the median of a distribution of control subjects, or(ii) about 7.7 log2(1 +TPM).

10. The GSPT1 degrader for use according to any one of claims 6-9, wherein, where the reference level is determined from a distribution of control subjects, the control subjects have cancer, optionally wherein:(i) the cancer of the control subjects is the same type as the cancer of the patient and optionally wherein the control subjects are taken from The Cancer Genome Atlas Program (TCGA) database; and / or(ii) the cancer of the control subjects is:(A) lung cancer, for example, non-small cell lung cancer (NSCLC), for example, lung adenocarcinoma (LUAD), and optionally wherein the control subjects are taken from The Cancer Genome Atlas Program (TCGA) database, or(B) prostate cancer, for example, castration resistant prostate cancer or hormone sensitive prostate cancer, or alternatively for example, neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer, or(C) breast cancer, for example, HR-positive, HER2-negative breast cancer or ER-positive breast cancer .11 . The GSPT 1 degrader for use according to any previous claim, wherein the level of a biomarker in the patient is measured by RNA sequencing, RT-qPCR or IHC, and / or wherein, where a reference level of a biomarker is used, the reference level of a biomarker is measured by RNA sequencing, RT-qPCR or IHC.

12. The GSPT1 degrader for use according to any previous claim, wherein the biomarker is selected from: mRNA, DNA, a polypeptide, a protein, phosphorylated forms of a protein and metabolites, for example, wherein the biomarker comprises mRNA or a protein.

13. The GSPT1 degrader for use according to any previous claim, wherein the cancer of the patient is a solid cancer including but not limited to cancers of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx and salivary glands), neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, uterus, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castration-resistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu-NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormoneinsensitive prostate cancer, chemotherapy -insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma; and blood bourne (liquid) orhematological cancers, including but not limited to leukemias, lymphomas, and myelomas, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM), for example, wherein the cancer is breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu-NETs), liver cancer, stomach cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, skin cancer, brain cancer, cervical cancer, ovarian cancer, melanoma and head and neck cancer, for example, wherein:(A) the cancer is lung cancer, such as non-small cell lung cancer, squamous cell lung cancer, small cell lung cancer, or lung adenocarcinoma (LUAD), or(B) prostate cancer, for example, castration resistant prostate cancer or hormone sensitive prostate cancer, or alternatively for example, neuroendocrine prostate cancer, castration-resistant neuroendocrine prostate cancer (NEPC), hormone refractory prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer or chemotherapy-insensitive prostate cancer, or(C) breast cancer, for example, HR-positive, HER2-negative breast cancer or ER-positive breast cancer, or(D) the cancer is diffuse large B-cell lympohoma.

14. The GSPTI degrader for use according to any previous claim, wherein the GSPT-1 degrader is a compound or pharmaceutically acceptable salt or stereoisomer thereof of formula I:I whereinX1is linear or branched C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, CMeF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-ealkyl, -OC(O)-Ci-ealkyl, -OC(0)-Ci-4alkylamino, -C(O)O-Ci- salkyl, -COOH, -Ci-ealkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkoxy, C1-4 alkylhydroxy, -CH2F, - N(H)C(O)-O-CI-6alkyl, and C(OH)(CF3); or X1together with the N atom of the carbamate forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, -N(H)C(O)-Ci-6alkyl, -OC(O)-Ci-6alkyl, - C(O)O-Ci-6alkyl, -COOH, -Ci-ealkylC(O)OH, -Ci-6alkylC(O)O-Ci-6alkyl, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy;X2is H, C3-6 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and C1-4 alkylhydroxy;L1is a covalent bond, linear or branched C1-6 alkyl;L2is a covalent bond, linear or branched C1-6 alkyl; andL3is a covalent bond, linear or branched C1-6 alkyl, -O-, or -C1-4 alkoxy, wherein linear or branched C1-6 alkyl is unsubstituted or substituted with one or more of halogen, for example, wherein:(i) X1is linear or branched -C1-6 alkyl, -C3-6 cycloalkyl, -Ce-io aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched -C1-4 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, NH2, C1- alkylhydroxy, and C1-4 alkoxy; or X1together with the N atom of the carbamate forms a 5-6 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-4 alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6 alkylamino, -CN, NH2, C1-4 alkylhydroxy, and C1-4 alkoxy; or(ii) X2is H, C3-6 cycloalkyl, Ce aryl, 5-6 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched C1-4 alkyl, -C1-4 alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, and -C1-4 alkylhydroxy; or(iii) L1is -CH2- or -CH(CH3)- and / or L2is a covalent bond, -CH2- or -CH(CH3)- and / or L3is a -CH2- , -O-, -CH2-O-, -CH2-CH2-O-.

15. The GSPTI degrader for use according to any one of claims 1 to 14, wherein the GSPT-1 degrader is compound 145 (shown below),or a pharmaceutically acceptable salt or stereoisomer thereof.

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