Treatment of Hematological Malignancies by Means of Satraplatin - Patent application

Abstract

The present invention relates to medical uses and methods of treatment using satraplatin, which are useful in the treatment of cancer, particularly hematological malignancies. The present invention also relates to methods for patient stratification and selection of treatment regimens, as well as diagnostic methods and biomarker panels.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to medical uses and methods of treatment using satraplatin, which are useful in the treatment of cancer, particularly hematological malignancies. The present invention also relates to methods for patient stratification and selection of treatment regimens, as well as diagnostic methods and biomarker panels. [Background technology]

[0002] Cisplatin, carboplatin and oxaliplatin are platinum-based drugs used worldwide for the treatment of cancer (1). All three drugs are administered intravenously, are primarily hydrophilic and are associated with similar or overlapping side effects, including nephrotoxicity, ototoxicity, neurotoxicity, cardiotoxicity, hematological toxicity, hepatotoxicity and gastrointestinal toxicity. Platinum toxicity is usually the main reason for modification of dosage or discontinuation of treatment. This is especially true for cisplatin, with the two most common nephrotoxic side effects including acute kidney injury and hypomagnesemia, which are reported to affect up to 90% of cisplatin-treated patients (2). Neurotoxicity and ototoxicity (60–90% of all patients) are the second and third most common platinum toxicities, with oxaliplatin causing primarily neurotoxicity and cisplatin causing ototoxicity. In an effort to develop less toxic and more tolerable platinum compounds, platinum(IV) complexes featuring an octahedral geometry with two additional ligand sites have been developed. These platinum(IV) complexes follow the classical prodrug concept, since their reduction to the corresponding platinum(II) analogues in tumor cells and induction of apoptotic cells is essential for their anticancer activity (3). Satraplatin (bis-acetato-amine-dichloro-cyclohexylamine-platinum) is a prime example of a novel platinum(IV) compound, developed as the first oral fourth-generation platinum compound with activity in platinum-sensitive and even some platinum-resistant preclinical models (4). Over the past two decades, satraplatin has been extensively studied in various in vitro and in vivo solid tumor models (5) and has consistently shown high activity (6).

[0003] Clinical development has been carried out in various cancer entities, including prostate cancer, which has traditionally been considered a platinum-resistant disease, with promising results. However, phase I / II satraplatin monotherapy trials in patients with hormone-refractory prostate cancer (HRPC) have demonstrated objective response rates of up to 31% (7). Based on these encouraging data, a large phase III registrational trial (SPARC) has been initiated to evaluate satraplatin in combination with prednisone versus prednisone and placebo as second-line therapy in patients with HRPC who have progressed after first-line chemotherapy. The trial met its primary endpoints and demonstrated a 33% reduction in the risk of progression or death (PFS; HR: 0.67; p < 0.001), a 36% reduction in the risk of pain progression, a PSA response (at least 50% PSA decline) of 25% vs. 12% (p = 0.001), and an objective RECIST response rate of 8% vs. 0.7% (p < 0.002). Unfortunately, no statistically significant overall survival (OS) benefit was observed (14.3 months vs. 14.3 months; HR: 0.98; p = 0.80), and clinical development was discontinued (8). As a result, satraplatin is not approved for the treatment of cancer.

[0004] Consistent with data from previous clinical trials, the SPARC study found that satraplatin-associated toxicities were generally mild, including moderate nausea, fatigue, anorexia, diarrhea, and changes in taste. Notably, the lack of nephrotoxicity, alopecia, or additional neurotoxicity makes this agent unique among its class of agents.

[0005] In view of the advantageous properties of satraplatin, including high activity and reduced toxicity, there is a clear clinical need for novel biomarkers that can be used to identify patients who would benefit from treatment with satraplatin. Summary of the Invention

[0006] The present invention provides a number of aspects related to pharmaceutical applications.

[0007] In a first aspect, the present invention provides satraplatin for use in the treatment of hematological malignancies, in patients identified as likely to benefit from such treatment by analysis of genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC1; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN.

[0008] In a second aspect, the present invention provides a method of treating hematological malignancies comprising administering satraplatin to a patient identified as likely to benefit from such treatment based on analysis of genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN.

[0009] In a third aspect, the present invention provides a method of treating a hematological malignancy, comprising: Obtaining a sample containing cells of a hematological malignancy; analyzing cells of the hematological malignancy for alterations associated with genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN; and administering satraplatin to patients identified based on such analysis as likely to benefit from such treatment; The present invention provides a method comprising:

[0010] In a fourth aspect, the present invention provides satraplatin for use in the treatment of hematological malignancies associated with loss of the 9p21 locus.

[0011] In a fifth aspect, the present invention provides satraplatin for use in the treatment of a hematological malignancy associated with a deficiency in a gene selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1. The deficiency may be a copy number loss for the gene.

[0012] In a sixth aspect, the present invention provides satraplatin for use in the treatment of hematological malignancies associated with mutations in genes selected from the group consisting of BCL2; AOC1; BOC1; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1.

[0013] In a seventh aspect, the present invention provides satraplatin for use in the treatment of hematological malignancies associated with high expression of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; or WRN.

[0014] In suitable embodiments of any of the first through seventh aspects of the invention, the hematological malignancy may be selected from the group consisting of lymphoma; myeloma; and leukemia. Particular forms of such hematological malignancies are described elsewhere herein.

[0015] In an eighth aspect, the present invention provides satraplatin for use as a second line therapy in the treatment of cancer non-responsive to immune checkpoint therapy.

[0016] In a ninth aspect, the present invention provides a method of treating a cancer non-responsive to immune checkpoint therapy comprising administering satraplatin to a patient suffering from such a cancer.

[0017] The present invention also provides numerous embodiments relating to patient stratification / selection of treatment regimens.

[0018] In a tenth aspect, the present invention provides a method for determining the likelihood that a hematological malignancy will respond favorably to satraplatin treatment, comprising: analyzing cells of the hematological malignancy for alterations associated with genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN; wherein identification of an alteration in the analyzed gene indicates that the hematological malignancy is likely to respond favorably; A method is provided.

[0019] The present invention also provides a number of embodiments relating to diagnostic methods.

[0020] In an eleventh aspect, the present invention provides a method comprising analyzing at least one gene selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN in cells of a hematological malignancy from a patient, wherein When the gene is a gene located at the 9p21 locus, the analyzing may include determining whether a deletion is present, e.g., by assessing copy number; When the gene is selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, the analyzing includes assaying for mutations in the gene; and When the gene is selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, the analyzing includes assaying for elevated expression of the gene.

[0021] In a twelfth aspect, the present invention provides a method comprising analyzing cells of a hematological malignancy from a patient for the presence of at least one genetic mutation selected from the group shown in Table 1 and Table 2.

[0022] The present invention also provides a number of embodiments related to biomarker panels.

[0023] In a thirteenth aspect, the present invention provides a signature panel characteristic of sensitivity of a hematological malignancy to treatment with satraplatin, comprising: Loss of copy number of at least one gene selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1; and / or A mutation in at least one gene selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1; and / or High expression of at least one gene selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN. A panel including:

[0024] In a fourteenth aspect, the present invention provides a signature biomarker panel characteristic of susceptibility of a hematological malignancy to treatment with satraplatin, the panel comprising at least one genetic mutation selected from the group shown in Tables 1 and 2.

[0025] In suitable embodiments of any of the first through seventh, tenth, or eleventh through fourteenth aspects of the invention, the hematological malignancy may be selected from the group consisting of lymphoma; myeloma; and leukemia. Particular forms of such hematological malignancies are described elsewhere herein.

[0026] The genetic mutation spectrum of cell lines and therefore tumor diseases is highly diverse and numerous. It is not possible a priori to predict the presence of mutations / deletions / methylations as biomarkers for enhanced response and therefore increased efficacy. This requires integrated and complex analyses such as those described herein in the context of hematological malignancies.

[0027] Furthermore, data are inconsistent regarding the prognostic significance of MTAP. Studies have been published showing that in a number of cancers (NSCLC, mantle cell lymphoma, Ewing's sarcoma) loss of MTAP worsens the prognosis of patients undergoing chemotherapy. Other authors have performed genetic analyses to find relevant biomarkers to predict cancer treatment response. An example can be a study of ovarian cancer, where MTAP was considered as a relevant biomarker and therefore analyzed. However, no association between MTAP deletion and response to treatment was found.

[0028] The present invention is not obvious because, at least in view of the complex data situation outlined above, it is not possible for one skilled in the art to predict a priori which biomarkers would be associated with optimized efficacy of satraplatin.

[0029] Throughout the description and claims of this specification, the term "comprising" and variations thereof mean "including, but not limited to," and they are not intended to (and do not exclude) other moieties, additives, components, integers, or steps.

[0030] Throughout the description and claims of this specification, the singular encompasses the plural unless the context dictates otherwise. In particular, where the indefinite article is used, it is understood that the specification contemplates both the plural and the singular, unless the context dictates otherwise.

[0031] It is understood that any feature, integer, property, compound, chemical moiety or group described in connection with a particular aspect, embodiment or example of the invention also applies to any other aspect, embodiment or example described herein, unless inconsistent.

[0032] Various aspects of the invention are described in further detail below. [Brief description of the drawings]

[0033] Embodiments of the invention are further described below with reference to the accompanying drawings, in which: [Figure 1] Figure 1 shows the cytotoxic activity of satraplatin in tumor cell lines of different origins as determined by the listed AUC values. The median AUC value across all tested cell lines is 2.35. Tumor entities are indicated on the x-axis. Significantly higher activity was observed in hematopoietic and lymphoid malignancies when compared to solid organ cancers (ANOVA p-value = 2.3e-08). [Diagram 2] Figure 2 shows the enhanced killing of hematological tumor cell lines using satraplatin compared to cisplatin. The delta of IC50 (μM) values ​​of satraplatin minus cisplatin is shown. [Diagram 3] Figure 3 shows a volcano plot of gene expression-AUC correlation analysis across hematopoietic and lymphoid cancers. Genes conferring increased satraplatin sensitivity are depicted on the left and genes conferring resistance on the right. Genes reaching statistical significance are shown as black squares (sensitive) and black triangles (resistant). [Figure 4]Figure 4 shows a volcano plot of signature genes separating mutation-level sensitive and insensitive groups in hematopoietic and lymphoid cancers. Genetic mutations conferring increased satraplatin sensitivity are depicted on the left, and gene mutations conferring resistance are depicted on the right. Genes reaching statistical significance are shown as black squares (sensitive) and black triangles (resistant). [Diagram 5] Figure 5 shows a volcano plot of signature genes separating high (left) and low (right) susceptibility groups at the level of DNA copy number loss in hematopoietic and lymphoid cancers. Genes that reach statistical significance are shown as black boxes (susceptibility). [Figure 6] Figure 6 shows the correlation of satraplatin IC50 activity (μM) (x-axis) against the cell line list tested (y-axis). Cell lines are listed according to satraplatin sensitivity, with the most sensitive at the top. The MTAP status of individual cell lines is coded as follows: Grey / Gray = MTAP wt; Black = MTAP lost; White = status undetermined / unknown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The patent, scientific and technical literature referenced herein attests to the knowledge available to those skilled in the art at the time of filing. The entire disclosures of issued patents, published and pending patent applications, and other publications cited herein are incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the event of any inconsistencies, the present disclosure will control.

[0035] Various aspects of the invention are described in further detail below.

[0036] Detailed Description of the Invention The present invention is based, at least in part, on the inventors' identification of a number of gene-associated alterations that, when present in cells of a hematological malignancy, are indicative of sensitivity of that cancer to the chemotherapy drug satraplatin.

[0037] Identifying markers capable of identifying hematological cancers sensitive to satraplatin offers an important advantage in that treatment with satraplatin can be targeted to patients who will derive therapeutic benefit from the treatment. It is well recognized that the ability to target treatment to appropriate patients is important both in achieving optimal clinical outcomes (by ensuring that patients are provided with a high probability of efficacious treatment from the earliest stage of treatment) and in avoiding unnecessary or ineffective treatment using therapeutic agents that do not achieve the desired outcome (treatment that may cause unnecessary side effects as well as unduly delay successful treatment).

[0038] The genetic alterations of interest are described more fully below, but certain key alterations noted by the inventors include defects such as copy number losses for genes at the 9p21 locus (particularly MTAP, but also CDKN2B, CDKN2A and DMRTA1), mutations in a subset of genes (exemplified but not limited to BCL2), and high expression of a panel of proteins including TULP3. Each of the identified alterations, when present in cells of a hematological malignancy, indicates that the cancer is more likely to be successfully treated with satraplatin.

[0039] The discovery that cancers with loss of the 9p21 locus (including MTAP, CDKN2B, CDKN2A and DMRTA1) are more sensitive to treatment with satraplatin identifies this agent as highly useful for treating these cancers. Because loss of 9p21 confers resistance to immune checkpoint therapies that might otherwise be used to treat such cancers, satraplatin provides a needed second-line therapy for cancers that might otherwise prove difficult to treat.

[0040] It will therefore be appreciated that the inventors' discovery enables new methods of treatment and pharmaceutical uses of satraplatin, and also enables new methods by which patients can be stratified and appropriate cancer treatments selected. The discovery also makes available new methods useful in the diagnosis of cancer (and particularly hematological malignancies), as well as new and useful panels of biomarkers. These various aspects of the invention are described in more detail under the appropriate headings below.

[0041] Treatment methods and medical uses of the invention In its first to ninth aspects the present invention relates to a method of treatment using satraplatin or to the pharmaceutical use of satraplatin. The defined methods of treatment and pharmaceutical uses relate to the use of satraplatin in the treatment of certain forms of cancer.

[0042] In particular, the first to seventh aspects of the invention relate to methods of treatment and pharmaceutical uses useful in the treatment of hematological malignancies that may be characterized by reference to genetic alterations or protein overexpression. The eighth and ninth aspects of the invention are directed to methods of treatment and pharmaceutical uses used in the treatment of cancers that may be characterized by reference to resistance to other forms of cancer therapy, in particular lack of response to immune checkpoint therapy.

[0043] These aspects of the invention are based, at least in part, on the inventors' identification of a number of genetic alterations that increase or decrease the sensitivity of cancer cells, such as the sensitivity of hematological malignancies, to satraplatin, and thus indicate that patients suffering from cancers harboring such genetic alterations will or will not benefit from treatment with the agent. The identified alterations are described in more detail elsewhere.

[0044] The inventors are the first to recognize that identifying the presence or absence of these alterations in a hematological malignancy provides valuable guidelines as to how the hematological malignancy in question may be effectively treated.

[0045] In the first and second embodiments of the present invention, the analysis of genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN makes it possible to identify patients suffering from hematological malignancies who are likely to benefit from cancer treatment using satraplatin. The analysis may identify alterations associated with one or more genes that show increased sensitivity to satraplatin, suggesting that the hematological malignancies will respond well to this chemotherapeutic agent.

[0046] In the method of the third aspect of the invention, cells from the hematological malignancy of the patient are obtained from a sample, and the sample is analyzed for genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN. Furthermore, in cases where an alteration associated with one or more genes is identified, this indicates that the hematological malignancy will respond well to satraplatin. Satraplatin is then administered to patients identified in this manner as likely to benefit from such treatment.

[0047] In a suitable embodiment of any of the first, second or third aspects of the present invention, the gene is a gene located at the 9p21 locus, and the analysis identifies a defect (such as a copy number loss) associated with the gene. For example, the gene may be selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1, and the analysis may identify a defect, such as a copy number loss, associated with the gene. In such an embodiment, particularly in an embodiment in which a copy number loss is observed, the hematological malignancy may be suitably selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; and multiple myeloma.

[0048] In suitable embodiments of any of the first, second or third aspects of the invention, the gene is selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, and the analysis identifies mutations in the gene. Specific examples of mutations for which analysis may be performed are described elsewhere herein. In these embodiments, the hematological malignancy may suitably be selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+.

[0049] In a further suitable embodiment of any of the first, second or third aspects of the invention, the gene is selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies elevated expression of the gene.

[0050] The fourth, fifth, sixth and seventh aspects of the present invention relate to the pharmaceutical use of satraplatin in a subpopulation of patients suffering from hematological malignancies. In the case of the fourth aspect, the subpopulation is one in which the hematological malignancies are associated with a loss of the 9p21 locus. In the fifth aspect, the subpopulation is one in which the hematological malignancies are associated with a defect in a gene selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1 (such as a reduction in the copy number of one or more genes selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1). In the sixth aspect, the subpopulation is one in which the hematological malignancies are associated with a mutation in a gene selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1. In a seventh embodiment, the subpopulation is one in which the hematological malignancy is associated with high expression of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; or WRN. Each of these subpopulations represents a newly identified group of patients who may derive particular benefit from treatment of the hematological malignancy with satraplatin.

[0051] The eighth and ninth aspects of the present invention are directed to a method of treatment and a medical use, wherein satraplatin is used as a second line therapy in the treatment of cancers non-responsive to immune checkpoint therapy.

[0052] The cancer in question may no longer respond to immune checkpoint therapy, or it may never have responded to immune checkpoint therapy.

[0053] The cancer for which satraplatin is used as second-line therapy may have been previously treated with an anti-PD-1 and / or anti-PD-L1 agent, for example, the cancer may have been previously treated with pembrolizumab.

[0054] It is known that loss of all or part of the 9p21 locus can alter the immune response within the tumor microenvironment such that immune checkpoint therapy is ineffective (Han et al., Nat Commun. 2021 Sep 23;12(1):5606). This aspect of the invention is based on the inventors' novel observation that such alterations also increase the sensitivity of cancer cells to satraplatin. Thus, satraplatin is useful in the treatment of cancers that are unresponsive to immune checkpoint therapy, providing patients with an important opportunity for further treatment of these cancers that may otherwise prove difficult to manage clinically. Those skilled in the art can identify methods by which a cancer can be determined to be unresponsive to immune checkpoint therapy, including the use of suitable in vitro assays.

[0055] Suitably, the cancer that may benefit from treatment according to the eighth or ninth aspects of the invention may be a solid tumour, such as a solid tumour described elsewhere in this disclosure. Alternatively, the cancer may be a haematological malignancy.

[0056] Patient stratification and selection of treatment regimens A tenth aspect of the present invention relates to methods that may be used to determine an appropriate course of treatment for use in the management of hematological malignancies. In particular, this aspect of the invention provides a method by which it can be determined whether a hematological malignancy is likely to respond favorably to satraplatin.

[0057] The method of the tenth aspect of the invention again takes advantage of the inventors' identification of alterations associated with genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN, which can predict whether cells of a hematological malignancy will be sensitive to satraplatin. In the case of this aspect of the invention, this information is used to determine that hematological malignancies in which such alterations are found are likely to respond well to treatment with satraplatin.

[0058] In a suitable embodiment of the tenth aspect of the invention, the gene is a gene located at the 9p21 locus, and analysis determines whether a defect exists with respect to the gene. For example, the gene may be selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1, and analysis determines whether a defect exists in one or more of these genes.

[0059] In a suitable embodiment of the tenth aspect of the present invention, the gene is a gene located at the 9p21 locus, and the analysis identifies a decrease in the copy number of the gene.For example, the gene can be selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1, and the analysis identifies a decrease in the copy number of the gene.In such an embodiment, the hematological malignancy can be suitably selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma.

[0060] In suitable embodiments of the tenth aspect of the invention, the gene is selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, and the analysis identifies mutations in the gene. Specific examples of mutations that may be analyzed are described elsewhere herein. In these embodiments, the hematological malignancy may suitably be selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+.

[0061] In a more suitable embodiment of this aspect of the invention, the gene is selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies elevated expression of the gene.

[0062] The above methods are intended to identify treatments that will kill cells of hematological malignancies, thereby providing a treatment for the disease.

[0063] A method according to the tenth aspect of the invention may include the step of selecting an appropriate course of treatment for the patient.Such a method may include the step of prescribing a treatment for the patient based on the results of the method.

[0064] The method according to the tenth aspect of the invention may also comprise, in appropriate embodiments, the further step of providing treatment using an agent identified as suitable. Thus, the method of the tenth aspect of the invention may optionally comprise the further step of providing treatment with satraplatin, depending on the results reached.

[0065] Methods useful in the diagnosis of hematological malignancies Both the eleventh and twelfth aspects of the invention provide methods of analyzing cells of a hematological malignancy, which may be useful to clinicians or other parties providing care to patients with hematological malignancies.

[0066] In the method of the eleventh embodiment, the analysis is performed on at least one gene selected from the group consisting of genes located at 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN. The analysis can be performed to identify the alteration associated with said at least one gene.

[0067] Where the gene is a gene located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1), the analysis may include determining whether a defect is present with respect to the selected gene. Defects in the context of the present invention, and how they may be analyzed, are described elsewhere in this disclosure.

[0068] For example, when the gene is a gene located at 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1), the analysis can include evaluating copy number changes, and when changes exist, identifying the copy number changes.For the purpose of the present invention, copy number loss can be considered as a defect for the gene in question.In such an embodiment, the hematological malignancy can be selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma.

[0069] When the gene is selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, the analysis includes assaying for mutations in the gene. Specific mutations in these genes are described elsewhere herein, and one or more of these genes may be analyzed to determine the presence or absence of one or more of the specific mutations disclosed in practicing the method according to this aspect of the invention. In an embodiment of this type of invention, the hematological malignancy may be selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+.

[0070] When the gene is selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, the analysis includes assaying high expression of the gene. Methods that can be used in performing such analysis are described elsewhere in this disclosure.

[0071] In the event that the analysis is "positive" (i.e., the analysis indicates the presence of a defect (such as a copy number alteration, reduced gene expression, or absent gene expression), the presence of a mutation, or the presence of high expression, as appropriate), this may indicate that the hematological malignancy in question would benefit from treatment with satraplatin.

[0072] The methods of the eleventh and twelfth aspects of the invention may optionally further comprise the step of obtaining cells of the hematological malignancy being tested. The cells may be obtained as part of a blood sample, or by other suitable means known to those of skill in the art.

[0073] The biomarker panel of the present invention The thirteenth and fourteenth aspects of the present invention provide a signature biomarker panel, the presence of which in a sample of a hematological malignancy can characterize the malignancy as sensitive to treatment with satraplatin.

[0074] The biomarker panel of the thirteenth aspect of the present invention is defined with reference to a number of gene-related alterations indicative of sensitivity to satraplatin treatment. Such alterations include loss of copy number of at least one gene selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1. Alternatively or additionally, such alterations may include mutations in at least one gene selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1. The alterations may further or alternatively include high expression of at least one gene selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN.

[0075] The biomarker panel of the fourteenth aspect of the present invention is defined by reference to the presence of one or more of a number of genetic mutations that are indicative of sensitivity of a hematological malignancy to treatment with satraplatin, these mutations being set out in Tables 1 and 2.

[0076] The signature biomarker panel of the present invention provides newly identified combinations of biomarkers that are useful for characterizing hematological conditions in a manner that facilitates their treatment. These combinations, and their relevance in determining the susceptibility of hematological conditions to treatment with satraplatin, have not been previously recognized or reported.

[0077] A biomarker panel according to either the thirteenth or fourteenth aspects of the invention includes at least one of the markers listed in Tables 1 and 2, and may include all of the markers listed in Tables 1 and 2.

[0078] Relevant biomarkers may be suitably determined based on the diagnosis of the hematological malignancy of interest (which may be performed using conventional methods, such as via histology or genetic markers), as considered in conjunction with the present disclosure.

[0079] The biomarker panels of the invention may include all of the markers listed in Tables 1 and 2 for the hematological malignancy of interest, or may include a subset of such markers.

[0080] By way of example only, the biomarker panel used for the hematological malignancy DLBCL NOS (GCB) is: one or more mutations in genes selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; ETNK2; SLFN5; BRCA2; FRG1B; KIAA1683; USP22; and AP4E1; and / or Copy number loss or copy number loss of one or more genes selected from the group consisting of MTAP; CDKN2B; and CDKN2A. may include.

[0081] A biomarker panel according to this embodiment of the invention may comprise 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more of the above mutations. Suitably, such a biomarker panel may comprise all of the above mutations.

[0082] Alternatively or additionally, a biomarker panel according to this embodiment of the invention may include one or more, or two or more of the above copy number losses. Suitably, such a biomarker panel may include the above copy number losses.

[0083] The biomarker panel for use with the hematological malignancy DLBCL NOS (ABC) is One or more mutations in a gene selected from the group consisting of BCL2; and DDX3X. may include.

[0084] A biomarker panel according to this embodiment of the invention may include one or both of the above mutations.

[0085] A biomarker panel for use with the hematological malignancy Burkitt's lymphoma includes: one or more mutations in genes selected from the group consisting of BCL2; AOC1; BOC; DDX3X; BRCA2; FRG1B; USP22; and AP4E1; and / or Copy number losses or losses of MTAP, CDKN2B, CDKN2A, and DMRTA1, respectively may include.

[0086] A biomarker panel according to this embodiment of the invention may comprise one or more, two or more, three or more, four or more, five or more, six or more, or seven or more of the above mutations. Suitably, such a biomarker panel may comprise all of the above mutations.

[0087] Alternatively or additionally, a biomarker panel according to this embodiment of the invention may include one or more, two or more, or three or more of the above copy number losses. Suitably, such a biomarker panel may include all of the above copy number losses.

[0088] The biomarker panel for use in the hematological malignancies ALCL ALK+ is: one or more mutations in a gene selected from the group consisting of DDX3X; SLFN5; and AP4E1; and / or Copy number losses or losses of MTAP, CDKN2B, CDKN2A, and DMRTA1, respectively may include.

[0089] A biomarker panel according to this embodiment of the invention may comprise one or more, or more than one, of the mutations described above. Suitably, such a biomarker panel may comprise all of the mutations described above.

[0090] Alternatively or additionally, a biomarker panel according to this embodiment of the invention may include one or more, two or more, or three or more copy number losses as described above. Suitably, such a biomarker panel may include all of the copy number losses as described above.

[0091] A biomarker panel for use with the hematological malignancy multiple myeloma includes: One or more mutations in a gene selected from the group consisting of BRCA2; and FRG1B; and / or Copy number loss or copy number loss of one or more genes selected from the group consisting of MTAP; CDKN2B; and CDKN2A may include.

[0092] A biomarker panel according to this embodiment of the invention may include one or both of the above mutations.

[0093] Alternatively or additionally, a biomarker panel according to this embodiment of the invention may include one or more, or more than one of the above copy number losses. Suitably, such a biomarker panel may include all of the above copy number losses.

[0094] A biomarker panel for use with the hematological malignancy mantle cell lymphoma includes: One or more mutations in FRG1B and / or Copy number losses or losses of MTAP, CDKN2B, CDKN2A, and DMRTA1, respectively may include.

[0095] A biomarker panel according to this embodiment of the invention may comprise one or more, two or more, or three or more of the above copy number losses. Suitably, such a biomarker panel may comprise all of the above copy number losses.

[0096] Alternatively or additionally, such a biomarker panel may also include the mutations set forth above.

[0097] The biomarker panel for use with the hematological malignancy CTCL is Copy number losses or losses of MTAP, CDKN2B, CDKN2A, and DMRTA1, respectively may include.

[0098] A biomarker panel according to this embodiment of the invention may include one or more, two or more, or three or more copy number losses. Suitably, such a biomarker panel may include all of the copy number losses listed above.

[0099] Cells of a hematological malignancy may contain one or more markers of the biomarker panel according to the invention. The presence of such markers may characterize the hematological malignancy as sensitive to treatment with satraplatin. Alternatively, if cells of a hematological malignancy do not contain one or more markers of the biomarker panel according to the invention, this may characterize the hematological malignancy as not sensitive to treatment with satraplatin. The considerations presented above with respect to the biomarker panels associated with the particular hematological malignancies listed may also apply to biomarkers that may be present in cells representative of such malignancies.

[0100] Alterations associated with the gene or locus of interest: mutations, high expression, and gene deletions and locus losses The present inventors have identified a number of gene-associated alterations that, when present in cells of a hematological malignancy, provide useful guidance regarding appropriate treatment regimens that can be used to treat the hematological malignancy. These alterations include gene mutations, high gene expression, and gene deletions. Each of these is further defined below.

[0101] Gene-associated alterations can be examined for genes of interest, either alone or in independently selected combinations.

[0102] The inventors have also identified that loss of specific genetic loci is associated with beneficial changes in the sensitivity of hematological malignancies to satraplatin, which loss can be examined in combination with one or more of the genetic associated changes mentioned herein.

[0103] Specific details of exemplary alterations identified by the inventors are set forth below, and the considerations in the paragraphs below should be used, unless the context requires otherwise, when interpreting appropriate alterations related to these genes in the various aspects and embodiments of the invention.

[0104] Loss of the 9p21 locus or associated genes The present inventors have found that loss of the 9p21 locus in cells of hematological malignancies is associated with an increase in the sensitivity of the malignancies to satraplatin. Thus, loss of the 9p21 locus, or loss of genes associated with this locus, can be used as an indicator that a hematological malignancy will respond well to treatment with satraplatin.

[0105] mutation The inventors have identified that mutations in one or more of the genes BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1 present in cells of hematological malignancies increase the sensitivity of these cells to satraplatin, and therefore this compound may be effectively used in the treatment of hematological malignancies.

[0106] Mutations of interest for any of these genes can be any changes in the gene present in cells of hematological malignancies compared to wild-type genes. Such changes may not cause changes in protein gene products ("silent" mutations) or may cause detectable changes in gene products. Analysis of gene mutations can be performed by determining the presence of changes in the nucleic acid sequence of the gene or gene transcript, or by determining the presence of changes in the gene product (for this purpose, it can also include determining the absence of the gene product).

[0107] By way of example, a mutation may include one or more of the following changes in the nucleic acid sequence of a gene or gene transcript compared to a wild-type gene (or transcript thereof): a deletion; an insertion; a substitution; or a truncation (particularly with respect to gene transcripts). Such a mutation may result in a change in the gene transcript or gene product, or may alter the transcription or translation process, such as altering the splicing of the gene transcript such that an alternative gene product is produced (e.g., generating a splice acceptor variant).

[0108] Similarly, a mutation can include one or more of the following changes in the amino acid sequence of the gene product, as compared to the sequence of the product of the wild-type gene: a deletion; an insertion; a substitution; a truncation; or the absence of a gene product.

[0109] The mutations may be analyzed for one or more genes independently selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1. Preferably, the mutations analyzed relate to BCL2 and / or AOC1 and / or BOC and / or DDX3X and / or CRYBG3 and / or SLFN5 and / or ETNK2 and / or BRCA2 and / or USP22 and / or KIAA1683 and / or AP4E1.

[0110] In a suitable embodiment, the mutation is related to BCL2. In a suitable embodiment, the mutation is related to AOC1. In a suitable embodiment, the mutation is related to BOC. In a suitable embodiment, the mutation is related to DDX3X. In a suitable embodiment, the mutation is related to CRYBG3. In a suitable embodiment, the mutation is related to SLFN5. In a suitable embodiment, the mutation is related to ETNK2. In a suitable embodiment, the mutation is related to BRCA2. In a suitable embodiment, the mutation is related to USP22. In a suitable embodiment, the mutation is related to KIAA1683. In a suitable embodiment, the mutation is related to AP4E1. In each of these cases, the mutation can be analyzed for the identified gene alone or for the identified gene in combination with one or more other genes. In each of these cases, the mutation can be present for the identified gene alone or for the identified gene in combination with one or more other genes.

[0111] Details of the specific mutations that the inventors have identified as being particularly associated with satraplatin sensitivity in particular cell lines, and therefore in the hematological malignancies that these cell lines represent, are provided in Tables 1 and 2.

[0112] Throughout this specification, references to mutations in BCL2, AOC1, BOC, DDX3X, CRYBG3, SLFN5, ETNK2, BRCA2, USP22, KIAA1683 or AP4E1 may be taken as encompassing any of the mutations in these various genes shown in Tables 1 and 2, unless the context requires otherwise.

[0113] Similarly, references herein to mutations associated with a particular form of hematological malignancy may be interpreted as encompassing any of the mutations identified in Table 1 or Table 2 as being particularly associated with cell lines representative of the hematological malignancy in question. [Table 1-1] [Table 1-2] [Table 1-3] [Table 2-1] [Table 2-2] [Table 2-3]

[0114] Mutations related to BCL2 may be particularly relevant for hematological malignancies selected from the group consisting of DLBCL NOS (GCB); DLBCL NOS (ABC); and Burkitt's lymphoma.

[0115] Mutations in BCL2 that are relevant for the hematological malignancy DLBCL NOS (GCB) may be selected from: • Mutations causing a change at position 200 of the gene product, e.g. a G to A change at position 60985302 of chromosome 18 causing a G to S change at position 200 of the gene product; • Mutations causing a change at position 48 in the gene product, e.g., an A to T change at position 60985758 on chromosome 18 causing an I to F change at position 48 in the gene product; • A mutation causing a change at position 129 in the gene product, e.g. a C to T change at position 60985515 on chromosome 18 causing an R to C change at position 129 in the gene product; • A mutation causing a change at position 59 in the gene product, e.g. a C to A change at position 60985725 on chromosome 18 causing a P to T change at position 59 in the gene product; • A silent mutation at position 60985876 on chromosome 18, e.g., a C to A change; • A silent mutation at position 60985357 on chromosome 18, e.g., a C to G change; • A mutation causing a change at position 59 in the gene product, e.g. a G to A change at position 6098572 on chromosome 18 causing a P to L change at position 59 in the gene product; • A silent mutation at position 60985351 on chromosome 18, e.g., a C to G change; • Mutations causing a change at position 47 in the gene product, e.g. a C to T change at position 60985760 on chromosome 18 causing a G to D change at position 47 in the gene product; • Mutations that prevent expression of a gene product, e.g., an A to C change at position 60986612 on chromosome 18; • A mutation that prevents expression of the gene product, e.g., a deletion of A at position 60986384 on chromosome 18; and • A mutation causing a change at position 4 of the gene product, for example a C to T change at position 60985890 of chromosome 18 causing an A to T change at position 4 of the gene product.

[0116] Mutations in BCL2 that are relevant for the hematological malignancy DLBCL NOS (ABC) can be selected from: • A mutation causing a change at position 198 in the gene product, e.g. a C to T change at position 60985307 on chromosome 18 causing an A to V change at position 198 in the gene product.

[0117] Mutations in BCL2 that are relevant for the hematological malignancy Burkitt's lymphoma can be selected from: • A silent mutation at position 60985521 on chromosome 18, e.g., a G to T change; • A silent mutation at position 60985549 on chromosome 18, e.g., a G to A change; • A silent mutation at position 60985492 on chromosome 18, e.g., a C to T change; • A silent mutation at position 60985399 on chromosome 18, e.g., a C to T change; • A silent mutation at position 60985480 on chromosome 18, e.g., a G to A change; • A silent mutation at position 60985410 on chromosome 18, e.g., a G to T change; and • A silent mutation at position 60985348 on chromosome 18, e.g., a G to A change.

[0118] Our discovery that mutations in the BCL2 gene are associated with increased sensitivity to satraplatin is surprising because such mutations have not previously been identified as markers of sensitivity to other platinum-based chemotherapy compounds, such as cisplatin. Indeed, many of the mutations identified by the inventors as indicative of sensitivity of hematological malignancies to treatment with satraplatin appear to be specific to sensitivity with respect to this agent, rather than to more general platinum-based chemotherapies.

[0119] Mutations in AOC1 may be particularly relevant for hematological malignancies selected from the group consisting of: multiple myeloma; DLBCL NOS (GCB); and Burkitt's lymphoma.

[0120] Mutations in AOC1 that are relevant for the hematological malignancy multiple myeloma can be selected from: • Mutations causing a change at position 235 in the gene product, e.g. a C to G change at position 150554261 of chromosome 7 causing a Q to E change at position 235 in the gene product (a mutation seen in two different multiple myeloma cell lines, and in Burkitt's lymphoma, as mentioned below).

[0121] Mutations in AOC1 that are relevant for the hematological malignancy DLBCL NOS (GCB) can be selected from: • A mutation causing a change at position 113 in the gene product, e.g., a G to A change at position 150553895 on chromosome 7 causing an E to K change at position 113 in the gene product; and • A silent mutation at position 150554662 of chromosome 7, e.g., a change from G to A.

[0122] Mutations in AOC1 that are relevant for the hematological malignancy Burkitt's lymphoma can be selected from the following: • Mutations causing a change at position 235 in the gene product, e.g. a C to G change at position 150554261 on chromosome 7 causing a Q to E change at position 235 in the gene product (a mutation also seen in two different multiple myeloma cell lines).

[0123] Mutations for BOC may be particularly relevant for hematological malignancies selected from the group consisting of DLBCL NOS (GCB); and Burkitt's lymphoma.

[0124] For hematological malignancies DLBCL NOS (GCB), the relevant mutation for BOC may be selected from: • A mutation causing a change at position 331 in the gene product, e.g., a C to A change at position 112991945 on chromosome 3 causing a Q to K change at position 331 in the gene product; and • A silent mutation at position 112993352 on chromosome 3, e.g., a change from G to A.

[0125] Mutations for BOC that are relevant for the hematological malignancy Burkitt's lymphoma can be selected from: • A mutation causing a change at position 292 in the gene product, e.g. a G to C change at position 112991463 on chromosome 3 causing an E to Q change at position 292 in the gene product.

[0126] Mutations for DDX3X may be particularly relevant for hematological malignancies selected from the group consisting of DLBCL NOS (ABC); DLBCL NOS (GCB); Burkitt's lymphoma; and ALCL ALK+.

[0127] Mutations in DDX3X that are relevant for hematological malignancies DLBCL NOS (ABC) may be selected from: • A mutation causing a change at position 603 in the gene product, e.g. a G to A change at position 41206603 in chromosome X causing an R to Q change at position 603 in the gene product.

[0128] Mutations in DDX3X that are relevant for the hematological malignancy DLBCL NOS (GCB) may be selected from: • A mutation causing a change at position 472 in the gene product, e.g., an A to T change at position 41205581 of chromosome X causing an H to L change at position 472 in the gene product; • A mutation causing a change at position 529 in the gene product, e.g. an A to C change at position 41205845 in chromosome X causing an I to L change at position 529 in the gene product; • A mutation causing a change at position 537 in the gene product, e.g. an A to G change at 41205869 on chromosome X causing an N to D change at position 537 in the gene product; - a mutation that prevents expression of the gene product, e.g., a change at position 41203490 of chromosome X that causes the formation of a splice acceptor variant; and • Mutations that prevent expression of a gene product, e.g., a T to C change at position 41203654T on chromosome X causing an alteration of a splice site.

[0129] Mutations in DDX3X that are relevant for the hematological malignancy Burkitt's lymphoma may be selected from: • A silent mutation at position 41204526 of chromosome X, e.g., a change from G to A; • A mutation causing a change at position 653 in the gene product, e.g. an A to G change at position 41206941 in chromosome X causing an N to S change at position 653 in the gene product; • A silent mutation at position 41202597 of chromosome X, e.g., a C to T change; • A silent mutation at position 41204511 of chromosome X, e.g., a T to C change; • A silent mutation at position 41206933 of chromosome X, e.g., an A to G change; • A silent mutation at position 41202546 on chromosome X, e.g., an A to G change; • A silent mutation at position 41205606 on chromosome X, e.g., an A to G change; • A silent mutation at position 41205649 of chromosome X, e.g., a T to C change; • Mutations that prevent expression of the gene product, e.g., a deletion from position 41204541 to 41204542 on chromosome X; • Mutations that prevent expression of a gene product, e.g., a T to G change at position 41203654 of chromosome X; • A silent mutation at position 41203518 of chromosome X, e.g., a T to C change; • A silent mutation at position 41202498 of chromosome X, e.g., a C to T change.

[0130] Mutations in DDX3X that are relevant for hematological malignancies PTCL, ALCL ALK+ may be selected from: • A mutation causing a change at position 567 in the gene product, e.g. a G to A change at position 41206195 in chromosome X causing a V to M change at position 567 in the gene product.

[0131] Mutations in CRYBG3 may be particularly relevant for the hematological malignancy DLBCL NOS (GCB).

[0132] Mutations in CRYBG3 that are relevant for the hematological malignancy DLBCL NOS (GCB) may be selected from: • A mutation causing a change at position 79 in the gene product, e.g., an A to G change at position 97596118 on chromosome 3 causing an H to R change at position 79 in the gene product; • A mutation causing a change at position 788 in the gene product, e.g., a G to C change at position 97634545 on chromosome 3 causing an A to P change at position 788 in the gene product; and • A mutation causing a change at position 5 of the gene product, for example an A to C change at position 97595897 of chromosome 3 causing a Q to H change at position 5 of the gene product.

[0133] Mutations in ETNK2 may be particularly relevant for the hematological malignancy DLBCL NOS (GCB).

[0134] Mutations in ETNK2 that are relevant for the hematological malignancy DLBCL NOS (GCB) may be selected from: • A mutation causing a change at position 265 in the gene product, e.g., a G to A change at position 204109237 on chromosome 1 causing an R to Q change at position 265 in the gene product; and • A mutation causing a change at position 222 in the gene product, e.g. an A to C change at position 204110562 on chromosome 1 causing a V to G change at position 222 in the gene product.

[0135] Mutations in SLFN5 may be particularly relevant for hematological malignancies selected from the group consisting of: multiple myeloma; DLBCL NOS (GCB); and ALCL ALK+.

[0136] Mutations in SLFN5 that are relevant for the hematological malignancy multiple myeloma can be selected from: • Mutations that cause a change at position 754 in the gene product, e.g., a G to C change at position 33592491 of chromosome 17 that causes a V to L change at position 754 in the gene product (a mutation seen in two different multiple myeloma cell lines); and • Mutations causing a change at position 495 in the gene product, e.g. a T to C change at position 33591546 on chromosome 17 causing a C to R change at position 495 in the gene product (another mutation seen in two different multiple myeloma cell lines).

[0137] Mutations in SLFN5 that are relevant for the hematological malignancy DLBCL NOS (GCB) may be selected from: • A mutation causing a change at position 697 in the gene product, e.g. a C to T change at position 33592320 on chromosome 17 causing a P to S change at position 697 in the gene product. • A mutation causing a change at position 612 in the gene product, e.g. a C to A change at position 33591899 on chromosome 17 causing an N to K change at position 612 in the gene product.

[0138] Mutations in SLFN5 that are relevant for hematological malignancies ALCL ALK+ may be selected from: • A mutation causing a change at position 578 in the gene product, e.g. a G to A change at position 33591796 on chromosome 17 causing a G to D change at position 578 in the gene product.

[0139] Mutations in BRCA2 may be particularly relevant for hematological malignancies selected from the group consisting of Burkitt's lymphoma; DLBCL NOS (GCB); and multiple myeloma.

[0140] Mutations in BRCA2 that are relevant for the hematological malignancy Burkitt's lymphoma may be selected from the following: • Mutations that cause truncation of the gene product, e.g., an A to T change at position 32972626 on chromosome 13 causing truncation of the gene product at position 3326; and • A mutation causing a change at position 448 in the gene product, e.g. a C to T change at position 32906957 on chromosome 13 causing an R to C change at position 448 in the gene product.

[0141] Mutations in BRCA2 that are relevant for the hematological malignancy DLBCL NOS (GCB) may be selected from: • A mutation causing a change at position 326 in the gene product, e.g., a C to A change at position 32906593 on chromosome 13 causing an S to R change at position 326 in the gene product; and • A mutation causing a change at position 3079 in the gene product, e.g. a G to C change at position 32954261 on chromosome 13 causing a V to L change at position 3079 in the gene product.

[0142] Mutations in BRCA2 that are relevant for the hematological malignancy multiple myeloma can be selected from: • A mutation causing a change at position 2668 in the gene product, e.g. an A to G change at position 32937341 on chromosome 13 causing an R to G change at position 2668 in the gene product.

[0143] Mutations in FRG1B may be particularly relevant for hematological malignancies selected from the group consisting of: multiple myeloma; Burkitt's lymphoma; DLBCL NOS (GCB); and mantle cell lymphoma.

[0144] Mutations in FRG1B that are associated with the hematological malignancy multiple myeloma may be selected from: - mutations that cause truncation of the gene product, e.g., a G to T change at position 29632660 of chromosome 20 causing truncation of the gene product at position 159 (a mutation observed in two different multiple myeloma cell lines and in a DLBCL NOS (GCB) cell line); and • Mutations causing a change at position 180 of the gene product, e.g. an A to G change at position 29633900 of chromosome 20 causing an E to G change at position 180 of the gene product (a mutation also seen in Burkitt lymphoma, four different DLBCL NOS (GCB) cell lines, and mantle cell lymphoma).

[0145] Mutations in FRG1B that are relevant for the hematological malignancy Burkitt's lymphoma may be selected from: • Mutations causing a change at position 180 of the gene product, e.g. an A to G change at position 29633900 of chromosome 20 causing an E to G change at position 180 of the gene product (a mutation also seen in multiple myeloma, four different DLBCL NOS (GCB) cell lines, and mantle cell lymphoma); and • Mutations causing a change at position 41 in the gene product, for example a CG to TA change at positions 29625876 and 29625877 on chromosome 20 causing an A to T change at position 41 in the gene product.

[0146] Mutations in FRG1B that are relevant for the hematological malignancy DLBCL NOS (GCB) may be selected from: • Mutations causing a change at position 180 of the gene product, e.g. an A to G change at position 29633900 of chromosome 20 causing an E to G change at position 180 of the gene product (mutations observed for four different DLBCL NOS (GCB) cell lines, as well as multiple myeloma, Burkitt lymphoma and mantle cell lymphoma); and • Mutations that result in truncation of the gene product, for example a G to T change at position 29632660 on chromosome 20 resulting in truncation of the gene product at position 159 (a mutation also observed in two different multiple myeloma cell lines).

[0147] Mutations in FRG1B that are relevant for the hematological malignancy mantle cell lymphoma may be selected from: • Mutations causing a change at position 180 of the gene product, e.g. an A to G change at position 29633900 of chromosome 20 causing an E to G change at position 180 of the gene product (a mutation also seen in multiple myeloma, Burkitt lymphoma, and four different DLBCL NOS (GCB) cell lines).

[0148] Mutations in KIAA1683 may be particularly relevant for the hematological malignancy DLBCL NOS (GCB).

[0149] Mutations in KIAA1683 that are relevant for DLBCL NOS (GCB) may be selected from: • A mutation causing a change at position 1367 in the gene product, e.g., an A to T change at position 18367995 of chromosome 19 causing an I to F change at position 1367 in the gene product; and • A mutation causing a change at position 496 in the gene product, e.g. a G to T change at position 18376863 on chromosome 19 causing an R to L change at position 496 in the gene product.

[0150] Mutations in USP22 may be particularly relevant for hematological malignancies selected from the group consisting of DLBCL NOS (GCB); and Burkitt's lymphoma.

[0151] Mutations in USP22 that are relevant for DLBCL NOS (GCB) may be selected from: • Mutations causing a change at position 96 in the gene product, e.g. a C to T change at position 20931872 on chromosome 17 causing an A to V change at position 96 in the gene product; • Mutations causing truncation of the gene product, e.g., a T to A change at position 20910270 on chromosome 17 causing truncation of the gene product at position 421.

[0152] Mutations in USP22 that are relevant for Burkitt's lymphoma may be selected from the following: • A silent mutation at position 20946086 on chromosome 17, e.g., a C to A change; • A silent mutation at position 20946041 on chromosome 17, e.g., a C to T change; • A mutation causing a change at position 19 of the gene product, e.g., a C to G change at position 20946094 of chromosome 17 causing an A to P change at position 19 of the gene product; and • A silent mutation at position 20907601 of chromosome 17, e.g., an A to G change.

[0153] Mutations for AP4E1 may be particularly relevant for hematological malignancies selected from the group consisting of ALCL ALK+; and Burkitt's lymphoma; and DLBCL NOS (GCB).

[0154] Mutations in AP4E1 that are relevant for ALCL ALK+ may be selected from: • A mutation causing a change at position 33 in the gene product, e.g. a C to T change at position 51201073 on chromosome 15 causing an S to F change at position 33 in the gene product.

[0155] Mutations in AP4E1 that are relevant for Burkitt's lymphoma may be selected from the following: • A silent mutation at position 51226869 on chromosome 15, e.g., a T to C change.

[0156] Mutations in AP4E1 that are relevant for DLBCL NOS (GCB) may be selected from: • A silent mutation at position 51216153 of chromosome 15, e.g., an A to G change.

[0157] High expression As shown in the examples below, as well as in various embodiments of the present invention previously described, elevated expression of at least one gene selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN is associated with increased sensitivity of hematological malignancies to treatment with satraplatin.

[0158] High expression of a gene of interest can be determined by referring to high transcription and / or high translation. Thus, high expression can be indicated by an increase in mRNA, which indicates the transcription of the gene, and / or an increase in protein, which indicates the translation of the gene. Suitable examples of techniques by which high expression can be analyzed and identified are shown below in more detail. Unless the context requires otherwise, any of these suitable techniques can be carried out to analyze high expression for any of the genes identified above for which this property can be noted.

[0159] In suitable embodiments of the first, second, third, seventh, tenth, eleventh or thirteenth aspects of the invention, high expression may be analyzed for one or more of the following genes: TULP3 and / or PAN3 and / or AC073343.11.1 and / or PHF2 and / or KLHDC1 and / or BRCA2 and / or WRN.

[0160] Preferably, high expression can be analyzed for TULP3. Preferably, high expression can be analyzed for PAN3. Preferably, high expression can be analyzed for AC073343.11.1. Preferably, high expression can be analyzed for PHF2. Preferably, high expression can be analyzed for KLHDC1. Preferably, high expression can be analyzed for BRCA2. Preferably, high expression can be analyzed for WRN. In each of these cases, high expression can be analyzed for the identified gene alone or for the identified gene in combination with one or more other genes. In each of these cases, high expression can be present for the identified gene alone or for the identified gene in combination with one or more other genes.

[0161] Elevation of the gene of interest may be assessed with reference to any appropriate comparator. Those skilled in the art can readily identify suitable comparators, which may include (for example) housekeeping genes, or the expression levels of the gene of interest in healthy comparator tissue.

[0162] High expression of a gene of interest may be assessed to be present when analysis indicates that expression is at least 5% greater than expression in a suitable comparator, at least 10% greater, at least 25% greater, at least 50% greater, at least 75% greater, at least 100% greater than expression in a suitable comparator. By way of example only, high expression may be assessed to be present when analysis indicates that expression of the gene of interest is at least 2-fold greater, at least 3-fold greater, at least 4-fold greater, at least 5-fold greater, or at least 10-fold greater than expression in a suitable comparator.

[0163] Genetic defects A fifth aspect of the present invention relates to satraplatin for pharmaceutical use in hematological malignancies associated with defects in genes selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1.

[0164] An eleventh aspect of the invention relates to a method by which genes located at the 9p21 locus can be analyzed to determine whether a defect is present (which is useful in determining how a hematological malignancy may respond to satraplatin treatment).

[0165] Analysis of genes located at the 9p21 locus (and in particular MTAP, CDKN2B, CDKN2A, or DMRTA1) for the presence of deletions also constitutes suitable embodiments of other aspects of the invention, including (but not limited to) the first, second, third, and tenth aspects.

[0166] For the present purposes, reference to a "defect" in a gene includes any means by which the function of the gene product is lost in a cell. This may be due to loss of the gene itself (e.g., due to loss of copy number) or due to an alteration in the gene or gene product that reduces the function of the gene product.

[0167] In suitable embodiments, the genetic defect is selected from the group consisting of a loss of copy number of the gene; a mutation or modification that reduces transcription or translation of the gene; and a mutation that reduces the function of the gene product. By way of example only, a "stop" mutation (a mutation in which a novel stop codon is introduced by the mutation) represents a suitable embodiment of such a mutation.

[0168] Thus, in the case of an MTAP deficiency, this may be selected from the group consisting of: a loss in copy number of the MTAP gene; a mutation or modification that reduces transcription or translation of the MTAP gene; and a mutation that reduces the function of the MTAP gene product.

[0169] In the case of a CDKN2B deficiency, this may be selected from the group consisting of a loss in copy number of the CDKN2B gene; a mutation or modification that reduces transcription or translation of the CDKN2B gene; and a mutation that reduces the function of the CDKN2B gene product.

[0170] In the case of a CDKN2A deficiency, this may be selected from the group consisting of a loss in copy number of the CDKN2A gene; a mutation or modification that reduces transcription or translation of the CDKN2A gene; and a mutation that reduces the function of the CDKN2A gene product.

[0171] In the case of a DMRTA1 deficiency, this may be selected from the group consisting of a loss in copy number of the DMRTA1 gene; a mutation or modification that reduces transcription or translation of the DMRTA1 gene; and a mutation that reduces the function of the DMRTA1 gene product.

[0172] Suitably, analysis for defects can be performed to identify loss of copy number, and / or mutations or modifications that reduce transcription or translation, and / or mutations that reduce function, of genes such as MTAP. A defect can be determined to be present when one or more of such changes are found.

[0173] By way of example only, a deficiency assessed with respect to a reduction in transcription or translation of a gene of interest may cause at least a 5% reduction, at least a 10% reduction, at least a 20% reduction, or at least a 30% reduction in the relevant parameter. A deficiency may cause at least a 40% reduction, at least a 50% reduction, at least a 60% reduction, at least a 70% reduction, or even greater reduction in the relevant parameter. In a suitable embodiment, a deficiency may be a complete loss (100% reduction) compared to a suitable comparator.

[0174] Copy number loss From the above, it will be appreciated that copy number loss or copy number reduction for a gene of interest are relevant embodiments of a deficiency for such a gene.

[0175] As shown in the examples below, the inventors have found that copy number loss or copy number reduction of a gene of interest can be associated with increased sensitivity of hematological malignancies to satraplatin.Preferably, copy number loss can be copy number loss of at least one gene located at the 9p21 locus.Examples of such genes include genes selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1.Therefore, copy number loss can be analyzed for MTAP and / or CDKN2B and / or CDKN2A and / or DMRTA1.

[0176] In a suitable embodiment, the copy number loss is related to MTAP. In a suitable embodiment, the copy number loss is related to CDKN2B. In a suitable embodiment, the copy number loss is related to CDKN2A. In a suitable embodiment, the copy number loss is related to DMRTA1. In each of these cases, the copy number loss can be analyzed for the identified gene alone or for the identified gene in combination with one or more other genes. In each of these cases, the copy number loss can be present for the identified gene alone or for the identified gene in combination with one or more other genes.

[0177] The inventors have found that in satraplatin-sensitive hematological malignancies, the prevalence of copy loss among the above-listed genes, from highest to lowest, is MTAP, then CDKN2B, then CDKN2A, then DMRTA1. Thus, in a suitable embodiment, the copy number loss or copy number loss analysis can be only for MTAP. In another suitable embodiment, the copy number loss or copy number loss analysis can be for MTAP and CDKN2B. In a further suitable embodiment, the copy number loss or copy number loss analysis can be for MTAP and CDKN2A. In yet a further suitable embodiment, the copy number loss or copy number loss analysis can be for MTAP, CDKN2A and CDKN2B.

[0178] Copy number loss or copy number loss for one or more genes selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1 may be associated with increased sensitivity to satraplatin for hematological malignancies selected from the group consisting of DLBCL; Burkitt's lymphoma; multiple myeloma; CTCL; ALCL ALK+; and mantle cell lymphoma.

[0179] In the case of DLBCL or multiple myeloma, the increased sensitivity to satraplatin may be indicated by a loss of copy number or a decrease in copy number of one or more genes selected from the group consisting of MTAP; CDKN2B; and CDKN2A. The increased sensitivity of DLBCL or multiple myeloma to satraplatin may be indicated by a loss of copy number or a decrease in copy number of MTAP, CDKN2B, and CDKN2A, respectively.

[0180] In the case of Burkitt's lymphoma, CTCL, mantle cell lymphoma, or ALCL ALK+, increased sensitivity to satraplatin may be indicated by copy number losses or copy number losses, particularly for MTAP, CDKN2B, CDKN2A, and DMRTA1, respectively.

[0181] Genetic analysis The present invention utilizes analysis of genes associated with cells of hematological malignancies in a number of different contexts, including, as described above, analysis for losses of the 9p21 locus, analysis for deletions (e.g., gene copy number losses), analysis for the presence of mutations (common or specific) of the gene of interest, and analysis for hyperexpression of the gene.

[0182] The analysis is performed on a suitable sample from the patient. Such a sample may be, for example, cells of the hematological malignancy of interest. Suitable cells may be obtained, for example, by a blood sample.

[0183] The results obtained by the selected analytical method may be compared to appropriate reference values ​​to identify gene-associated alterations that are present.

[0184] Analysis of the 9p21 locus for loss or copy number loss Analysis of the 9p21 locus for loss or copy number loss for a gene of interest can be performed using any suitable technique known to those of skill in the art. Examples of genes that can be examined for copy number changes are provided elsewhere herein.

[0185] By way of example only, suitable analyses may be performed using any of the following techniques: whole exome sequencing, whole genome sequencing, comparative genomic hybridization (including array comparative genomic hybridization), or fluorescent in situ hybridization.

[0186] Analysis of target gene mutations Analysis of a selected gene for mutations, or to identify the presence of one or more particular mutations of interest, may be carried out by any suitable means known to those of skill in the art. Examples of such genes, and particular mutations that may be examined in connection with various aspects or embodiments of the invention, are provided elsewhere herein.

[0187] By way of example, suitable analyses may be performed using any of the following techniques: whole exome sequencing, whole genome sequencing.

[0188] Analysis of high expression of genes of interest Analysis of the gene of interest for high expression can be carried out by any suitable means known to the skilled artisan. Examples of genes that can be analyzed for high expression are given elsewhere in this specification.

[0189] High expression can be determined by analyzing for the presence of an increase in mRNA, which indicates an increase in gene transcription, or by analyzing for the presence of an increase in protein levels, which indicates an increase in translation to produce the gene product. When analysis is performed on mRNA levels, the analysis can be limited to only the transcripts of the gene of interest, or the entire transcriptome can be analyzed and the results compared for the gene of interest.

[0190] By way of example only, suitable analyses may be performed using any of the following techniques: RNA sequencing, eg, next generation sequencing analysis; quantitative RT-PCR; and immunolabeling (performed on relevant gene products).

[0191] Analysis of deletions in the gene of interest Those of skill in the art are aware of many suitable techniques by which defects related to a gene of interest can be identified. Those of skill in the art may utilize any such suitable technique to practice the present invention.

[0192] As mentioned above, defects in a gene of interest (including genes located at the 9p21 locus) can occur for one or more reasons, including loss of copy number of the gene; mutations or modifications that reduce the transcription or translation of the gene; or mutations that reduce the function of the gene product. Appropriate techniques can be selected with reference to the nature of the defect. By way of example only, suitable analysis can be carried out using any of the following techniques: RNA sequencing (as mentioned above), quantitative RT-PCR; immunolabeling.

[0193] Cancer and Hematological Malignancies Various aspects of the invention relate to methods of treatment, pharmaceutical uses, patient stratification methods, diagnostic methods and biomarker panels that may be useful in the treatment of various cancers, particularly hematological malignancies. Unless the context requires otherwise, the considerations presented herein with respect to cancer and hematological malignancies should be considered applicable to all aspects or embodiments of the invention.

[0194] Suitably, references to "cancer" in the context of the present invention should be deemed to include, in addition to the hematological malignancies listed below, glioblastoma; diffuse glioma; mesothelioma; melanoma; as well as non-hematological cancers selected from the group consisting of esophageal squamous cell carcinoma; bladder urothelial carcinoma; pancreatic adenocarcinoma; non-small cell lung carcinoma, head and neck squamous cell carcinoma; cholangiocarcinoma; GEJ adenocarcinoma; sarcoma; adrenocortical carcinoma; renal carcinoma; invasive breast carcinoma; prostate cancer; and colorectal cancer.

[0195] However, the invention is particularly relevant to hematological malignancies, which encompass all blood cancers and may include lymphomas, myelomas, and leukemias. In particular, various aspects and embodiments of the invention may be useful in connection with lymphomas or myelomas.

[0196] In a suitable embodiment, the myeloma is multiple myeloma.

[0197] In suitable embodiments, the lymphoma is a mature B cell lymphoma or a mature T cell lymphoma.

[0198] In suitable embodiments, the lymphoma or myeloma is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma (PTCL); anaplastic large cell lymphoma (ALCL); primary DLBCL of the central nervous system (CNS); secondary CNS lymphoma (SCNSL); cutaneous T-cell lymphoma; Sezary syndrome; and multiple myeloma.

[0199] The mature B-cell lymphoma may be selected from the group consisting of plasma cell myeloma (multiple myeloma); mantle cell lymphoma; Burkitt's lymphoma; diffuse large B-cell lymphoma (DLBCL); DLBL NOS; DLBCL NOS germinal center B-cell (GCB); DLBCL NOS activated B-cell (ABC); primary DLBCL of the central nervous system (CNS); and secondary CNS lymphoma (SCNSL).

[0200] Suitably, the mature B cell lymphoma may be a primary DLBCL of the central nervous system (CNS).

[0201] Suitably, the mature B cell lymphoma may be C5 type or MCD subtype DLBCL.

[0202] Preferably, the mature T-cell lymphoma is peripheral T-cell lymphoma (PTCL); PTCL NOS; anaplastic large T-cell lymphoma (ALCL); anaplastic large T-cell lymphoma; ALK + (ALK + ALCL); cutaneous T-cell lymphoma (CTCL); Sezary syndrome; and primary cutaneous CD30+ T-cell lymphoproliferative disorder.

[0203] Preferably, the mature T-cell neoplasm may be cutaneous T-cell lymphoma (CTCL).

[0204] In the case of the hematological malignancy DLBCL NOS (GCB), increased sensitivity to satraplatin may be associated with the presence of one or more mutations in genes selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; ETNK2; SLFN5; BRCA2; FRG1B; KIAA1683; USP22; and AP4E1, and / or increased sensitivity to satraplatin may be associated with copy number loss or copy number reduction of one or more genes selected from the group consisting of MTAP; CDKN2B; and CDKN2A.

[0205] In the case of the hematological malignancy DLBCL NOS (ABC), increased sensitivity to satraplatin may be associated with the presence of one or more mutations in genes selected from the group consisting of BCL2; and DDX3X.

[0206] In the case of the hematological malignancy Burkitt's lymphoma, increased sensitivity to satraplatin may be associated with the presence of one or more mutations in genes selected from the group consisting of BCL2; AOC1; BOC; DDX3X; BRCA2; FRG1B; USP22; and AP4E1, and / or increased sensitivity to satraplatin may be associated with copy number loss or copy number reduction for each of MTAP, CDKN2B, CDKN2A and DMRTA1.

[0207] In the case of the hematological malignancy ALCL ALK+, increased sensitivity to satraplatin may be associated with the presence of one or more mutations in genes selected from the group consisting of DDX3X; SLFN5; and AP4E1, and / or increased sensitivity to satraplatin may be associated with copy number loss or copy number reduction for each of MTAP, CDKN2B, CDKN2A and DMRTA1.

[0208] In the case of the hematological malignancy multiple myeloma, increased sensitivity to satraplatin may be associated with the presence of one or more mutations in genes selected from the group consisting of BRCA2; and FRG1B, and / or increased sensitivity to satraplatin may be associated with copy number loss or copy number reduction of one or more genes selected from the group consisting of MTAP; CDKN2B; and CDKN2A.

[0209] In the case of the hematological malignancy mantle cell lymphoma, increased sensitivity to satraplatin may be associated with the presence of one or more mutations in FRG1B and / or increased sensitivity to satraplatin may be associated with copy number loss or copy number reduction for each of MTAP, CDKN2B, CDKN2A and DMRTA1.

[0210] In the case of the hematological malignancy CTCL, increased sensitivity to satraplatin may be associated with copy number losses or losses for MTAP, CDKN2B, CDKN2A and DMRTA1, respectively.

[0211] Satraplatin Satraplatin (INN) is also known as JM-216 or as bis(acetato)amminedichloro(cyclohexylamine)platinum(IV).

[0212] The molecular formula of satraplatin is C 10 H 22 N 2 Cl 2 O 4 Pt and has a molecular weight of 500.29 Da. Satraplatin can be synthesized according to the methods disclosed in US Pat. Nos. 5,072,011 and 5,244,919, or by appropriate modification of the methods disclosed in US Pat. No. 6,518,428.

[0213] The chemical structure of satraplatin is: [ka] It is.

[0214] Satraplatin is a member of a class of platinum(IV) compounds that are absorbed via the oral route.

[0215] The lipophilicity of these compounds, and therefore their absorbability, is believed to be determined in large part by the nature of the axial acetate ligand.Unlike cisplatin and carboplatin, which are quadrilateral planar platinum(II) complexes, satraplatin is an octahedral platinum(IV) compound.

[0216] Forms of Satraplatin Suitable for Use in the Present Invention Satraplatin for use according to the various aspects and embodiments of the invention described herein may be suitably formulated for oral administration. Similarly, when administered in the methods of the invention, satraplatin may be administered orally.

[0217] Doses and Therapeutically Effective Amounts of Satraplatin Suitable for Use in the Present Invention Those skilled in the art can determine the appropriate dosage and administration schedule based on publicly available information. The appropriate dosage and administration schedule can be determined by those skilled in the art, such as physicians. Therefore, the following description should be considered as guidance only.

[0218] Exemplary doses may be defined in terms of milligrams or micrograms of satraplatin per kilogram of patient body weight. Advantageously, satraplatin as defined herein may range from about 1 microgram per kilogram to about 500 milligrams per kilogram. For example, a suitable dose may be between about 100 micrograms per kilogram and about 50 milligrams per kilogram. By way of example only, in the case of a patient weighing about 70 kg, a suitable unit dose of satraplatin may be about 0.05 mg to 2000 mg, for example about 0.1 mg to 1000 mg.

[0219] A suitable unit dose may be administered 1, 2, 3 or more times per day. The unit dose may also be administered 1 to 7 times per week.

[0220] Those skilled in the art will further understand that the dose can also be defined in terms of the amount of satraplatin administered per given body surface area. In such a definition, a 70 kg patient can be considered to have a body surface area of ​​about 1.8 square meters. A suitable dose defined in this manner can be between about 50 micrograms per square meter and about 15 grams per square meter, for example, about 5 milligrams per square meter and about 1.5 grams per square meter, or about 50 milligrams per square meter and about 150 milligrams per square meter. The exact dose is ultimately at the discretion of the attending physician.

[0221] In a suitable embodiment, satraplatin is administered at 60 to 140 mg / m on days 1 to 5 every 35 days. 2 Oral (60-140 mg / m2 po day 1-5 q 35 days). By way of example, satraplatin may be administered at 80 mg / m on days 1-5 of every 35 days. 2 Alternatively, the satraplatin may be administered at a dose of 60-80 mg / m on days 1-5 every 28 days. 2 It may be for administration on an oral dosing schedule.

[0222] A typical and preferred dosing schedule is 80 mg / m on days 1-5 every 35 days. 2 Oral, 100 mg / m on days 1 to 5 every 35 days 2 Oral, 120 mg / m on days 1 to 5 every 35 days 2 140 mg / m PO or on days 1 to 5 every 35 days 2 orally or 120, whereas in combination therapy it was 20 mg / m 2 or 40 mg / m 2 More typical and preferred is daily administration of low doses such as 80 mg / m on days 1-5 every 35 days. 2 It is administered on an oral dosing schedule.

[0223] In another embodiment, an exemplary and preferred dosing schedule is 60-80 mg / m on days 1-5 every 28 days. 2 It may be administered orally, e.g., 60 mg / m on days 1-5 every 28 days. 2 PO or 70 mg / m on days 1 to 5 every 28 days 2 PO or 80 mg / m on days 1 to 5 every 28 days 2 An oral administration schedule may be preferred.

[0224] It will be understood that it may be necessary to make routine variations to the dosages suggested above, depending on factors such as the age and weight of the patient, and the severity of the hematological malignancy or cancer being treated.

[0225] patient In the context of the present invention, reference to a "patient" should be interpreted as including both an individual undergoing treatment for cancer (e.g., hematological malignancies), or an individual in need of treatment and for whom an appropriate treatment regimen has been selected. The first interpretation is particularly appropriate in relation to the first to ninth aspects of the invention, and the second interpretation is particularly appropriate in relation to the tenth aspect of the invention.

[0226] A patient for the purposes of the present invention is preferably a human.

[0227] treatment For purposes of this disclosure, the terms "treatment" and "treating" should be considered as embracing both therapeutic treatment and prophylactic or preventative measures. Treatment may be performed to prevent, slow or reduce undesirable physiological changes or disorders, such as the growth, progression or spread of cancer or hematological malignancies. For purposes of this invention, beneficial or desired results include, but are not limited to, alleviation of symptoms, reduction in the extent of disease, stabilized state of disease (i.e., disease that has not worsened), delay or slowing of disease progression, improvement or mitigation of disease state, and remission (whether partial or total).

[0228] Treatment may result in an increase in survival compared to expected survival in the absence of treatment. Alternatively or additionally, treatment may result in an improvement in the patient's standard of living compared to expected standard of living in the absence of treatment.

[0229] Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in which the disorder is to be prevented.

[0230] Unless otherwise specified herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. For example, Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d Ed., John Wiley and Sons, NY (1994); and Hale and Marham, The Harper Collins Dictionary of Biology, Harper Perennial, NY (1991) provide those skilled in the art with a general dictionary of many terms used in the present invention. Although any method and material similar or equivalent to those described herein can be used to practice the present invention, the preferred method and material are described herein. Therefore, the terms defined immediately below are more fully explained by reference to the entire specification. Also, as used herein, singular expressions and similar expressions include plural references unless the context clearly indicates otherwise. Unless otherwise indicated, nucleic acids are written from left to right in 5' to 3' direction, and amino acid sequences are written from left to right in amino to carboxy direction, respectively. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents described, which may vary depending on the context in which they are used by those of skill in the art.

[0231] Aspects of the present invention are illustrated by the following non-limiting examples. EXAMPLES

[0232] Example 1 - Satraplatin exhibits high cytotoxic activity in genetically defined lymphoid malignancies material and method Cell lines and reagents. The cell lines listed in Table 3 were tested. All cell lines were cultured in appropriate media supplemented with 10–15% fetal bovine serum (Cat# FND500, ExCell Bio, People's Republic of China) at a temperature of 37°C, 5% CO2, and 95% humidity. Cell viability was measured using the CTG Luminescent Cell Viability Assay (Promega, Madison, WI, USA) by standard procedures as described below. Satraplatin was purchased from MedChemExpress (Shanghai, PRC) and cisplatin from Qilu Pharm (Jinan, Shandong, PRC), respectively. 1 mM stock solutions of both drugs were prepared for storage at -20°C as previously described (5). [Table 3-1] [Table 3-2]

[0233] Determination of half-maximal inhibitory concentration (IC50). Cells were harvested during logarithmic growth phase and counted using a Count-star (Inno-Alliance Biotech, USA). The cell density was 4.44 × 10 4 Then, 90 μL of the cell suspension was added in triplicate to a 96-well plate to give a final cell density of 4 × 10 3 cells / well. After 24 hours, 10 μL of serially diluted solutions of either cisplatin or satraplatin were transferred to each well in triplicate to give final drug concentrations per well of 100 μM, 31.6 μM, 10 μM, 3.16 μM, 1.0 μM, 316 nM, 100 nM, 31.6 nM and 10 nM, respectively. Culture was incubated at 37°C, 5% CO 2The test plates were incubated for 72 h in a humidified incubator at 4 °C and then evaluated using the CTG Cell Viability Assay (Promega). For that purpose, the plates were equilibrated at room temperature for approximately 30 min. Then, 50 μL CTG reagent was added to each well. The contents were mixed on an orbital shaker for 5 min to induce cell lysis, and the plates were incubated at room temperature for 20 min to stabilize the luminescence signal. Luminescence was recorded using an EnVision Multi Label Reader (Perkin Elmer, Richmond, CA, USA).

[0234] Data analysis. Data were analyzed and visualized using GraphPad Prism 5.0 (GraphPad Software, San Diego, CA, USA) and Think-Cell 11 (Think-Cell Software, Berlin, Germany). To calculate absolute IC50, dose-response curves were fitted using a nonlinear regression model with a sigmoidal dose-response. The formula for calculating cell viability was: Cell viability in Cx (%) = (Cx-M) / (NM) x 100% where Cx is the luminescence signal of cells cultured with any concentration of the test compound, M is the luminescence signal of the blank control (without cells), and N is the vehicle control with medium containing 0.25% (v / v) dimethyl sulfoxide. Absolute IC50 was calculated according to the dose-response curve generated by GraphPad Prism 5.0. The raw cell viability data was then used to fit a standard four-parameter monotonic log-logistic dose-response curve using the R package dr4pl (9). To investigate the drug efficacy in the 66 test cell lines, we calculated several indices from the dose-response curves and used the area under the curve (AUC) value as an expression of drug efficacy. The efficacy among cell lines derived from different tissues was compared by analysis of variance, and a p-value >0.05 indicated no significant difference in sensitivity to the drug among the tested indications.

[0235] Whole transcriptome sequencing (RNAseq). Total RNA extraction of baseline cell line samples was performed according to the Qiagen Cat#74106 protocol (Qiagen, Hilden, Germany). Total RNA integrity was determined by 2100 Bioanalyser (Agilent, Santa Clara, CA, USA) and quantified using a NanoDrop (Thermo Fisher Scientific, Waltham, MA, USA). High quality RNA samples (OD 260 / 280 = 1.8-2.2, O.D. 260 / 230 Sequencing libraries were constructed using only 1000 ng of total RNA (RNA > 500 ng, RNA integrity number > 2.0, RNA integrity number > 7, total RNA > 500 ng). PolyA mRNA was purified from total RNA using oligo-dT-conjugated magnetic beads and then fragmented with fragmentation buffer. These short fragments were used as templates to synthesize first-strand cDNA using reverse transcriptase and random primers, followed by second-strand cDNA synthesis by standard methods. The synthesized cDNA was used for end repair, phosphorylation, and "A" base addition according to the library construction protocol (TruSeq RNA Sample Preparation v2 Guide). Sequencing adapters were then added to cDNA fragments of both sizes. After polymerase chain reaction amplification of the cDNA fragments, targets of 250–350 bp were purified. After library construction, the concentration of the resulting sequencing library was quantified using the Qubit 2.0 fluorometer dsDNA HS Assay (Thermo Fisher Scientific) and the size distribution was analyzed using an Agilent BioAnalyzer 2100. After library validation, clusters were generated using the Illumina cBOT Cluster Generation System (Illumina, San Diego, CA, USA) with HiSeq PE Cluster Kits. Paired-end sequencing was performed using an Illumina NovaSeq 6000 platform following the protocol provided by Illumina for 2 × 150 paired-end sequencing.

[0236] Gene expression analysis. The quality of the RNAseq fastq raw reads was checked by FastQC software (Babraham Bioinformatics, https: / / www.bioinformatics.babraham.ac.uk / projects / fastqc / ). Adapters and low quality sequences were trimmed by Trimmomatic software (10). Reads were mapped to reference genes (ENSEMBL GRCh37.66) by Bowtie software (11) and the gene expression was calculated by MMSEQ software (12). Final expression values ​​were log2-transformed fragments per kilobase of exon model per million mapped fragment values. For each cohort of cell lines tested, we started with a gene expression matrix of 49,442 annotated genes for the involved cell lines for which expression data were available. To identify genes positively and negatively correlated with drug sensitivity, the expression of 49,442 genes across 66 cell lines was correlated with AUC values. For genes correlated with increased sensitivity, Spearman correlation coefficient <-0.55 and p <0.05 were used as cutoffs, whereas for genes correlated with resistance, Spearman correlation coefficient >0.55 and p <0.05 were used as cutoffs.

[0237] To investigate the genomic similarities and dissimilarities of cell lines that behave differently in drug response, we performed principal component analysis (PCA) on the complete transcriptomes of the relevant cell lines with expression data. For all genes, we calculated the Spearman correlation between gene expression and AUC across samples. We identified differentially expressed (DE) genes between the more and less sensitive groups with the limma package (13) and performed gene ontology (GO) enrichment, pathway enrichment analysis on the DE genes. We performed gene set variation analysis (GSVA) ​​(14) on a set of 2,057 well-curated genes from the MSigDB database (https: / / www.gsea-msigdb.org / gsea / msigdb).

[0238] Whole exome sequencing (WES). Genomic DNA extraction from baseline cell line samples for WES was performed using MagMAX TM The DNA Multi-Sample Ultra 2.0 Kit (ABI, Waltham, MA, USA) was used to perform the analysis using KingFisher Flex (Thermo Fisher Scientific). Genomic DNA was quantified using a NanodropTM 2000 spectrophotometer (Thermo Fisher Scientific). High-quality DNA (concentration >100 ng / μl, OD 260 / 280 ≧1.8-2.2, O.D. 260 / 230Only 100% 100% 100% 15 ...

[0239] Gene mutation analysis. The quality of WES fastq raw data was checked by FastQC software. Adapters and low-quality sequences were trimmed by Trimmomatic software (10). Reads were aligned to the hg19 genome by BWA software (15), variants were called by GATK software (16), and annotated by VEP software (17). Mutation driver status was predicted according to the method of CancerGenomeInterpreter database (18). Wilcoxon signed-rank test and Benjamini-Hochberg adjusted p-values ​​were calculated between mutation status and efficacy endpoints (AUC values). Calculation of the difference in AUC between cell lines carrying mutations and those carrying wild-type genes is as follows: AUC difference = average AUC for the cell lines - average AUC for the cell lines with no somatic point mutations. An AUC difference >0 indicates that the gene mutation is enriched in resistant cell lines (high AUC), whereas an AUC difference <0 indicates that the gene mutation is enriched in sensitive cell lines (low AUC).The maximum information coefficient (MIC) for each gene was calculated between AUC and gene mutation status, and for each gene, the ratio of mutation recurrence rate in the current cohort to mutation recurrence rate in all cell lines was calculated.

[0240] Analysis of copy number variation. Aligned sequences from WES data were used to estimate gene copy number (CN) with the CopyWriteR R package (19). Genes with copy values ​​>3 were defined as copy number gains, whereas gene copy number losses with copy values ​​<1 were defined as copy number losses. Wilcoxon signed-rank tests and Benjamini-Hochberg adjusted p-values ​​were calculated between amplification / deletion status and efficacy endpoints (AUC values). MICs of each gene were calculated between AUC and amplification / deletion status, and for each gene, the ratio of amplification / deletion recurrence rate in the current cohort to recurrence rate in all cell lines was calculated.

[0241] result In lymphoid malignancies, satraplatin has high cytotoxic activity. As described, the cytotoxic activity profile of satraplatin was tested in a standard cell-based assay in 66 cancer cell lines (Table 3). To examine and compare efficacy, AUC values ​​were used as an expression of efficacy. By analysis of variance (ANOVA), we found significant differences in AUC values ​​across all cancer types for satraplatin (Figure 1). Satraplatin was significantly more active in hematological malignancies compared to solid organ cancers (p-value = 2.3e-08). Therefore, the cohort was divided into solid organ cancers (n = 22) and hematological malignancies (n = 44), and only the latter was used for further analysis. Satraplatin was significantly more active within the group of hematological malignancies than standard cisplatin (p-value = 0.009) (Figure 2), and achieved IC50 values ​​at low to submicromolar levels. When classified by histology, satraplatin showed high activity in diffuse large B-cell lymphoma (DLBCL), T-cell lymphoma, mantle cell lymphoma (MCL), multiple myeloma (MM) and Burkitt's lymphoma (BL) cell lines, respectively. Furthermore, statistical significance was calculated for some cell lines of particular interest, showing that satraplatin was significantly more active than cisplatin, especially for the cell line OCI-LY3, with a p-value of 0.0006. Similar results were obtained for other DLBCL cell lines, such as SU-DHHL-5 (p = 0.003) and SU-DHL-6 (p = 0.007).

[0242] Identification of overexpressed genes leading to increased satraplatin sensitivity. Using gene expression analysis, we identified seven genes that were positively correlated with increased satraplatin sensitivity, using a cutoff of Spearman correlation coefficient <-0.55 and p-value <0.05 (Figure 3). The gene conferring the highest level of sensitivity was TULP3, followed by PAN3, PHF2, KLHDC1, and WRN. Other overexpressed genes known to be associated with platinum sensitivity, such as BRCA2, were identified for both platinum compounds, supporting the validity of the analysis. In total, we identified 31 overexpressed genes leading to satraplatin resistance, with MTAP achieving the highest Spearman correlation.

[0243] Single gene mutations leading to increased satraplatin sensitivity. At the single gene level, 19 genes were identified that, when mutated, resulted in either increased (12 genes) or decreased (7 genes) satraplatin cytotoxic activity (Figure 4). The BCL2 apoptosis regulator was found to be the single most significantly mutated gene associated with increased satraplatin cytotoxic activity. Importantly, BCL2 gene mutations were not identified as markers for cisplatin activity and appear to be a unique feature for satraplatin sensitivity. Further gene mutations highlighting satraplatin sensitivity were AOC1, BOC, DDX3X, ETNK2 and USP22. Furthermore, BRCA2 gene mutations were identified as a sensitivity marker for both satraplatin and cisplatin.

[0244] DNA copy number (CN) deletion analysis identifies recurrent chromosomal abnormalities at the 9p21 locus.Finally, copy number analysis was performed as described and identified 10 genes [chromosome 8 open reading frame 76 (C8orf76), alpha 1 chain type XIV collagen (COL14A1), delrin 1 (DERL1), sequence similarity family 83 member A (FAM83A), hyaluronan synthase 2 (HAS2), mitochondrial ribosomal protein L13 (MRPL13), zinc finger and homeobox 2 (ZHX2), NBPF member 9 (NBPF9), phosphodiesterase 4D interacting protein (PDE4DIP), and peptidyl prolyl isomerase A-like 4G (PPIAL4G)] with DNA CN amplification levels that showed reduced satraplatin sensitivity. However, when DNA CN deletions were analyzed, we identified four genes (CDKN2A, CDKN2B, MTAP, and DMRTA1) known to be located at the 9p21 locus that served as biomarkers for increased satraplatin sensitivity (Figure 5). Having identified MTAP overexpression as a marker for satraplatin resistance, we performed detailed analyses linking MTAP deficiency with satraplatin activity (Figure 6). The IC50 values ​​for satraplatin were plotted against MTAP status (defined using publicly available datasets) and showed significantly higher efficacy of satraplatin in MTAP-loss cell lines (p = 3.03e-07).

[0245] Consideration We have completed a phylogenetic analysis of satraplatin activity in common hematological malignancies, showing that DLBCL and its respective cell lines are highly sensitive to satraplatin, with IC50 values ​​at low or even submicromolar doses. Compared to cisplatin, satraplatin is not only significantly better at killing DLBCL cell lines such as OCI-LY7 cells, but also, and more importantly, satraplatin killed the cell line OCI-LY3 very efficiently. The OCI-LY3 cell line is particularly interesting because it harbors a stable mutation pattern (20) that includes mutations in MYD88, PIM1, CD79B, CARD11, and PRDM1, respectively (Table 4). These mutations resemble the genetic landscape of the so-called cluster 5 DLBCL, as recently described by Chapuy et al. (21). Cluster 5 DLBCL genes contain frequent BCL2 gains, concordant MYD88L265P / CD79B mutations, and additional mutations in ETV6, PIM1, GRHPR, TBL1XR1, and PRDM1. These mutations are typical for DLBCL patients with primary CNS lymphoma (PCNSL) and / or extranodal lymphomas such as testicular lymphoma. As described in their landmark publication, lymphoma tissues from 8 out of 9 PCNSL patients fulfilled the C5 cluster criteria (Fisher's exact test, p <0.001), laying the foundation for the acceptance of the C5 genetic signature resembling PCNSL. Recently, the association of the C5 DLBCL cluster with PCNSL was confirmed by mutation profiling of DLBCL samples from an additional 48 PCNSL patients at MD Anderson Cancer Center. Therefore, and based on the mutational pattern, OCI-LY3 was suggested to be the most tolerated PCNSL-like human DLBCL cell line and highly suitable for predicting and comparing the efficacy of investigational compounds such as satraplatin for the treatment of PCNSL. [Table 4]

[0246] A similar DLBCL classification system based on genetic signatures was developed by Wright et al. (22). They published a probabilistic classification of DLBCL patient samples and used the Chapuy data as a validation cohort. This classification also reveals genetic similarities between the various DLBCL subtypes. It is noteworthy that the MCD cohort they characterized shows great similarity with the C5 cohort defined by Chapuy et al. in terms of mutation patterns. MCD DLBCL is defined primarily by MYD88L265P and CD79B mutations and is known to metastasize secondary to extranodal sites in 30% of all cases, with the CNS being the most common site. Similar to the C5 DLBCL cluster, MCD DLBCL is best represented by the OCI-LY3 cell line (22). Given the data presented herein, satraplatin should be particularly useful in the treatment of DLBCL presenting with primary extranodal lymphoma, such as lymphoma of the central nervous system, vitreous retina, testis, and / or breast. Satraplatin is lipophilic and therefore able to enter the cerebrospinal fluid at sufficient dose levels.(23) Furthermore, it can be orally administered and has a favorable side effect profile, including the absence of neurotoxicity and ototoxicity, providing a rationale for further studies of satraplatin, particularly focusing on PCNSL, as reviewed.

[0247] In a second step, we undertook a more comprehensive molecular biomarker analysis to better understand the potential relationship between the genetic characteristics of different lymphoma entities and satraplatin sensitivity. There are many possible mechanisms of action of satraplatin, and predictive biomarkers are important to better select the appropriate patients who will benefit the most. Surprisingly, we were able to clearly demonstrate meaningful differences between satraplatin and cisplatin, since although a few genetic alterations such as BRCA2 mutations or reduced BRCA2 expression were common in both platinum compounds, most of the other genetic alterations identified clearly distinguished the two. Focusing on single gene mutation analysis, specific satraplatin activity is observed in cell lines harboring either BCL2, USP22 or ETNK2 mutations, respectively. Interestingly, these mutations were not observed in cisplatin, and the association with BCL2 mutations in particular could be a potential explanation for the more severe hematological toxicity of satraplatin observed in previous clinical trials. Furthermore, platinum resistance and refractory disease have been associated with increased expression of anti-apoptotic genes such as BCL2 in cell lines derived from solid organ tumors (30). In that study, satraplatin, in contrast to oxaliplatin, was significantly more effective and was able to reduce BCL2 expression up to 13-fold independent of P53 mutation status. The BCL2 inhibitory function of satraplatin also established a link with hematological diseases in which BCL2 overexpression is a key driver, and BCL2 inhibition with venetoclax has shown significant clinical efficacy, for example, for the treatment of MCL, acute myeloid leukemia, and chronic lymphocytic leukemia (31).

[0248] Finally, satraplatin was more active against a wide variety of lymphoma cell lines harboring gene copy number deletions at the 9p21 locus, including MTAP / CDKN2A / CDKN2B / DMRTA1. Cases with CDKN2A and / or CDKN2B deletions are frequent features of various lymphoma entities, such as T-cell lymphoma / T-cell acute leukemia / cutaneous T-cell lymphoma (CTCL), DLBCL including PCNSL, MCL, and CLL. The methylthioadenosine phosphorylase (MTAP) gene is adjacent to the CDKN2A tumor suppressor gene and is frequently co-deleted with CDKN2A, the most commonly deleted gene in human cancers, including solid and hematological malignancies. It occurs in approximately 15% of all cancers, and MTAP deletions have been reported to be associated with shorter survival and more aggressive tumors when compared to wild-type MTAP (24). MTAP deletion increases the intracellular concentration of its substrate methylthioadenosine (MTA), and by competing with S-adenosyl-L-methionine (SAM), MTA binds and partially inhibits protein arginine methyltransferase 5 (PRMT5). Due to its critical role in the spliceosome machinery, normal PRMT5 function is particularly important for the hematopoietic compartment to maintain homologous recombination and DNA repair (25). Complete inhibition causes severe, even fatal, pancytopenia, as shown in PRMT5 knockout mice (26). Recently, pharmacological inhibition of PRMT5 in MCL cell lines was shown to reinitiate the proapoptotic program and synergize with the bcl-2 inhibitor venetoclax (27). As described above, satraplatin is highly active in MTAP-deficient hematopoietic cell lines, most likely because it causes severe DNA damage lesions in the context of homologous recombination deficiency (functional PRMT inhibition). Additionally, the simultaneous observation of unique BCL2 inhibition that specifically elicits superior activity compared to cisplatin may be an important point.

[0249] Satraplatin is ideally suited to exploit the vulnerability of hematological malignancies to p16 / CDKN2A and MTAP loss and should be confirmed in solid organ tumors, excluding lymphoid neoplasms. We hypothesize that satraplatin is the preferred platinum for the treatment of tumors with the indicated gene mutations, gene expression reductions, especially 9p21 deletion / methylation tumors. In lymphoma entities, satraplatin has been of particular interest for the treatment of PCNSL and CTCL. For PCNSL, del9p21 and / or BCL2 mutations are present in nearly 80% of cases (28). For CTCL, CDKN2A / CDKN2B deletions have been described as a feature in most subtypes of mycosis fungoides (MF) and Sézary syndrome (SS)-like. This deletion is sequential, occurring more frequently with disease progression, and is associated with a more aggressive clinical behavior (29). In localized forms of MF, as they progress towards systemic SS, there is an increased loss of CDKN2A / B copy numbers and therefore an increased MTAP deletion. Also, the high efficacy of satraplatin with a low micromolar IC50 in the representative CTCL cell line HUT78 supports this idea. As in PCNSL, in this disease too, satraplatin's lipophilicity is well suited, and a high treatment efficacy is expected. Following these data, clinical trials in both entities are being prepared.

[0250] The reader's attention is directed to all papers and documents relating to this application filed contemporaneously or prior to this application and in the public domain herewith, the contents of all such papers and documents being incorporated herein by reference.

[0251] All features disclosed in this specification (including the accompanying claims, abstract and drawings), and / or all steps of the disclosed methods or processes, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive.

[0252] Each feature disclosed in this specification (including the accompanying claims, abstract and drawings), unless expressly stated otherwise, may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic family of equivalent or similar features.

[0253] The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel, or any novel combination of, features disclosed in this specification (including the accompanying claims, abstract and drawings), or any novel, or any novel combination of method or process steps disclosed.

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[0255] Illustrative embodiments of the invention The invention will now be further described with reference to the following numbered embodiments. 1. Satraplatin for use in the treatment of hematological malignancies, in patients identified as likely to benefit from such treatment by analysis of genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN. 2. Satraplatin for use according to embodiment 1, wherein the hematological malignancy is lymphoma or myeloma. 3. Satraplatin for use according to embodiment 2, wherein the lymphoma or myeloma is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma (PTCL); anaplastic large cell lymphoma (ALCL); primary DLBCL of the central nervous system (CNS); secondary CNS lymphoma (SCNSL); cutaneous T-cell lymphoma; Sezary syndrome; and multiple myeloma. 4. Satraplatin for use according to any one of embodiments 1 to 3, wherein the gene is located at the 9p21 locus and the analysis identifies a reduction in the copy number of said gene. 5. Satraplatin for use according to embodiment 4, wherein the genes are selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1, and the analysis identifies a defect in said genes. 6. Satraplatin for use according to embodiment 5, wherein the genetic defect is a reduction in the copy number of said gene. 7. Satraplatin for use according to any one of embodiments 4 to 6, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma. 8. Satraplatin for use according to any one of embodiments 1 to 3, wherein the genes are selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, and the analysis identifies mutations in the genes. 9. Satraplatin for use according to embodiment 8, wherein the mutations are selected from those shown in Tables 1 and 2. 10. Satraplatin for use according to embodiment 8 or embodiment 9, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 11. Satraplatin for use according to any one of embodiments 1 to 3, wherein the genes are selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies high expression of said genes. 12. Satraplatin for use in the treatment of hematological malignancies with loss of the 9p21 locus. 13. Satraplatin for use in the treatment of hematological malignancies associated with defects in genes selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1. 14. Satraplatin for use according to embodiment 13, wherein the defect is a reduction in the copy number of a gene selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1. 15. Satraplatin for use according to any one of embodiments 12 to 14, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma. 16. Satraplatin for use in the treatment of hematological malignancies associated with mutations in genes selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1. 17. Satraplatin for use according to embodiment 16, wherein the mutation is selected from the group shown in Tables 1 and 2. 18. Satraplatin for use according to embodiment 16 or embodiment 17, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 19. Satraplatin for use in the treatment of hematological malignancies with high expression of TULP3;PAN3;AC073343.11.1;PHF2;KLHDC1;BRCA2;or WRN. 20. A method for determining the likelihood that a hematological malignancy will respond favorably to satraplatin treatment, comprising analyzing cells of the hematological malignancy for alterations in genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN; wherein identification of an alteration in the analyzed gene indicates that the hematological malignancy is likely to respond favorably; method. 21. The method of embodiment 20, wherein the gene is located at the 9p21 locus and the analysis identifies a defect in the gene. 22. The method of embodiment 21, wherein the gene is a gene located at the 9p21 locus, and the analysis identifies a reduction in copy number of the gene. 23. The method of embodiment 21 or embodiment 22, wherein the genes are selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1. 24. The method of any one of embodiments 20 to 23, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma. 25. The method of embodiment 20, wherein the gene is selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, and the analysis identifies a mutation in the gene. 26. The method of embodiment 25, wherein the mutation is selected from the mutations shown in Tables 1 and 2. 27. The method of embodiment 25 or embodiment 26, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 28. The method of embodiment 20, wherein the genes are selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies high expression of the genes. 29. A method for treating a hematological malignancy, comprising administering satraplatin to a patient identified as likely to benefit from such treatment based on analysis of genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN. 30. The method of embodiment 29, wherein the hematological malignancy is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma (PTCL); anaplastic large cell lymphoma (ALCL); primary DLBCL of the central nervous system (CNS); secondary CNS lymphoma (SCNSL); cutaneous T-cell lymphoma; Sezary syndrome; multiple myeloma; and leukemia. 31. The method of embodiment 29 or embodiment 30, wherein the gene is located at the 9p21 locus, and the analysis identifies a defect in the gene. 32. The method of embodiment 31, wherein the gene is a gene located at the 9p21 locus and the analysis identifies a reduction in copy number of the gene. 33. A method according to any one of embodiments 29 to 32, wherein the gene is selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1. 34. The method of any one of embodiments 31 to 33, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma. 35. The method of embodiment 29, wherein the gene is selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, and the analysis identifies a mutation in the gene. 36. The method of embodiment 39, wherein the mutation is selected from the mutations shown in Tables 1 and 2. 37. The method of embodiment 36, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 38. The method of embodiment 29, wherein the gene is selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies high expression of the gene. 39. A method for treating a hematological malignancy, comprising: Obtaining a sample containing cells of a hematological malignancy; analyzing cells of the hematological malignancy for alterations associated with genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN; and administering satraplatin to patients identified based on such analysis as likely to benefit from such treatment; A method comprising: 40. The method of embodiment 39, wherein the hematological malignancy is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma (PTCL); anaplastic large cell lymphoma (ALCL); primary DLBCL of the central nervous system (CNS); secondary CNS lymphoma (SCNSL); cutaneous T-cell lymphoma; Sezary syndrome; multiple myeloma; and leukemia. 41. The method of embodiment 39, wherein the gene is a gene located at the 9p21 locus, and the analysis identifies a defect related to the gene. 42. The method of embodiment 41, wherein the deficiency is a reduction in copy number for the gene. 43. A method according to any one of embodiments 39 to 42, wherein the gene is selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1, and the analysis identifies a reduction in the copy number of the gene. 44. The method of embodiment 43, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma. 45. The method of embodiment 39, wherein the gene is selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, and the analysis identifies a mutation in the gene. 46. ​​The method of embodiment 39, wherein the mutation is selected from the mutations shown in Tables 1 and 2. 47. The method of embodiment 46, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 48. The method of embodiment 39, wherein the gene is selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies high expression of the gene. 49. A method comprising analyzing at least one gene selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN in cells of a hematological malignancy from a patient, wherein When the gene is a gene located at the 9p21 locus, the analyzing can include determining whether a deletion is present, e.g., by assessing copy number; When the gene is selected from the group consisting of: BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, the analyzing includes assaying for mutations in the gene; and When the gene is selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, the analyzing comprises assaying for elevated expression of the gene. 50. The method of embodiment 49, wherein the hematological malignancy is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma (PTCL); anaplastic large cell lymphoma (ALCL); primary DLBCL of the central nervous system (CNS); secondary CNS lymphoma (SCNSL); cutaneous T-cell lymphoma; Sezary syndrome; multiple myeloma; and leukemia. 51. The method of embodiment 49 or 50, wherein the gene located at the 9p21 locus is selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1. 52. The method of embodiment 51, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma. 53. The method of embodiment 49, wherein the mutation is selected from the mutations shown in Tables 1 and 2. 54. The method of embodiment 53, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 55. A method comprising analyzing cells of a hematological malignancy from a patient for the presence of at least one genetic mutation selected from the group set forth in Tables 1 and 2. 56. The method of embodiment 55, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 57. A signature panel characteristic of sensitivity of hematological malignancies to treatment with satraplatin, comprising: Loss of copy number of at least one gene selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1; and / or A mutation in at least one gene selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1; and / or High expression of at least one gene selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN. Including, a panel. 58. The signature panel of embodiment 57, wherein the hematological malignancy is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma (PTCL); anaplastic large cell lymphoma (ALCL); primary DLBCL of the central nervous system (CNS); secondary CNS lymphoma (SCNSL); cutaneous T-cell lymphoma; Sezary syndrome; multiple myeloma; and leukemia. 59. The signature panel of embodiment 57, wherein the genes are selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1, and the analysis identifies a decrease in copy number of the genes. 60. The signature panel of embodiment 59, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma. 61. The signature panel described in embodiment 57, wherein the genes are selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, and the analysis identifies mutations in the genes. 62. The signature panel of embodiment 57, wherein the mutation is selected from the group shown in Tables 1 and 2. 63. The signature panel of embodiment 62, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 64. The signature panel described in embodiment 57, wherein the genes are selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies high expression of the genes. 65. A signature biomarker panel characteristic of sensitivity of hematological malignancies to treatment with satraplatin, the panel comprising at least one genetic mutation selected from the group shown in Tables 1 and 2. 66. The signature panel of embodiment 65, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+. 67. Satraplatin for use as second-line therapy in the treatment of cancers non-responsive to immune checkpoint therapy.

Claims

1. Satraplatin for use in the treatment of hematological malignancies, in patients identified as likely to benefit from such treatment by analysis of genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN.

2. 2. Satraplatin for use according to claim 1, wherein the hematological malignancy is lymphoma or myeloma.

3. Satraplatin for use according to claim 2, wherein the lymphoma or myeloma is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma (PTCL); anaplastic large cell lymphoma (ALCL); primary DLBCL of the central nervous system (CNS); secondary CNS lymphoma (SCNSL); cutaneous T-cell lymphoma; Sezary syndrome; and multiple myeloma.

4. Satraplatin for use according to any one of claims 1 to 3, wherein the gene is located at the 9p21 locus and the analysis identifies a reduction in the copy number of said gene.

5. 5. Satraplatin for use according to claim 4, wherein the gene is selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1, and the analysis identifies a defect in said gene.

6. Satraplatin for use according to claim 4 or claim 5, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma.

7. Satraplatin for use according to any one of claims 1 to 3, wherein the genes are selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1, and the analysis identifies mutations in said genes.

8. Satraplatin for use according to claim 8, wherein the mutations are selected from those shown in Tables 1 and 2.

9. 9. Satraplatin for use according to claim 7 or claim 8, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+.

10. Satraplatin for use according to any one of claims 1 to 3, wherein the genes are selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies high expression of said genes.

11. Satraplatin for use in the treatment of hematological malignancies with loss of the 9p21 locus.

12. Satraplatin for use in the treatment of hematological malignancies associated with defects in genes selected from the group consisting of: MTAP; CDKN2B; CDKN2A; and DMRTA1.

13. Satraplatin for use according to claim 12, wherein the defect is a reduction in the copy number of a gene selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1.

14. Satraplatin for use according to any one of claims 11 to 13, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma.

15. Satraplatin for use in the treatment of hematological malignancies associated with mutations in genes selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1.

16. 16. Satraplatin for use according to claim 15, wherein the mutation is selected from the group shown in Tables 1 and 2.

17. 17. Satraplatin for use according to claim 15 or claim 16, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+.

18. Satraplatin for use in the treatment of hematological malignancies with high expression of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; or WRN.

19. 1. A method for determining the likelihood that a hematological malignancy will respond favorably to satraplatin treatment, comprising: analyzing cells of the hematological malignancy for alterations in genes selected from the group consisting of genes located at the 9p21 locus (such as MTAP, CDKN2B, CDKN2A, or DMRTA1); BCL2; TULP3; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; AP4E1; PAN3; AC073343.11.1; PHF2; KLHDC1; and WRN; wherein identification of an alteration in the analyzed gene indicates that the hematological malignancy is likely to respond favorably; method.

20. 1. A signature panel characteristic of sensitivity of a hematological malignancy to treatment with satraplatin, comprising: Loss of copy number of at least one gene selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1; and / or A mutation in at least one gene selected from the group consisting of BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1; and / or High expression of at least one gene selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN Includes signature panels.

21. the gene with copy number loss is selected from the group consisting of MTAP; CDKN2B; CDKN2A; and DMRTA1; and the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; CTCL; multiple myeloma; ALCL ALK+; and mantle cell lymphoma; 21. The signature panel of claim 20.

22. the gene with the mutation is selected from the group consisting of: BCL2; AOC1; BOC; DDX3X; CRYBG3; SLFN5; ETNK2; BRCA2; USP22; KIAA1683; and AP4E1; and the mutation is selected from the group shown in Table 1 and Table 2, and The hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+.

21. The signature panel of claim 20.

23. 21. The signature panel of claim 20, wherein the genes are selected from the group consisting of TULP3; PAN3; AC073343.11.1; PHF2; KLHDC1; BRCA2; and WRN, and the analysis identifies high expression of the genes.

24. A signature biomarker panel characteristic of sensitivity of a hematological malignancy to treatment with satraplatin, the signature biomarker panel comprising at least one genetic mutation selected from the group shown in Tables 1 and 2, wherein the hematological malignancy is selected from the group consisting of Burkitt's lymphoma; DLBCL; and ALCL ALK+.

25. Satraplatin for use as a second line therapy in the treatment of cancer non-responsive to immune checkpoint therapy.

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