Epigenetic modulation of cell states to improve response to antibody drug conjugates

Abstract

The present application discloses methods for modulating the response to antibody- drug conjugates (ADC) therapies in cancer. The present application provides methods for treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a KDM1 A inhibitor.

Description

Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025EPIGENETIC MODULATION OF CELL STATES TO IMPROVE RESPONSE TO ANTIBODY DRUG CONJUGATESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional PatentApplication No. 63 / 703,402, filed on October 4, 2024, the content of which is hereby incorporated by reference in its entirety. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application.

[0002] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records but otherwise reserves any and all copyright rights.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0003] This invention was made with government support under CA261152, and CA221757 awarded by the National Institutes of Health. The government has certain rights in the invention.SEQUENCE LISTING

[0004] The instant application contains a sequence listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML file, created October 3, 2025, is named 0019240_01335W01_SL.xml, and is 9,704 bytes in size.SUMMARY OF THE INVENTION

[0005] The present application is based, at least in part, on preventing or treating cancer by modulating response to antibody-drug conjugates (ADC) therapies through epigenetic reprogramming of cell states, resulting in increased expression of one or more ADC-targeted cell surface proteins.

[0006] In one aspect, the present application provides a method of preventing or treating- 1 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 cancer in a subject in need thereof comprising: administering to the subject a therapeutically effective amount of a KDM1 A inhibitor and administering to a subject a therapeutically effective amount of an antibody-drug conjugate (ADC) that binds to a tumor-associated antigen.

[0007] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a carcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is metastatic bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic, triple-negative breast cancer.

[0008] In some embodiments, the ADC binds NECTIN4. In some embodiments, the ADC binds TROP2. In some embodiments, the ADC comprises Sacituzumab govitecan. In some embodiments, the ADC comprises Enfortumab vedotin. In some embodiments, the ADC binds HER2. In some embodiments, the ADC comprises Trastuzumab deruxtecan, or Trastuzumab emtansine.

[0009] In some embodiments, the KDM1 A inhibitor comprises a tranylcypromine (TCP) derivative. In some embodiments, the KDM1A inhibitor comprises GSK-LSD1. In some embodiments, the KDM1A inhibitor comprises ORY-1001. In some embodiments, the KDM1 A inhibitor comprises GSK-2879552. In some embodiments, the KDM1 A inhibitor comprises IMG-7289. In some embodiments, the KDM1 A inhibitor comprises INCB059872. In some embodiments, the KDM1A inhibitor comprises ORY-2001. In some embodiments, the KDM1 A inhibitor comprises any tranylcypromine (TCP) derivative. In some embodiments, the KDM1 A inhibitor comprises an inhibitory RNA for a messenger RNA sequence encoding a KDM1 A protein. In some embodiments, the KDM1 A inhibitor comprises a CRISPR cassette comprising a gRNA or sgRNA specific for the nucleotide gene sequence encoding a KDM1A gene or a controlling transcription of a KDM1A gene.

[0010] In some embodiments, the KDM1 A inhibitor is administered before administering the ADC. In some embodiments, the KDM1 A inhibitor is co-administered with the ADC. In some embodiments, the KDM1 A inhibitor is administered after administering the ADC. In some embodiments, the KDM1 A inhibitor is administered before, after, or in combination with radiation therapy.

[0011] In some embodiments, the KDM1 A inhibitor increases expression levels of - 2 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025NECTIN4 and / or TROP2 in tumor cells of the cancer.

[0012] In some embodiments, the KDM1 A inhibitor decreases the IC50 of the ADC as compared to the IC50 when administering the ADC without the KDM1 A inhibitor. In some embodiments, the KDM1 A inhibitor decreases the therapeutically effective amount of the ADC as compared to the therapeutically effective amount of the ADC when administering the ADC without the KDM1 A inhibitor.

[0013] In one aspect, the present application provides a method of modulating a response to an antibody-drug conjugates (ADC) therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a KDM1 A inhibitor.

[0014] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a carcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is metastatic bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic, triple-negative breast cancer.

[0015] In some embodiments, the KDM1 A inhibitor comprises a tranylcypromine (TCP) derivative. In some embodiments, the KDM1A inhibitor comprises GSK-LSD1. In some embodiments, the KDM1A inhibitor comprises ORY-1001. In some embodiments, the KDM1 A inhibitor comprises GSK-2879552. In some embodiments, the KDM1 A inhibitor comprises IMG-7289. In some embodiments, the KDM1 A inhibitor comprises INCB059872. In some embodiments, the KDM1A inhibitor comprises ORY-2001.

[0016] In some embodiments, the KDM1 A inhibitor comprises an inhibitory RNA for a messenger RNA sequence encoding a KDM1 A protein. In some embodiments, the KDM1 A inhibitor comprises a CRISPR cassette comprising a gRNA or sgRNA specific for the nucleotide gene sequence encoding a KDM1A gene or a controlling transcription of a KDM1A gene.

[0017] In some embodiments, the KDM1 A inhibitor is administered before, after, or in combination with radiation therapy.

[0018] In some embodiments, the KDM1 A inhibitor increases expression levels of NECTIN4 and / or TROP2 in tumor cells of the cancer. In some embodiments, the KDM1 A- 3 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 inhibitor decreases the IC50 of the ADC as compared to the IC50 when administering the ADC without the KDM1 A inhibitor.

[0019] In some embodiments, the ADC therapy comprises administering to a subject a therapeutically effective amount of an antibody-drug conjugate (ADC) that binds to a tumor- associated antigen. In some embodiments, the ADC binds NECTIN4. In some embodiments, the ADC binds TROP2. In some embodiments, the ADC binds HER2.

[0020] In some embodiments, the ADC comprises Sacituzumab govitecan. In some embodiments, the ADC comprises Enfortumab vedotin. In some embodiments, the ADC comprises Trastuzumab deruxtecan, Trastuzumab emtansine, or a combination thereof.

[0021] In some embodiments, the KDM1 A inhibitor is administered before administering the ADC. In some embodiments, the KDM1 A inhibitor is co-administered with the ADC. In some embodiments, the KDM1 A inhibitor is administered after administering the ADC.

[0022] In some embodiments, the subject is human.BRIEF DESCRIPTION OF FIGURES

[0023] The patent or application file contains at least one drawing executed in color. To conform to the requirements for PCT patent applications, many of the figures presented herein are black and white representations of images originally created in color.

[0024] FIG. 1 shows drugs and doses for screen.

[0025] FIGS. 2A-B show a small molecule screen for restoration of luminal state. FIG. 2 A shows KRT8 RT-PCR results of a small molecule drug screen to look for epigenetic regulators of luminal identity. FIG. 2B depicts immunofluorescence for KERATIN8 and KERATIN14 in SCBO-5 and SCBO-7 to show basal to luminal state change in organoids after GSK-LSD1 treatment.

[0026] FIGS. 3A-C show inhibition of KDM1A can restore luminal state. FIG. 3A shows immunofluorescence for KERATIN8 and KERATIN14 in SCBO-5, SCBO-7, and SCBO-14 to show basal to luminal state change in organoids after GSK-LSD1 treatment. FIG. 3B shows RT-PCR of multiple luminal markers to show increase of the luminal markers KRT8, GATA3, and FOXA1 after GSK-LSD1 treatment. FIG. 3C depicts - 4 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 immunofluorescence for KERATIN8 and KERATIN14 in SCBO-5 and SCBO-7 to show basal to luminal state change in organoids after ORY-lOOl treatment.

[0027] FIGS. 4A-B show knockdown of KDM1 A reverts luminal-basal plasticity. FIG.4A shows immunofluorescence for KERATIN8 and KERATIN14 in SCBO-5 show basal to luminal state change in organoids after KDM1 A knockdown. FIG. 4B shows RT-PCR of multiple luminal markers to show increase of the luminal markers KRT8, GAT A3, and FOXA1 and lowered expression of KDM1 A after KDM1 A knockdown.

[0028] FIGS. 5A-B show KDM1 A inhibition can maintain luminal state. FIG. 5A shows immunofluorescence for KERATIN8 and KERATIN14 in fresh patient organoids showing luminal state stabilization in organoids after KDM1 A inhibition by GSK-LSD or ORY-lOOl over 3-4 weeks. FIG. 5B is scRNA-seq data of a freshly isolated patient sample treated with ORY-lOOl showing the maintenance of luminal marker PPARG and the reduction of basal marker TP63 when compared to the DMSO control.

[0029] FIGS. 6A-B depict expression levels of NECTIN4 and TROP2 after treatment with GSK inhibitors. FIG. 6A shows scRNA-seq violin plots showing upregulation of NECTIN4 in the patient derived organoid line SCBO-5 after treatment with either DMSO or the KDM1A inhibitors GSK-LSD1, ORY-lOOl, and SP2509 at 24 hours and 7 days. Both GSK-LSD1 and ORY-lOOl show efficacy in upregulating NECTIN4. FIG. 6B shows scRNA-seq violin plots showing upregulation of TROP2 (TACSTD2) in the patient derived organoid line SCBO-5 after treatment with either DMSO or the KDM1 A inhibitors GSK- LSD 1, ORY-lOOl, and SP2509 at 24 hours and 7 days. Both GSK-LSD 1 and ORY-lOOl show efficacy in upregulating TROP2 (TACSTD2).

[0030] FIG. 7 shows Western blot of SCBO-5 treated with either DMSO or GSK-LSD 1. GSK-LSD 1 treatment results in an increase of NECTIN4 protein.

[0031] FIGS. 8A-B show flow cytometry of NECTIN4 after KDM1 A inhibition. FIG. 8A shows flow cytometric quantification of cell surface levels of NECTIN4 in the patient derived organoid line SCBO-5 after 4 days of GSK-LSD 1 treatment. Cell surface levels of NECTIN4 are greatly increased after treatment. FIG. 8B depicts flow cytometric quantification of cell surface levels of NECTIN4 in the patient derived organoid line SCBO- 19.2 after 4 days of GSK-LSD1 treatment. Cell surface levels of NECTIN4 are greatly- 5 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 increased after treatment.

[0032] FIG. 9 shows dose response curve of enfortumab vedotin in the patient derived organoid line SCBO-5 after 4 days of GSK-LSD1 treatment showing a dramatic increase in sensitivity to Enfortumab-vedotin.BACKGROUND

[0033] Antibody Drug Conjugates (ADCs) is a class of biologies that functions by attaching a chemotherapy agent to a monoclonal antibody that preferentially binds a cell surface protein on tumor cells. This approach allows for much higher doses of chemotherapy to be delivered to a patient with fewer side effects than seen with conventional therapies. For this approach to work, the tumor must express the surface marker that is targeted by the ADC.

[0034] NECTIN4 and TACSTD2 (TROP2) are examples of cell surface proteins that serve as surface markers for ADCs. However, low expression of these proteins on tumor cells can result in incomplete therapy response, and decreased expression of these proteins may represent a mechanism of tumor resistance to ADC therapy. Therefore, there is a need for a regulator to increase their expression and improve the response of certain tumors to ADC therapies.DETAILED DESCRIPTION OF THE INVENTION

[0035] The singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0036] As would be apparent to one of ordinary skill in the art, any method or composition described herein can be implemented with respect to any other method or composition described herein.

[0037] These, and other, embodiments of the invention will be better appreciated and understood when considered in conjunction with the following description and the accompanying drawings. It should be understood, however, that the following description,- 6 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 while indicating various embodiments of the invention and numerous specific details thereof, is given by way of illustration and not of limitation. Many substitutions, modifications, additions and / or rearrangements may be made within the scope of the invention without departing from the spirit thereof, and the invention includes all such substitutions, modifications, additions and / or rearrangements.

[0038] An “effective amount”, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, for example, to reduce or ameliorate the severity and / or duration of an affliction or condition, or one or more symptoms thereof, prevent the advancement of conditions related to an affliction or condition, prevent the recurrence, development, or onset of one or more symptoms associated with an affliction or condition, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects.

[0039] The terms “animal,” “subject” and “patient” as used herein includes all members of the animal kingdom including, but not limited to, mammals, animals (e.g., cats, dogs, horses, swine, etc.) and humans.

[0040] The corresponding NCBI Gene IDs for the genes are provided herein. The full nucleic acid and amino acid sequences of these genes can be readily obtained by accessing the National Center for Biotechnology Information (NCBI) database using the provided Gene IDs. These sequences are publicly available and can be retrieved using standard bioinformatics tools or direct database queries. The nucleic acid and amino acid sequences of the genes identified by their respective Gene IDs are hereby incorporated by reference in their entirety.

[0041] The corresponding PubChem ID for the compounds are provided herein. The information of the compounds can be readily obtained by accessing the National Center for Biotechnology Information (NCBI) PubChem database using the provided PubChem IDs. The information on the compounds is publicly available and is hereby incorporated by reference in its entirety.

[0042] The present application is, at least in part, directed to inhibitors of KDM1 A, an - 7 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 epigenetic regulator, for the treatment of cancer. The present application is at least in part directed to the treatment of cancer in a subject using KDM1 A inhibition to increase ADC target protein expression. In some embodiments, KDM1 A is also known as Lysine-specific demethylase (LSD1).

[0043] Enfortumab vedotin and Sacituzumab govitecan are both members of a class of biologies called ADCs, which function by attaching a chemotherapy agent to a monoclonal antibody that preferentially binds a cell surface protein on tumor cells. This approach allows for much higher doses of chemotherapy to be delivered to a patient with fewer side effects than seen with systemic chemotherapy. For this approach to work, the tumor must express the surface marker that is targeted by the ADC. For Enfortumab vedotin, this cell surface protein is NECTIN4, while for Sacituzumab govitecan, the cell surface protein is TACSTD2 (TROP2). Low expression of these proteins on tumor cells can result in incomplete therapy response and decreased expression of these proteins may represent a mechanism of tumor resistance to ADC therapy.

[0044] The present application provides, at least in part, a new approach for modulating response to ADC therapies in cancer through epigenetic reprogramming of cell states, resulting in increased expression of the ADC-targeted cell surface protein. In some embodiments, the cancer is bladder cancer. NECTIN4 and TROP2 are markers of luminal tumor cells in bladder cancer and are expressed at lower levels in basal tumor cells. By altering cell states in basal subtype bladder tumors using inhibitors of the epigenetic regulator KDM1A (also known as LSD1), which encodes a histone demethylase, NECTIN4 and / or TROP2 expression can be increased and consequently ADC response in patients. In some embodiments, the KDM1 A inhibitor is a small molecule inhibitor. Additionally, KMT2C and KMT2D are members of the COMPASS complex and are often mutated in both bladder and breast cancer. There is a correlation between response to KDM1 A inhibition and the loss of function mutations in KMT2C / KMT2D during tumorigenesis. This may be because the epigenetic marks that KMT2C / KMT2D are capable of writing (H3K4mel / 2) are the same marks that KDM1 A is capable of erasing. Thereby KDM1 A inhibition can serve as an antidote to KMT2C / KMT2D loss of function.- 8 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025Methods of Treating and Preventing Cancer

[0045] In one aspect, the present application provides a method of treating or preventing cancer in a subject in need thereof comprising: administering to the subject a therapeutically effective amount of a KDM1 A inhibitor and administering to a subject a therapeutically effective amount of an antibody-drug conjugate (ADC) that binds to a tumor-associated antigen.

[0046] The inhibitors or compositions used to treat or prevent cancer described herein may be formulated into pharmaceutical compositions or formulations using one or more pharmaceutically acceptable excipients, carriers, or diluents. These pharmaceutical compositions or formulations may be designed for various routes of administration, including but not limited to oral, intravenous, intramuscular, subcutaneous, intranasal, intraperitoneal, intradermal, or topical delivery. Suitable excipients may include stabilizers, preservatives, solubilizers, emulsifiers, buffers, and agents that enhance bioavailability or control release kinetics. Such pharmaceutical compositions or formulations may be tailored to improve stability, shelf-life, patient compliance, and therapeutic performance. The pharmaceutical compositions or formulations may be provided in dosage forms such as tablets, pills, capsules, solutions, suspensions, emulsions, injectables, or transdermal patches, depending on the intended use and delivery method.

[0047] The dosage and administration of the compositions or formulations described herein may vary depending on several factors, including but not limited to the nature and severity of the condition being treated, the route of administration, the formulation used, and the individual characteristics of the subject such as age, weight, sex, and overall health status. Determining the appropriate dosing regimens may be established based on clinical guidelines, preclinical data, and routine experimentation. Dosages may be adjusted to achieve optimal therapeutic efficacy while minimizing potential side effects. In certain embodiments, the compositions or formulations may be administered in a single dose, multiple doses, or as part of a continuous or intermittent dosing schedule.

[0048] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a carcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is metastatic bladder cancer. In some embodiments, the cancer is- 9 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 breast cancer. In some embodiments, the cancer is metastatic, triple-negative breast cancer. In some embodiments, the cancer is an early-stage cancer. In some embodiments, the cancer is Stage 0 cancer. In some embodiments, the cancer is Stage I cancer. In some embodiments, the cancer is Stage II cancer. In some embodiments, the cancer is Stage III cancer. In some embodiments, the cancer is Stage IV cancer. In some embodiments, the cancer is an advanced stage or an end-stage cancer.

[0049] In some embodiments, the ADC binds NECTIN4. In some embodiments, the ADC binds TROP2. In some embodiments, the ADC is Sacituzumab govitecan. In some embodiments, the ADC is Enfortumab vedotin. In some embodiments, the ADC binds HER2. In some embodiments, the ADC is Trastuzumab deruxtecan, or Trastuzumab emtansine.

[0050] In some embodiments, the KDM1 A inhibitor comprises a tranylcypromine (TCP) derivative. In some embodiments, the KDM1A inhibitor comprises GSK-LSD1. In some embodiments, the KDM1A inhibitor comprises ORY-1001. In some embodiments, the KDM1 A inhibitor comprises GSK-2879552. In some embodiments, the KDM1 A inhibitor comprises IMG-7289. In some embodiments, the KDM1 A inhibitor comprises INCB059872. In some embodiments, the KDM1A inhibitor comprises ORY-2001. In some embodiments, the KDM1 A inhibitor comprises any tranylcypromine (TCP) derivative.

[0051] In some embodiments, the KDM1 A inhibitor is administered before administering the ADC. In some embodiments, the KDM1 A inhibitor is co-administered with the ADC. In some embodiments, the KDM1 A inhibitor is administered after administering the ADC. In some embodiments, the KDM1 A inhibitor is administered before, after, or in combination with radiation therapy.

[0052] In some embodiments, the KDM1 A inhibitor can be administered, about 1 hour before the ADC, about 2 hours before the ADC, about 4 hours before the ADC, about 6 hours before the ADC, about 8 hours before the ADC, about 12 hours before the ADC, about 1 day before the ADC, about 2 days before the ADC, about 3 days before the ADC, about 4 days before the ADC, about 5 days before the ADC, about 6 days before the ADC, or about 1 week before the ADC.

[0053] In some embodiments, the KDM1 A inhibitor can be administered, about 1 hour- 10 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 after the ADC, about 2 hours after the ADC, about 4 hours after the ADC, about 6 hours after the ADC, about 8 hours after the ADC, about 12 hours after the ADC, about 1 day after the ADC, about 2 days after the ADC, about 3 days after the ADC, about 4 days after the ADC, about 5 days after the ADC, about 6 days after the ADC, or about 1 week after the ADC.

[0054] In some embodiments, the KDM1 A inhibitor increases expression levels of NECTIN4, TROP2, or a combination thereof in tumor cells of the cancer. Expression levels (e.g. mRNA levels, protein levels, or a combination thereof) can be measured by a variety of methods known in the art, including but not limited to, RNAseq, single-cell RNAseq, quantitative PCR, microarrays, Western Blotting, ELISA, mass spectrometry, and in situ hybridization.

[0055] In some embodiments, the KDM1 A inhibitor decreases the IC50 of the ADC as compared to the IC50 when administering the ADC without the KDM1 A inhibitor. IC50 is the concentration of the ADC required to reduce its potency in killing target cells by 50%. Methods of determining killing of target cells are known in the art and include, but are not limited, to MTT assay, CellTiter-Glo assay, or CellTiter-Glo 3D assay. In some embodiments, the IC50 is measured in vitro using a cancer cell line.

[0056] In some embodiments, the KDM1 A inhibitor decreases the therapeutically effective amount of the ADC as compared to the therapeutically effective amount of the ADC when administering the ADC without the KDM1 A inhibitor.

[0057] In some embodiments, the subject is human.

[0058] In some embodiments, the KDM1A inhibitor comprises GSK-LSD1 (PubChem ID: 71522234). GSK-LSD1 can be referred to as its systemic name: N-[(lR,2S)-2- phenylcyclopropyl]piperidin-4-amine. In some embodiments, GSK-LSD1 comprises, consists essentially of, or consists of the structure:, or analogs or pharmaceutically acceptable salts thereof.

[0059] In some embodiments, the KDM1A inhibitor comprises ORY-1001 (PubChem ID: 71664305). ORY-1001 can be referred to as its systemic name: 4-N-[(lR,2S)-2-- 11 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 phenylcyclopropyl]cyclohexane-l,4-diamine;dihydrochloride. In some embodiments, ORY- 1001 comprises, consists essentially of, or consists of the structure:, or analogs or pharmaceutically acceptable salts thereof.See Maes T, Mascaro C, Tirapu I, et al. ORY-1001, a Potent and Selective Covalent KDM1 A Inhibitor, for the Treatment of Acute Leukemia. Cancer Cell. 2018;33(3):495-51 l.el2, the contents of which are hereby incorporated by reference in its entirety.

[0060] In some embodiments, the KDM1 A inhibitor comprises GSK-2879552 (PubChem ID: 66571643). GSK-2879552 can be referred to as its systemic name: 4-[[4-[[[(lR,2S)-2- phenylcyclopropyl]amino]methyl]piperidin-l-yl]methyl]benzoic acid. In some embodiments, GSK-2879552 comprises, consists essentially of, or consists of the structure:, or analogs, or pharmaceutically acceptable salts thereof.

[0061] In some embodiments, the KDM1A inhibitor comprises IMG-7289 (PubChem ID: 122460381). IMG-7289 can be referred to as its systemic name: N-[(2S)-5-[[(lR,2S)-2-(4- fluorophenyl)cyclopropyl]amino]- 1 -(4-methylpiperazin- 1 -yl)- 1 -oxopentan-2-yl]-4-(triazol- 1 - yl)benzamide. In some embodiments, IMG-7289 comprises, consists essentially of, or consists of the structure:, or analogs, or pharmaceutically acceptable salts thereof.

[0062] In some embodiments, the KDM1 A inhibitor comprises INCB059872 (PubChem- 12 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025ID: 118290753). INCB059872 can be referred to as its systemic name: l-[[4- (methoxymethyl)-4-[[[(lR,2S)-2-phenylcyclopropyl]amino]methyl]piperidin-l- yl]methyl]cyclobutane-l-carboxylic acid. In some embodiments, INCB059872 comprises, consists essentially of, or consists of the structure:or analogs, or pharmaceutically acceptable salts thereof.

[0063] In some embodiments, the KDM1A inhibitor comprises ORY-2001 (Vafi dem stat). In some embodiments, the PubChem ID of ORY-2001 is 66714983. In some embodiments, ORY-2001 can also be referred to as its systemic name: 5-[[[(lR,2S)-2-(4- phenylmethoxyphenyl)cyclopropyl]amino]methyl]-l,3,4-oxadiazol-2-amine. In some embodiments, ORY-2001 comprises, consists essentially of, or consists of the structure:or analogs, or pharmaceutically acceptable salts thereof.

[0064] In some embodiments, the KDM1A inhibitor comprises 5-[[[(lS,2R)-2-(4- phenylmethoxyphenyl)cyclopropyl]amino]methyl]-l,3,4-oxadiazol-2-amine (PubChem ID:- 13 -ACTIVEUS 211910937Atly. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 202556639835). In some embodiments, 5-[[[(l S,2R)-2-(4- phenylmethoxyphenyl)cyclopropyl]amino]methyl]-l,3,4-oxadiazol-2-amine comprises,consists essentially of, or consists of the structure: or analogs, or pharmaceutically acceptable salts thereof.

[0065] In some embodiments, KDM1 A is inhibited through genetic alterations. In certain aspects, described herein are nucleic acids encoding RNAs of interest, which includes, but is not limited to an interfering RNA (iRNA), and variants thereof, that can silence a target gene, such as KDM1A (GenelD: 23028). An iRNA can down-regulate the expression of a target gene, e.g., KDM1A. An inhibitory RNA (iRNA) may act by one or more of a number of mechanisms, including post-transcriptional cleavage of a target mRNA sometimes referred to in the art as RNAi, or pre-transcriptional or pre-translational mechanisms. An iRNA can be a double stranded (ds) iRNA. A ds iRNA includes more than one, and in certain embodiments two, strands in which interchain hybridization can form a region of duplex structure. A strand refers to a contiguous sequence of nucleotides (including non-naturally occurring or modified nucleotides). At least one strand can include a region which is sufficiently complementary to a target RNA. Such strand is termed the antisense strand. A second strand comprised in the dsRNA which comprises a region complementary to the antisense strand is termed the sense strand. However, a ds iRNA can also be formed from a single RNA molecule which is, at least partly; self-complementary, forming, e.g., a hairpin or panhandle structure, including a duplex region. In such case, the term strand refers to one of the regions of the RNA molecule that is complementary to another region of the same RNA molecule. Nonlimiting examples of inhibitory RNA include miRNA, siRNA, shRNA, and piRNA. iRNA as described herein, including ds iRNA and siRNA, can mediate silencing of a gene,- 14 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 e.g., by RNA degradation. In certain embodiments, the gene to be silenced is KDM1A. In some embodiments, KDM1A translation is downregulated or inhibited via small interfering RNA targeting the KDM1 A mRNA.

[0066] In certain embodiments, the CRISPR cassette comprises an oligonucleotide comprising a guide RNA (gRNA) or single guide RNA (sgRNA). The CRISPR / Cas9 gene editing technique promotes a new human gene therapy strategy by editing DNA at pre-chosen sites without altering the endogenous regulation of target genes. This system consists of two key components: Cas9 protein and a guide RNA, e.g., a single guide RNA (sgRNA), as well as a correction template when needed. In some embodiments, a CRISPR cassette refers to a DNA construct that contains all necessary elements for CRISPR-based gene editing, typically including the sgRNA sequence, the Cas9 coding region, and regulatory elements for expression. sgRNA contains two components: a 17-20 nucleotide sequence termed CRISPR RNA that is complementary to the target DNA region, and a tracrRNA (trans-activating CRISPR RNA) that serves as the binding scaffold for a Cas nuclease. In some embodiments, the CRISPR cassette comprises the sgRNA sequence, wherein the other elements for CRISPR-based gene editing are provided separately. The cassette enables delivery and expression of the CRISPR components in target cells, facilitating precise genome editing. The sgRNA recognizes the target DNA and guides the Cas9 nuclease to the region for editing.

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention.

[0068] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are considered to be within the scope of this invention, and are covered by the following claims.

[0069] All publications and other references mentioned herein are incorporated by- 15 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 reference in their entirety, as if each individual publication or reference were specifically and individually indicated to be incorporated by reference. Publications and references cited herein are not admitted to be prior art.EXAMPLES

[0070] Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results.Example 1: Small molecule screen for restoration of luminal state

[0071] The SCBO-5 organoid line was passaged as per protocols provided by Lee, S. H., Hu, W., Matulay, J. T., Silva, M. V., Owczarek, T. B., Kim, K., Chua, C. W., Barlow, L. J., Kandoth, C., Williams, A. B., Bergren, S. K., Pietzak, E. J., Anderson, C. B., Benson, M. C., Coleman, J. A., Taylor, B. S., Abate-Shen, C., McKiernan, J. M., Al-Ahmadie, H., Solit, D. B., ... Shen, M. M. (2018). Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer. Cell, 173(2), 515-528. el7. doi.org / 10.1016 / j. cell.2018.03.017 (“Lee et al.”), the contents of which are hereby incorporated by reference in its entirety. 34x 100,000 cells were seeded in a 5% Matrigel slurry with media into distinct wells of 2 ultralow attachment 24-well tissue culture plates and was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, the compounds listed on the following slide plus a DMSO control was added at the doses stated and the cells were incubated with the drug for the next four days. On the fourth day, RNA was isolated from each treated sample and cDNA was produced from it. This cDNA was then used for RT-PCR quantification of KRT8 RNA levels as a measure of reluminalization. The primer sequences used are provided in Table 1 below. The RT-PCR results were quantified using PRISM.- 16 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025Table 1Example 2: Inhibition of KDM1A can restore luminal state

[0072] The SCBO-5, SCBO-7, and SCBO-14 organoid lines were passaged as per protocols provided by Lee et al., and 6x 200,000 cells were seeded in 5% Matrigel slurry with media which was added to six distinct wells of an ultralow attachment 6-well tissue culture, and the plate was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, 1 pM GSK-LSD1 or DMSO were added to appropriate wells. After 4 days, the cells were removed from culture and washed with hanks balanced salt solution. The resulting organoids were then split into two groups for each condition. One group was formalin fixed and paraffin embedded (FFPE), after which the block was sectioned, stained with antibodies specific for Keratin8 (Luminal marker) and Keratinl4 (Basal marker), and imaged on a confocal microscope. For the other group, RNA was isolated from each treated sample and cDNA was produced from it. This cDNA was then used for RT-PCR quantification of KRT8, FOXA1, and GATA3 RNA levels as a measure of reluminalization.

[0073] The SCBO-5 and SCBO-7 organoid lines were passaged as per protocols provided by Lee et al., and 6x 200,000 cells were seeded in 5% Matrigel slurry with media which was added to four distinct wells of an ultralow attachment 6-well tissue culture, and the plate was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, 1 pM ORY- 1001 or DMSO were added to appropriate wells. After 4 days, the cells were removed from culture and washed with hanks balanced salt solution. The resulting organoids were then split into two groups for each condition. One group was formalin fixed and paraffin embedded (FFPE), after which the block was sectioned, stained with antibodies specific for Keratin8 (Luminal marker) and Keratin 14 (Basal marker), and imaged on a confocal microscope. The primer sequences used are provided in Table 2 below. The RT-PCR results were quantified using PRISM.- 17 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025Table 2Example 3: Knockdown of KDM1A reverts luminal-basal plasticity

[0074] The SCBO-5 organoid was passaged and 2x 200,000 cells were infected with lentivirus that expressed either a nontargeting shRNA construct (e.g., shLacz) or an shRNA against KDM1A (GenelD: 23028) with a puromycin resistance cassette. The shRNA sequences used are provided in Table 3 below. The cells were then seeded in ultralow attachment 6-well tissue culture in a 5% Matrigel slurry with media 5 ug / ml of polybrene and the plate was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, the virus was removed, and the cells were washed with hanks balanced salt solution (HBSS) and reseeded into fresh 5% Matrigel slurry with media and allowed to incubate overnight. The following day, the cells were selected with 2 ug / ml of puromycin until all uninfected cells were dead. The cells were then allowed to recover and form new organoids in culture, after which, one Matrigel for each viral construct was broken up by enzymatic digestion with neutral protease and mechanical disruption with a micropipette. The resulting organoids were then split into two groups for each condition. One group was formalin fixed and paraffin embedded (FFPE), after which the block was sectioned, stained with antibodies specific for Keratin8 (Luminal marker) and Keratinl4 (Basal marker), and imaged on a confocal microscope. For the other group, RNA was isolated from each treated sample and cDNA was produced from it. This cDNA was then used for RT-PCR quantification of- 18 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025KDM1 A, KRT8, F0XA1, and GATA3 RNA levels as a measure of reluminalization and to confirm KDM1 A knockdown. The primer sequences used are provided in Table 4 below. The RT-PCR results were quantified using PRISM.Table 3Table 4Example 4: KDM1A inhibition can maintain luminal state

[0075] Organoids were isolated from a consented patient’s transurethral resection of bladder tumor (TURBT) and seeded into two 100% Matrigel buttons which was allowed to- 19 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 set in 3 distinct wells of an ultralow attachment 6-well tissue culture plate. After the Matrigel button had solidified, 2 ml of complete organoid media was added to each of the 3 wells and the plate was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, 1 uM GSK-LSD1, 1 pM ORY-lOOl, or DMSO was added to the appropriate well. The organoids were treated like this for 3-4 weeks, after which, they were split in two groups for each condition. One group was formalin fixed and paraffin embedded (FFPE), after which, the block was sectioned, stained with antibodies specific for Keratin8 (Luminal marker) and Keratinl4 (Basal marker), and imaged on a confocal microscope. The other group was spun down and snap frozen for later single nuclei RNA-seq. Nuclei were isolated from the snap frozen sample and single nuclei RNA-seq was then performed. Upon receipt of the sequencing results, they were processed using the CellRanger software and differentially gene expression was performed using the Seruat R package.Example 5: SCBO-5 KDM1A scRNA-seq Treatment

[0076] The SCBO-5 organoid line was passaged as per protocols provided by Lee et al., and 8x 200,000 cells were seeded in 100% Matrigel button, which was allowed to set in 8 distinct wells across 2 ultralow attachment 6-well tissue culture plates. After the Matrigel button had solidified, 2 ml of complete organoid media was added to each of the 8 wells and the plate was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, 1 pM GSK-LSD1, 1 pM ORY-lOOl, 1 pM SP2509, or DMSO were added to two designated wells, ensuring sufficient cell numbers for both the 24 hour and 7-day timepoint. The next morning, one Matrigel button for each condition was broken up by enzymatic digestion with neutral protease and mechanical disruption with a micropipette. The cell clusters were then broken up further with TrypLE and passed through a 40-micron filter followed by a 20-micron filter to isolate single cells. All four conditions were then hashed using antibody tagged oligos and submitted as a single cell RNA-seq run on the lOx Genomics platform. On day 4, the media for the day 7 timepoint was exchanged for new media and fresh drug treatment. On day 7, the above processing protocol was repeated and the day 7 timepoint was submitted identically.

[0077] Upon receipt of the sequencing results, they were processed using the CellRanger software and differentially gene expression was performed using the Seruat R package.- 20 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025Example 6: Western for NECTIN4 after KDM1A Inhibition

[0078] The SCBO-5 organoid line was passaged as per protocols provided by Lee et al., and 2x 200,000 cells were seeded in 100% Matrigel button, which was allowed to set in 2 distinct wells of an ultralow attachment 6-well tissue culture plate. After the Matrigel button had solidified, 2 ml of complete organoid media was added to each of the 2 wells and the plate was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, 1 pM of GSK-LSD1 or DMSO control were added to their respective wells. After 4 days, both Matrigel buttons were broken up by enzymatic digestion with neutral protease and mechanical disruption with a micropipette. The cells were washed 2x with cold Hanks Balanced Salt Solution (HBSS) to eliminate residual Matrigel and were pelleted. The cell pellets were then lysed using lx Radioimmunoprecipitation assay (RIP A) buffer supplemented with freshly added protease and phosphatase inhibitors. The lysates were then homogenized via multiple passes through 31 -gauge insulin syringe and insoluble material was separated away by centrifugation. The cleared lysates protein concentration was then quantified. To visualize NECTIN4 levels equivalent protein masses were loaded on a denaturing, gradient, polyacrylamide gel and were separated by gel electrophoresis. The separated protein was then transferred to a PVDF membrane via wet tank transfer. After transfer, the PVDF membrane was blocked with 5% bovine serum albumin and probed by a rabbit antibody specific for NECTIN4 followed by an anti rabbit IgG secondary antibody conjugated to horseradish peroxidase. The blot was then visualized using chemiluminescence and image capture by a charge-couple device camera. The blot was then stripped, and as a protein loading control, ACTIN was probed for via an identical approach as above.Example 7: Flow Cytometry NECTIN4 after KDM1A Inhibition

[0079] The SCBO-5 and SCBO-19.2 organoid lines were passaged as per protocols provided by Lee et al., and 2x 200,000 cells were seeded, per line, in 100% Matrigel button, which was allowed to set in 4 distinct wells of an ultralow attachment 6-well tissue culture plate. After the Matrigel button had solidified 2 ml of complete organoid media was added to each of the wells and the plate was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, 1 pM of GSK-LSD1 or DMSO control were added to their respective wells. After 4 days, all Matrigel buttons were broken up by enzymatic digestion with neutral protease and mechanical disruption with a micropipette. The cell clusters were- 21 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 then broken up further with TrypLE and passed through a 40-micron filter to isolate single cells. Single cells were then stained with NECTIN4-PE and EPCAM-APC. The stained cells were then analyzed on a NovoCyte flow cytometer. The resulting data was then analyzed and visualized in FlowJo.Example 8: Dose Response Curve for Enfortumab Vedotin

[0080] The SCBO-5 organoid line was passaged as per protocols provided by Lee et al., and 2x 200,000 cells were seeded in 100% Matrigel button which was allowed to set in 2 distinct wells of an ultralow attachment 6-well tissue culture plate. After the Matrigel button had solidified, 2 ml of complete organoid media was added to each of the 2 wells and the plate was placed in a humidified, 5% CO2, 37°C cell culture incubator. The next morning, 1 pM of GSK-LSD1 or DMSO control were added to their respective wells. After 4 days, both Matrigel buttons were broken up by enzymatic digestion with neutral protease and mechanical disruption with a micropipette. The cell clusters were then broken up further with TrypLE and passed through a 40-micron filter to isolate single cells. These single cells were then seeded in equal number into 96-well plates with either GSK-LSD1 or DMSO as matching the cells’ previous treatment. The next morning, dilutions of Enfortumab vedotin at 10 pg / ml, 5 pg / ml, 2.5 pg / ml, 1.25 pg / ml, 0.625 pg / ml, 0.3125 pg / ml, 0.15625 pg / ml, and 0 pg / ml were added. The cells were then incubated for 14 days, after which viability was read out using CellTiterGlo 3D and a plate luminometer. Dose response curves were created using Prism.

[0081] Using human patient-derived bladder tumor organoid models to pharmacologically inhibit KDM1 A greatly increased expression of NECTIN4 and TROP2 in a subset of these organoid lines, as demonstrated by single cell RNA-sequencing (scRNA- seq) (FIGS. 6A-B), Western blotting (FIG. 7), and flow cytometry (FIGS. 8A-B). Furthermore, using an organoid line that is sensitive to KDM1 A inhibitor in culture, shows that the IC50 of Enfortumab vedotin significantly decreases by 2-log units (from 0.39 pg / ml to 0.0014 pg / ml) after pharmacological KDM1 A inhibition (FIG. 9). These results demonstrate that KDM1 A inhibition provides a method for increasing ADC target protein expression, resulting in improved ADC activity. Consequently, administration of a KDM1 A inhibitor before administration of one of these ADCs or co-administration of a KDM1 A inhibitor together with one of these ADCs should result in greatly improved patient response- 22 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025 in comparison to the ADC alone.

[0082] It is important to note that Sacituzumab govitecan is also approved for treatment of metastatic triple-negative breast cancer, and that this approach of using KDM1 A inhibition to modulate luminal cell states to increase ADC target protein expression is broadly applicable in other carcinoma types, as well as with additional ADCs that have not yet been approved.ACTIVEUS 211910937

Claims

Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 2025CLAIMSWhat is claimed is:

1. A method of treating or preventing cancer in a subject in need thereof comprising: administering to the subject a therapeutically effective amount of a KDM1 A inhibitor, and administering to a subject a therapeutically effective amount of an antibody-drug conjugate (ADC) that binds to a tumor-associated antigen.

2. The method of claim 1, wherein the cancer is a solid tumor.

3. The method of claim 1, wherein the cancer is a carcinoma.

4. The method of claim 1, wherein the cancer is bladder cancer.

5. The method of claim 1, wherein the cancer is metastatic bladder cancer.

6. The method of claim 1, wherein the cancer is breast cancer.

7. The method of claim 1, wherein the cancer is metastatic, triple-negative breast cancer.

8. The method of any one of claims 1-7, wherein the ADC binds NECTIN4.

9. The method of any one of claims 1-7, wherein the ADC binds TROP2.

10. The method of any one of claims 1-7, wherein the ADC binds HER2.

11. The method of any one of claims 1-7, wherein the ADC comprises Sacituzumab govitecan.

12. The method of any one of claims 1-7, wherein the ADC comprises Enfortumab vedotin.

13. The method of any one of claims 1-7, wherein the ADC comprises Trastuzumab deruxtecan, Trastuzumab emtansine, or a combination thereof.

14. The method of any one of claims 1-13, wherein the KDM1 A inhibitor comprises a tranylcypromine (TCP) derivative.

15. The method of any one of claims 1-13, wherein the KDM1A inhibitor comprises GSK- LSD1.

16. The method of any one of claims 1-13 or 15, wherein the KDM1A inhibitor comprisesanalog thereof, or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 1-13, wherein the KDM1 A inhibitor comprises ORY- 1001.- 24 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 202518. The method of any one of claims 1-13 or 17, wherein the KDM1 A inhibitor comprises, an analog thereof, or a phamaceutically acceptable salt thereof.

19. The method of any one of claims 1-13, wherein the KDM1A inhibitor comprises GSK- 2879552.

20. The method of any one of claims 1-13 or 19, wherein the KDM1 A inhibitor comprises, an analog thereof, or a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 1-13, wherein the KDM1A inhibitor comprises IMG- 7289.

22. The method of any one of claims 1-13 or 21, wherein the KDM1 A inhibitor comprises,, an analog thereof, or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 1-13, wherein the KDM1 A inhibitor comprises INCB059872.ACTIVEUS 211910937Aty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 202524. The method of any one of claims 1-13 or 23, wherein the KDM1 A inhibitor comprises, an analog thereof, or a pharmaceutically acceptable salt thereof.

25. The method of any one of claims 1-13, wherein the KDM1 A inhibitor comprises ORY- 2001.

26. The method of any one of claims 1-13 or 25, wherein the KDM1 A inhibitor comprises, an analog thereof, or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 1-13, wherein the KDM1 A inhibitor comprises an inhibitory RNA for a messenger RNA sequence encoding a KDM1 A protein.

28. The method of any one of claims 1-13 or 27, wherein the KDM1 A inhibitor comprises a CRISPR cassette comprising a gRNA or sgRNA specific for the nucleotide gene sequence encoding a KDM1A gene or a controlling transcription of a KDM1A gene.

29. The method of any one of claims 1-28, wherein the KDM1 A inhibitor is administered before administering the ADC.

30. The method of any one of claims 1-28, wherein the KDM1 A inhibitor is co-administered with the ADC.ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 202531. The method of any one of claims 1-28, wherein the KDM1 A inhibitor is administered after administering the ADC.

32. The method of any one of claims 1-31, wherein the KDM1 A inhibitor is administered before, after, or in combination with radiation therapy.

33. The method of any one of claims 1-32, wherein the KDM1 A inhibitor increases expression levels of NECTIN4 and / or TR0P2 in tumor cells of the cancer.

34. The method of any one of claims 1-32, wherein the KDM1 A inhibitor decreases the IC50 of the ADC as compared to the IC50 when administering the ADC without the KDM1 A inhibitor.

35. The method of any one of claims 1-32, wherein the KDM1 A inhibitor decreases the therapeutically effective amount of the ADC as compared to the therapeutically effective amount of the ADC when administering the ADC without the KDM1 A inhibitor.

36. A method of modulating a response to an antibody-drug conjugates (ADC) therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a KDM1 A inhibitor.

37. The method of claim 36, wherein the cancer is a solid tumor.

38. The method of claim 36, wherein the cancer is a carcinoma.

39. The method of claim 36, wherein the cancer is bladder cancer.

40. The method of claim 36, wherein the cancer is metastatic bladder cancer.

41. The method of claim 36, wherein the cancer is breast cancer.

42. The method of claim 36, wherein the cancer is metastatic, triple-negative breast cancer.

43. The method of any one of claims 36-42, wherein the KDM1 A inhibitor comprises a tranylcypromine (TCP) derivative.

44. The method of any one of claims 36-42, wherein the KDM1 A inhibitor comprises GSK- LSD1.

45. The method of any one of claims 36-42 or 44, wherein the KDM1 A inhibitor comprisesanalog thereof, or a pharmaceutically acceptable salt thereof.

46. The method of any one of claims 36-42, wherein the KDM1 A inhibitor comprises ORY-1001.- 27 -ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 202547. The method of any one of claims 36-42 or 46, wherein the KDM1 A inhibitor comprises, an analog thereof, or a phamaceutically acceptable salt thereof.

48. The method of any one of claims 36-42, wherein the KDM1 A inhibitor comprises GSK- 2879552.

49. The method of any one of claims 36-42 or 48, wherein the KDM1 A inhibitor comprises, an analog thereof, or a pharmaceutically acceptable salt thereof.

50. The method of any one of claims 36-42, wherein the KDM1 A inhibitor comprises IMG- 7289.

51. The method of any one of claims 36-42 or 50, wherein the KDM1 A inhibitor comprises,, an analog thereof, or a pharmaceutically acceptable salt thereof.

52. The method of any one of claims 36-42, wherein the KDM1 A inhibitor comprises INCB059872.- 28 -ACTIVEUS 211910937Aty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 202553. The method of any one of claims 36-42 or 52, wherein the KDM1 A inhibitor comprises, an analog thereof, or a pharmaceutically acceptable salt thereof.

54. The method of any one of claims 36-42, wherein the KDM1 A inhibitor comprises ORY- 2001.

55. The method of any one of claims 36-42 or 54, wherein the KDM1 A inhibitor comprises, an analog thereof, or a pharmaceutically acceptable salt thereof.

56. The method of any one of claims 36-42, wherein the KDM1 A inhibitor comprises an inhibitory RNA for a messenger RNA sequence encoding a KDM1 A protein.

57. The method of any one of claims 36-42 or 56, wherein the KDM1 A inhibitor comprises a CRISPR cassette comprising a gRNA or sgRNA specific for the nucleotide gene sequence encoding a KDM1A gene or a controlling transcription of a KDM1A gene.

58. The method of any one of claims 36-57, wherein the KDM1 A inhibitor is administered before, after, or in combination with radiation therapy.

59. The method of any one of claims 36-58, wherein the KDM1 A inhibitor increases expression levels of NECTIN4 and / or TR0P2 in tumor cells of the cancer.ACTIVEUS 211910937Atty. Docket No.: 0019240-1335 WO1Date of Filing: October 3, 202560. The method of any one of claims 36-58, wherein the KDM1 A inhibitor decreases the IC50 of the ADC as compared to the IC50 when administering the ADC without the KDM1 A inhibitor.

61. The method of any one of claims 36-60, wherein the ADC therapy comprises administering to a subject a therapeutically effective amount of an antibody-drug conjugate (ADC) that binds to a tumor-associated antigen.

62. The method of claim 61, wherein the ADC binds NECTIN4.

63. The method of claim 61, wherein the ADC binds TROP2.

64. The method of claim 61, wherein the ADC binds HER2.

65. The method of claim 61, wherein the ADC comprises Sacituzumab govitecan.

66. The method of claim 61, wherein the ADC comprises Enfortumab vedotin.

67. The method of claim 61, wherein the ADC comprises Trastuzumab deruxtecan, Trastuzumab emtansine, or a combination thereof.

68. The method of any one of claims 61-67, wherein the KDM1 A inhibitor is administered before administering the ADC.

69. The method of any one of claims 61-67, wherein the KDM1 A inhibitor is co-administered with the ADC.

70. The method of any one of claims 61-67, wherein the KDM1 A inhibitor is administered after administering the ADC.

71. The method of claims 1-70, wherein the subject is a human.- 30 -ACTIVEUS 211910937

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