Combinations of LSD1 inhibitors for treatment of solid tumors

Abstract

The present invention relates to therapeutic combinations of LSD1 inhibitors with one or more additional active pharmaceutical ingredients or pharmaceutically acceptable salts thereof. The combination is particularly useful for the treatment of neoplastic diseases, such as cancer, in particular small cell lung cancer (SCLC).

Description

[0001] This application is a divisional application of Chinese patent application 201780029779.1. The filing date of the original application is March 13, 2017, and the name is “Combination of LSD1 inhibitors for the treatment of solid tumors”. Field of the Invention

[0002] The present invention relates to therapeutic combinations of LSD1 inhibitors with one or more additional active pharmaceutical ingredients or pharmaceutically acceptable salts thereof. The combinations are particularly useful in the treatment of tumor diseases, such as cancer, in particular small cell lung cancer (SCLC). Background of the Invention

[0003] Aberrant gene expression in affected tissues compared to normal tissues is a common feature of many human diseases. This is true for cancer and many neurological diseases, which are characterized by altered gene expression patterns. Gene expression patterns are controlled at multiple levels in the cell. Control of gene expression can occur through modifications of DNA: DNA promoter methylation is associated with the repression of gene expression. Several inhibitors of DNA methylation are approved for clinical use, including the blockbuster Vidaza. TM . Another class of modifications involves the histone proteins that form the protein scaffold that DNA is normally associated with (coiled up) in eukaryotic cells. Histones play a crucial role in organizing DNA, and the regulated winding and unwinding of DNA around histones is key to controlling gene expression - coiled DNA is typically not accessible for gene transcription. A number of histone modifications have been discovered, including histone acetylation, histone lysine methylation, histone arginine methylation, histone ubiquitination and histone sumoylation, many of which alter the accessibility of associated DNA by the cellular transcription machinery. These histone marks serve to recruit various protein complexes involved in transcription and repression. A growing number of studies are painting an intricate picture of how various combinations of histone marks control gene expression in a cell type-specific manner, and a new term has been coined to capture this concept: the histone code.

[0004] Typical histone mark is histone acetylation. Histone acetyltransferase and histone deacetylase are catalytic machines related to regulating the histone mark, although usually these enzymes are part of a multiprotein complex, which contains other proteins involved in reading and modifying histone marks. The components of these protein complexes are usually cell type specific, and usually include transcriptional regulators, repressors, co-repressors, receptors (for example, estrogen or androgen receptors) associated with gene expression regulation. Histone deacetylase inhibitors change the histone acetylation spectrum of chromatin. Therefore, it has been shown that histone deacetylase inhibitors such as vorinostat (SAHA), trichostatin A (TSA) and many other substances change gene expression in various in vitro and in vivo animal models. Clinically, histone deacetylase inhibitors have shown activity in cancer environments and are studying tumor indications and neurological disorders and other diseases.

[0005] Another modification involved in regulating gene expression is histone methylation, including lysine and arginine methylation. The methylation state of histone lysine has recently been shown to be important in the dynamic regulation of gene expression.

[0006] A group of enzymes called histone lysine methyltransferases and histone lysine demethylases are involved in histone lysine modification. 1 A specific human histone lysine demethylase, called lysine-specific demethylase-1 (LSD1), is involved in this critical histone modification. LSD1 shares considerable structural similarity and amino acid identity / homology with polyamine oxidases and monoamine oxidases, all of which (i.e., MAO-A, MAO-B, and LSD1) are flavin-dependent amine oxidases that catalyze the oxidation of nitrogen-hydrogen bonds and / or nitrogen-carbon bonds. LSD1 has been recognized as an interesting target for the development of new drugs to treat cancer, neurological disorders, and other diseases.

[0007] Cyclopropylamine-containing compounds are known to inhibit a number of medically important targets, including amine oxidases such as monoamine oxidase A (MAO-A or MAOA), monoamine oxidase B (MAO-B or MAOB), and lysine-specific demethylase-1 (LSD1). The active ingredient of LSD1 and one of the best examples of cyclopropylamine, which inhibits all of these enzymes. Since MAO-A inhibition may cause undesirable side effects, it is desirable to identify cyclopropylamine derivatives that exhibit potent LSD1 inhibitory activity while having no or substantially reduced MAO-A inhibitory activity.

[0008] Compounds that act as LSD1 inhibitors are known in the art. LSD1 inhibitors and methods for their preparation are disclosed, for example, in the following document: WO 2011 / 131697 2WO 2012 / 135113 3 WO 2013 / 057322 4 WO 2010 / 143582 5 WO 2011 / 131576 6 WO 2013 / 022047 7 WO 2013 / 025805 8 WO 2014 / 058071 9 WO2014 / 084298 10 WO 2014 / 085613 11 WO 2014 / 086790 12 ,WO2014 / 164867 13 WO 2014 / 194280 14 WO 2014 / 205213 15 WO 2015 / 021128 16 WO 2015 / 031564 17 WO 2015 / 089192 18 WO2015 / 120281 19 WO 2015 / 123465 20 WO 2015 / 123437 21 WO 2015 / 123424 22 WO 2015 / 123408 23 WO 2015 / 134973 24 WO 2015 / 156417 25 、WO 2015 / 168466、WO 2015 / 181380、WO2015200843、WO 2016003917、WO 2016 / 004105 26 WO 2016 / 007722 27 WO 2016 / 007727 28 WO2016 / 007731 29 WO 2016 / 007736 30 WO 2016 / 034946 31 WO 2016 / 037005 32 ,CN 105541806 33 WO 2016 / 123387 34 WO 2016 / 130952 35 ,CN 105924362 36, CN 105985265 37 、WO 2016 / 161282 38 , CN 106045862 39 , CN 106045881 40 、WO 2016 / 172496 41 、WO 2016 / 177656 42 、WO2017 / 004519 43 、WO 2017 / 027678 44 , which are incorporated herein by reference in their entirety.

[0009] WO 2012 / 135113 3 Compounds such as GSK2879552 [CAS Reg. No. 1401966-69-5], also known as 4-[[4-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]-1-piperidinyl]methyl]-benzoic acid (Example 26, p. 75; Example 29, p. 81), are disclosed as selective LSD1 inhibitors.

[0010]

[0011] WO 2017 / 027678 44 Disclosed is a p-toluenesulfonic acid salt of 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid.

[0012]

[0013] LSD1 inhibitors and methods for their preparation are disclosed, for example, in WO 2013 / 022047 7 4-[4-[2-[(cyclopropylmethylamino)methyl]cyclopropyl]phenyl]-1-methyl-pyrazole-4-carboxamide (Example 163), which are hereby incorporated by reference in their entirety.

[0014] LSD1 inhibitors and methods for their preparation are disclosed, for example, in WO 2011 / 131697 2 , particularly Examples 1-21 (pp. 90-103), which are incorporated herein by reference in their entirety.

[0015] LSD1 inhibitors and methods for their preparation are disclosed, for example, in WO 2013 / 057322 4 1-108 (pp. 155-191), which is incorporated herein by reference in its entirety.

[0016] WO 2013 / 057322 4 The specific LSD1 inhibitors described are shown in Table 1.

[0017] Table 1. WO 2013 / 057322 4 Specific LSD1 inhibitors disclosed in.

[0018]

[0019]

[0020]

[0021] WO 2013 / 057322 4 A more specific LSD1 inhibitor described in is (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine [CAS Reg. No. 1431304-21-0]

[0022]

[0023] It corresponds to Example 5 and its pharmaceutically acceptable salt. This compound is also known as ORY-1001.

[0024] It has been determined that additive or synergistic effects in inhibiting cancer cell growth in vitro and in vivo can be achieved by administering LSD1 inhibitors or pharmaceutically acceptable salts thereof in combination with certain additional specific active agents. The combinations and methods can be used to treat neoplastic diseases, such as cancer.

[0025] Therefore, the present invention provides a combination for treating a tumor disease in a mammal, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients selected from Table 2 or a pharmaceutically acceptable salt thereof.

[0026] Table 2. Active pharmaceutical ingredients suitable for combination with LSD1 inhibitors.

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035] The structures of the compounds in Table 2 are as follows:

[0036] ABT-199 (Venetoclax):

[0037] ABT-263 (Navitoclax):

[0038] ABT-737:

[0039] ABT-888 (Veliparib):

[0040] ACY-1215 (Ricolinostat):

[0041] Belinostat:

[0042] Bendamustine:

[0043] BGJ398 (Infigratinib):

[0044] BMS-906024:

[0045] Carboplatin:

[0046] CGK 733:

[0047] Cisplatin:

[0048] CPI-169:

[0049] CPI-203:

[0050] Docetaxel:

[0051] Doxorubicin:

[0052] EPZ-004777:

[0053] EPZ005687:

[0054] EPZ-5676 (Pinometostat):

[0055]

[0056] EPZ-6438 (Tazemetostat):

[0057] Erlotinib:

[0058] Etoposide:

[0059] FLI06:

[0060] Fluorouracil:

[0061] GDC-0449 (Vismodegib):

[0062] Gemcitabine:

[0063] GSK126:

[0064] GSK1324726A (I-BET726):

[0065] GSK343:

[0066] GSK-J1:

[0067] GSK1210151A (I-BET151):

[0068] Irinotecan:

[0069] (+)-JQ1:

[0070] Lapatinib:

[0071] LDE225 (Sonidegib):

[0072] LY2603618:

[0073] LY-3039478:

[0074] Menadione:

[0075] Methotrexate:

[0076] MK-0752:

[0077] MLN8237 (Alisertib):

[0078] MS 436:

[0079] Nutlin-3A:

[0080] Obakla:

[0081] OTX015:

[0082] Paclitaxel:

[0083] Panobinostat:

[0084] Pemetrexed:

[0085] PF-04217903:

[0086] PF-3084014:

[0087] SAHA (Vorinostat):

[0088] SGC 0946:

[0089] SNDX-275 (entinostat):

[0090] Taladegib:

[0091] Temozolomide:

[0092] Topotecan:

[0093] TW-37:

[0094] Vincristine: Detailed Description of the Invention

[0095] 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 the invention belongs. Although methods and materials similar or equivalent to those described herein can be used for implementation or testing of the present invention, suitable methods and materials are described below.

[0096] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0097] Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

[0098] Unless otherwise stated, any open valencies appearing on carbon, oxygen, sulfur, or nitrogen atoms in the structures herein indicate the presence of hydrogen.

[0099] When indicating the number of substituents, the term "one or more" is intended to range from one substituent to the highest possible number of substitution, ie, replacement of one hydrogen up to all hydrogens by substituents.

[0100] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, wherein the description includes instances where said event or circumstance occurs and instances where it does not.

[0101] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid addition salts and base addition salts.

[0102] The term "pharmaceutically acceptable acid addition salts" refers to those pharmaceutically acceptable salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids; and organic acids selected from aliphatic, alicyclic, araliphatic, heterocyclic, carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, o-benzoic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

[0103] The term "pharmaceutically acceptable base addition salt" refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins.

[0104] Stereochemical definitions and conventions used herein generally follow those of SP Parker 102 and Eliel, E. and Wilen, S. 103 In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center. The substituents attached to the chiral center in question are arranged according to the sequence rules of Cahn, Ingold, and Prelog. 102 The prefixes D and L or (+) and (-) are used to indicate the sign of the rotation of plane-polarized light by a compound, with (-) or L indicating that the compound is levorotatory and compounds with the (+) or D prefix being dextrorotatory.

[0105] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, for administration to a mammal, such as a human, in need thereof.

[0106] The term "pharmaceutically acceptable" refers to the nature of materials that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, neither biologically nor otherwise undesirable, and acceptable for veterinary as well as human pharmaceutical uses.

[0107] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant, which is used to formulate a pharmaceutical product.

[0108] The term "inhibitor" refers to a compound that competes with a specific receptor or enzyme, reduces or prevents the binding of a specific ligand to a specific receptor or enzyme, and / or reduces or prevents the activity of a specific protein, such as a receptor or enzyme.

[0109] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0110] As used herein, the term "animal" includes humans and non-human animals. In one embodiment, a "non-human animal" is a mammal, such as a rodent, such as a rat or mouse. In one embodiment, the non-human animal is a mouse.

[0111] The term "half maximal effective concentration" (EC 50 ) represents the plasma concentration of a specific compound or molecule required to achieve 50% of the maximum specific effect in vivo.

[0112] The term "therapeutically effective amount" (or "effective amount") means an amount of a compound or molecule of the invention which, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0113] The term "treating" of a disease state includes inhibiting the disease state, ie, arresting the development of the disease state or its clinical symptoms, or alleviating the disease state, ie, causing temporary or permanent regression of the disease state or its clinical symptoms.

[0114] The term "assessing a neoplastic disease" is used to indicate that the methods according to the present invention will assist medical professionals, including, for example, physicians, in assessing whether an individual has a neoplastic disease or is at risk of developing a neoplastic disease. The level of a genome, compared to one or more reference levels, indicates whether an individual has a neoplastic disease or is at risk of developing a neoplastic disease or predicts the course of a neoplastic disease. In one embodiment, the term "assessing a neoplastic disease" is used to indicate that the methods according to the present invention will assist medical professionals in assessing whether an individual has a neoplastic disease. In these embodiments, the level of a genome, compared to one or more reference levels, indicates whether an individual has a neoplastic disease.

[0115] The term "assessing therapy" is used to indicate that the methods according to the present invention will help medical professionals, including, for example, physicians, assess whether an individual suffering from a neoplastic disease should be treated with an effective amount of an LSD1 inhibitor. Levels of responder genes above a reference level, and / or levels of non-responder genes below a reference level, indicate that the patient should be treated with an effective amount of an LSD1 inhibitor. In certain embodiments, the term "at a reference level" refers to a gene level in a sample from an individual or patient that is substantially the same as a reference level or that differs from a reference level by at most 1%, at most 2%, at most 3%, at most 4%, or at most 5%.

[0116] In certain embodiments, the term "above a reference level" refers to a gene level in a genome in a sample from an individual or patient that is above a reference level or an overall increase of 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 100% or more compared to a reference level, as determined by the methods described herein. In certain embodiments, the term increase refers to an increase in the gene level in a genome in a sample from an individual or patient, wherein the increase is at least about 1.5-, 1.75-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 40-, 50-, 60-, 70-, 75-, 80-, 90- or 100-fold higher than a reference level, e.g., predetermined based on a reference sample.

[0117] In certain embodiments, the terms "reduced" or "lower" as used herein refer to levels of genes of a panel of genes in a sample from an individual or patient being lower than a reference level or being generally reduced by 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more compared to a reference level as determined by the methods described herein. In certain embodiments, the term "reduced" refers to a decrease in the levels of genes of a panel of genes in a sample from an individual or patient compared to a reference level, wherein the level of decrease is at most about 0.9-, 0.8-, 0.7-, 0.6-, 0.5, -0.4, -0.3-, 0.2-, 0.1-, 0.05-, or 0.01-fold or less, e.g., predetermined based on a reference sample.

[0118] As used herein, the term "biomarker" refers to a genetic gene whose expression or presence in or on a mammalian tissue or cell can be detected by standard methods (or methods disclosed herein) and can be predictive, diagnostic, and / or predictive of the sensitivity of a mammalian cell or tissue to a therapeutic regimen based on LSD1 inhibition using, for example, an LSD1 inhibitor, such as (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine bishydrochloride. In certain embodiments, the level of such a biomarker is determined to be higher or lower than the level observed in a reference sample.

[0119] As used herein, the term "comparison" refers to comparing the level of a biomarker in a sample from an individual or patient with the reference level of a biomarker specified elsewhere in this specification. It should be understood that comparison as used herein generally refers to the comparison of corresponding parameters or values, for example, comparing an absolute amount with an absolute reference amount, while comparing a concentration with a reference concentration or an intensity signal obtained from a biomarker. The sample in the sample is compared with the intensity signal of the same type obtained from a reference sample. The comparison can be performed manually or computer-assisted. Therefore, the comparison can be performed by a computing device (e.g., a system disclosed herein). The value and reference level of the measurement or detection level of a biomarker in a sample from an individual or patient can be compared with each other, and the comparison can be automatically performed by a computer program executing the algorithm for the method. The computer program performing the assessment will provide the required assessment in an output format. For computer-assisted comparisons, the value of a determined amount can be compared with the value corresponding to a suitable reference stored in a database by a computer program. The computer program can further evaluate the result of the comparison, i.e., automatically provide the required assessment in an output format. For computer-assisted comparisons, the value of a determined amount can be compared with the value corresponding to a suitable reference stored in a database by a computer program. The computer program can further evaluate the results of the comparison, ie automatically provide the desired evaluation in a suitable output format.

[0120] As used herein, the term "detecting" a biomarker refers to a method of detecting the presence of the amount of the biomarker in a sample using an appropriate detection method as described elsewhere herein.

[0121] As used herein, the term "measuring" the level of a biomarker refers to quantification of the biomarker, eg, quantification of the biomarker. The level of the biomarker in a sample is determined using an appropriate detection method as described elsewhere herein.

[0122] The term "monitoring the efficacy of therapy" is used to mean obtaining samples from a patient at least once (including serially) before and / or under treatment with an LSD1 inhibitor and measuring therein the levels of the gene panel to obtain an indication of whether the treatment is effective.

[0123] In monitoring treatment efficacy, gene panel levels are measured and, in one embodiment, compared to reference values ​​for the gene panel, or, in another embodiment, compared to gene panel levels in a sample obtained from the gene panel of the same patient at an earlier time point, e.g., while the patient was already on treatment or before the patient started treatment.

[0124] A "patient" or "subject" herein is any single human subject who is eligible for treatment and who has experienced or has experienced signs, symptoms or other indicators of one or more neoplastic diseases. Intended to be included as a subject are any subjects participating in clinical research trials who do not show any clinical symptoms of the disease, or subjects participating in epidemiological studies, or subjects who have been used as controls. The subject may have been previously treated with an LSD1 inhibitor or another drug, or may not have been so treated. When the treatment herein is started, the subject may be naive to the other drugs being used, that is, the subject may not have been previously treated with a treatment other than the LSD1 inhibitor at "baseline" (i.e., a set time point before the first dose of drug D is given in the treatment methods herein, such as the day when the subject is screened before starting treatment). Such "naive" subjects are genetically considered candidates for treatment with such additional drugs.

[0125] As used herein, the phrase "providing a diagnosis / assessment" refers to using assessed genetic information or data related to the genomic levels in a patient sample to diagnose / assess a patient's tumor disease. The information or data can be in any form, written, oral, or electronic. In some embodiments, the information or data generated using the generated information or data includes communicating, presenting, reporting, storing, sending, transferring, providing, broadcasting, distributing, or a combination thereof. In some embodiments, the communication, presentation, reporting, storing, sending, transferring, supplying, broadcasting, distributing, or a combination thereof is performed by a computing device, an analyzer unit, or a combination thereof. In some other embodiments, the communication, presentation, reporting, storing, sending, transferring, providing, broadcasting, distributing, or a combination thereof is performed by a laboratory or a medical professional. In some embodiments, the information or data includes a comparison of the genomic level with a reference level.

[0126] As used herein, the phrase "recommended treatment" refers to the use of assessed genetic information or data related to the levels of a gene panel in a patient sample to identify a patient as being appropriately treated or inappropriately treated. In some embodiments, the therapy may include an LSD1 inhibitor. In some embodiments, the phrase "recommended treatment / therapy" includes identifying a patient who needs to be administered an effective amount of an LSD1 inhibitor. In some embodiments, recommending treatment includes suggesting an adjustment in the amount of the LSD1 inhibitor administered. As used herein, the phrase "recommended treatment" may also refer to the use of information or data genes that have been assessed to provide or select a therapy comprising an LSD1 inhibitor for providing or selecting a patient who is more or less likely to respond to a therapy comprising an LSD1 inhibitor. The information or data or gene rating used may be in any form, whether written, oral, or electronic. In some embodiments, using the genetically graded information or data includes communicating, presenting, reporting, storing, sending, transferring, providing, broadcasting, distributing, or a combination thereof. In some embodiments, communicating, presenting, reporting, storing, sending, transferring, providing, broadcasting, distributing, or a combination thereof is performed by a computing device, an analyzer unit, or a combination thereof. In some further embodiments, the communication, presentation, reporting, storage, transmission, transfer, provision, transmission, distribution, or a combination thereof is performed by a laboratory or medical professional. In some embodiments, the information or data comprises a comparison of genomic levels to reference levels. In some embodiments, the information or data comprises an indication that the patient is being adequately treated or not being adequately treated with a therapy comprising an LSD1 inhibitor.

[0127] In certain embodiments, the term "reference level" herein refers to a predetermined value. In this context, "level" includes an absolute amount, relative amount, or concentration, as well as any value or parameter associated with or derivable therefrom. As will be understood by those skilled in the art, a reference level is predetermined and set to meet conventional requirements. Specificity and / or sensitivity. These requirements can vary, for example, from regulatory agency to regulatory agency. For example, the assay sensitivity or specificity can be set to certain limits, for example, 80%, 90%, 95%, or 98%, respectively. These requirements can also be defined using positive or negative predictive values. Nevertheless, based on the teachings provided by the present invention, a technician can always reach a reference level that meets these requirements. In one embodiment, the reference level is determined in a reference sample from a healthy individual. The reference level in one embodiment has been predetermined in a reference sample from a disease entity to which the patient belongs. In certain embodiments, the reference level can be set to any percentage between 25% and 75% of the total distribution of values ​​in the disease entity under investigation. In other embodiments, the reference level can be set to the median, tertile, or quartile, determined by the overall distribution of values ​​in the reference sample for the disease entity under investigation. In one embodiment, the reference level is set as the median, as determined by the overall distribution of values ​​in the disease entity under study. The reference level can vary according to various physiological parameters (e.g., age, sex, or subpopulation) and the means for determining the gene panel levels mentioned herein. In one embodiment, the reference sample is derived from cells, tissues, organs, or body fluids of substantially the same type as the sample from the individual or patient subjected to the method of the present invention. For example, if, according to the present invention, blood is used as a sample to determine the genome level in the individual, the reference level is also determined in blood or a portion thereof.

[0128] In the context of the present invention, the phrase "responsive to" means that a patient suffering from, suspected of suffering from, susceptible to suffering from, or diagnosed with a disorder as described herein shows a response to a treatment comprising an LSD1 inhibitor.

[0129] The term "sample" refers to a body fluid sample, a separated cell sample, or a sample from a tissue or organ. Body fluid samples can be obtained by well-known techniques, including samples of blood, plasma, serum, urine, lymph, sputum, ascites, bronchial lavage fluid, or any other body secretions or their derivatives. Tissue or organ samples can be obtained from any tissue or organ by, for example, biopsy. Cells separated from body fluids, tissues, or organs can be obtained by separation techniques (such as centrifugation or cell sorting). For example, cells, tissues, or organ samples can be obtained from those cells, tissues, or organs that express or produce biomarkers. Samples can be frozen, fresh, fixed (such as formalin fixation), centrifuged, and / or embedded (such as paraffin embedding), etc. Cell samples can certainly be prepared after various well-known collections before the amount of markers in the assessment sample, storage techniques (such as, nucleic acid and / or protein extraction, fixation, storage, freezing, ultrafiltration, concentration, evaporation, centrifugation, etc.). Similarly, biopsy can also be prepared and stored after collection, such as by fixing.

[0130] As used herein, the phrases "selecting a patient" or "identifying a patient" refer to the use of assessed genetic information or data related to genomic levels in a patient sample to identify or select patients who are more likely to benefit or less likely to benefit from a therapy comprising an LSD1 inhibitor. The information or data or genetic rating used can be in any form, written, oral or electronic. In some embodiments, using the generated information or data comprises communicating, presenting, reporting, storing, sending, transferring, providing, broadcasting, distributing, or a combination thereof. In some embodiments, communicating, presenting, reporting, storing, sending, transferring, providing, broadcasting, distributing, or a combination thereof is performed by a computing device, an analyzer unit, or a combination thereof. In some other embodiments, communicating, presenting, reporting, storing, sending, transferring, providing, broadcasting, or a combination thereof is performed by a laboratory or a medical professional. In some embodiments, the information or data comprises a comparison of genomic levels to a reference level. In some embodiments, the information or data comprises an indication that the patient is more likely or less likely to respond to a therapy comprising an LSD1 inhibitor.

[0131] As used herein, the phrase "selecting a treatment" refers to using assessed genetic information or data related to the levels of a gene panel in a patient sample to identify or select a treatment for a patient. In some embodiments, the therapy may include an LSD1 inhibitor. In some embodiments, the phrase "identifying / selecting a treatment" includes identifying a patient who needs to be adapted for an effective amount of an administered LSD1 inhibitor. In some embodiments, recommending a treatment includes recommending an adjustment in the amount of an administered LSD1 inhibitor. As used herein, the phrase "recommending a treatment" may also refer to using information or data genes that are assessed to suggest or select a treatment including an LSD1 inhibitor to identify or select patients who are more or less likely to respond to a treatment including an LSD1 inhibitor. The information or data used or generated may be in any form, whether written, oral, or electronic. In some embodiments, using the generated information or data includes communicating, presenting, reporting, storing, sending, transferring, providing, broadcasting, distributing, or a combination thereof. In some embodiments, communicating, presenting, reporting, storing, sending, transferring, providing, broadcasting, distributing, or a combination thereof is performed by a computing device, an analyzer unit, or a combination thereof. In some further embodiments, the communication, presentation, reporting, storage, transmission, transfer, provision, transmission, distribution, or a combination thereof is performed by a laboratory or medical professional. In some embodiments, the information or data comprises a comparison of gene panel levels to a reference level. In some embodiments, the information or data comprises an indication of a therapy comprising an LSD1 inhibitor suitable for the patient.

[0132] The term "responder genes" refers to a group of genes comprising ASCL1, HOXA10, NCAM1, NCAM2, NEUROD1, DDC, GRP, KRT8, ENO2, AVP, OXT, SYP, CHGA, CHGB, SOX21, and BCL2.

[0133] The term "non-responder gene" refers to the oncogene MYC.

[0134] The term "solid tumor" refers to an abnormal mass of tissue that usually does not contain cysts or areas of fluid. Solid tumors can be benign (not cancer) or malignant (cancer). Different types of solid tumors are named after the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) do not usually form solid tumors.

[0135] Treatment combinations

[0136] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients selected from the group consisting of compounds of Table 2 and pharmaceutically acceptable salts thereof.

[0137] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients selected from ABT-199, ABT-263, ABT-737, ABT-888, ACY-1215, belinostat, bendamustine, BGJ398, BMS-906024, carboplatin, CGK 733, cisplatin, CPI-169, CPI-203, docetaxel, doxorubicin, EPZ-004777, EPZ005687, EPZ-5676, EPZ-6438, erlotinib, etoposide, FLI 06, fluorouracil, GDC-0449, gemcitabine, GSK126, GSK1324726A, GSK343, GSK-J1, GSK1210151A, irinotecan, (+)-JQ1, lapatinib, LDE225, LY2603618, LY-3039478, menadione, methotrexate, MK-0752, MLN8237, MS436, Nutlin-3A, obaclava, OTX015, paclitaxel, panobinostat, pemetrexed, PF-04217903, PF-3084014, SAHA, SGC 0946, SNDX-275, Taladegib, temozolomide, topotecan, TW-37, vincristine and pharmaceutically acceptable salts thereof.

[0138] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients selected from BCL2 inhibitors, BET inhibitors, EZH2 inhibitors, DOT1L inhibitors, Chk inhibitors, DNA alkylating agents, HDAC inhibitors, topoisomerase inhibitors, antimitotic drugs, Aurora kinase inhibitors and pharmaceutically acceptable salts thereof.

[0139] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients selected from BCL2 inhibitors, BET inhibitors, EZH2 inhibitors, DOT1L inhibitors and pharmaceutically acceptable salts thereof.

[0140] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients selected from the group consisting of a BCL2 inhibitor, a BET inhibitor and pharmaceutically acceptable salts thereof.

[0141] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof.

[0142] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor selected from ABT-199, ABT-263, ABT-737, Obakola, TW-37 and pharmaceutically acceptable salts thereof.

[0143] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a BET inhibitor or a pharmaceutically acceptable salt thereof.

[0144] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a BET inhibitor selected from CPI-203, GSK1324726A, GSK1210151A, (+)-JQ1, MS 436, OTX015 and pharmaceutically acceptable salts thereof.

[0145] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an EZH2 inhibitor or a pharmaceutically acceptable salt thereof.

[0146] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an EZH2 inhibitor selected from CPI-169, EPZ005687, EPZ-6438, GSK126, GSK343 ​​and pharmaceutically acceptable salts thereof.

[0147] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a DOT1L inhibitor or a pharmaceutically acceptable salt thereof.

[0148] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a DOT1L inhibitor selected from EPZ-004777, EPZ-5676, SGC 0946 and pharmaceutically acceptable salts thereof.

[0149] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a Chk inhibitor or a pharmaceutically acceptable salt thereof.

[0150] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a Chk inhibitor selected from LY2603618 and a pharmaceutically acceptable salt thereof.

[0151] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a DNA alkylating agent or a pharmaceutically acceptable salt thereof.

[0152] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a DNA alkylating agent selected from bendamustine, carboplatin, cisplatin, temozolomide and pharmaceutically acceptable salts thereof.

[0153] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an HDAC inhibitor or a pharmaceutically acceptable salt thereof.

[0154] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an HDAC inhibitor selected from ACY-1215, belinostat, panobinostat, SAHA, SNDX-275 or a pharmaceutically acceptable salt thereof.

[0155] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0156] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor selected from the group consisting of etoposide, irinotecan, topotecan and pharmaceutically acceptable salts thereof.

[0157] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an Aurora kinase inhibitor or a pharmaceutically acceptable salt thereof.

[0158] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an Aurora kinase inhibitor selected from MLN8237 and a pharmaceutically acceptable salt thereof.

[0159] Specifically, the present invention provides therapeutic combinations comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an antimitotic drug or a pharmaceutically acceptable salt thereof.

[0160] Specifically, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an antimitotic drug selected from docetaxel, paclitaxel, vincristine and pharmaceutically acceptable salts thereof.

[0161] In one embodiment, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof, a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, and a DNA alkylating agent or a pharmaceutically acceptable salt thereof.

[0162] In one embodiment, the present invention provides a therapeutic combination comprising (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof, a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, and a DNA alkylating agent or a pharmaceutically acceptable salt thereof.

[0163] In one embodiment, the present invention provides a therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof, etoposide or a pharmaceutically acceptable salt thereof, and carboplatin or a pharmaceutically acceptable salt thereof.

[0164] In one embodiment, the present invention provides a therapeutic combination comprising (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof, etoposide or a pharmaceutically acceptable salt thereof, and carboplatin or a pharmaceutically acceptable salt thereof.

[0165] In one embodiment of the invention, the therapeutic combination results in a synergy score of higher than 6.4, particularly higher than 8, more particularly higher than 10, most particularly higher than 15.

[0166] In one embodiment of the invention, the therapeutic combination results in a synergy score of higher than 6.4, particularly higher than 8, more particularly higher than 10, most particularly higher than 15, wherein the synergy score is calculated as follows:

[0167] Synergy score = log f X log f Y ∑max(0,I 数据 )(I 数据 -I Loewe )

[0168] LSD1 inhibitors

[0169] In one aspect of the present invention, the LSD1 inhibitor is selected from WO 2011 / 131697 2 、WO 2012135113 3 and WO2013 / 057322 4 The compound described in .

[0170] In a specific embodiment of the present invention, the LSD1 inhibitor is selected from:

[0171] 4-[[4-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]-1-piperidinyl]methyl]-benzoic acid,

[0172] (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine,

[0173] (R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine,

[0174] 4-(aminomethyl)-N-((trans)-2-phenylcyclopropyl)cyclohexylamine,

[0175] N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine,

[0176] N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine,

[0177] N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine,

[0178] N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine,

[0179] N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0180] N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine,

[0181] N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0182] N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0183] N1-(2-(naphthalene-2-yl)cyclopropyl)cyclohexane-1,4-diamine,

[0184] N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide,

[0185] N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine, and pharmaceutically acceptable salts thereof.

[0186] In a specific embodiment of the present invention, the LSD1 inhibitor is selected from:

[0187] 4-[[4-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]-1-piperidinyl]methyl]-benzoic acid,

[0188] (trans)-N1-((1R, 2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine,

[0189] (R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine,

[0190] 4-(aminomethyl)-N-((trans)-2-phenylcyclopropyl)cyclohexylamine,

[0191] N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine,

[0192] N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine,

[0193] N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine,

[0194] N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine,

[0195] N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0196] N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine,

[0197] N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0198] N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0199] N1-(2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine,

[0200] N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide, and

[0201] N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof.

[0202] In a specific embodiment of the present invention, the LSD1 inhibitor is selected from:

[0203] 4-[[4-[[[(1R, 2S)-2-phenylcyclopropyl]amino]methyl]-1-piperidinyl]methyl]-benzoic acid (trans)-N1-((1R, 2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine,

[0204] (R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine,

[0205] 4-(aminomethyl)-N-((trans)-2-phenylcyclopropyl)cyclohexylamine,

[0206] N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine,

[0207] N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine,

[0208] N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine,

[0209] N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine,

[0210] N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0211] N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine,

[0212] N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0213] N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0214] N1-(2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine,

[0215] N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide,

[0216] N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine, and pharmaceutically acceptable salts thereof.

[0217] In a specific embodiment of the present invention, the LSD1 inhibitor is GSK2879552 [CAS Registry Number 1401966-69-5], also known as 4-[[4-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]-1-piperidinyl]methyl]-benzoic acid, or a pharmaceutically acceptable salt thereof.

[0218] In a specific embodiment of the present invention, the LSD1 inhibitor is selected from:

[0219] (trans)-N1-((1R, 2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine,

[0220] (R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine,

[0221] 4-(aminomethyl)-N-((trans)-2-phenylcyclopropyl)cyclohexylamine,

[0222] N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine,

[0223] N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine,

[0224] N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine,

[0225] N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine,

[0226] N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0227] N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine,

[0228] N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0229] N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine,

[0230] N1-(2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine,

[0231] N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide,

[0232] N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine, and pharmaceutically acceptable salts thereof.

[0233] In a specific embodiment of the present invention, the LSD1 inhibitor is (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine [CAS Registry No. 1431304-21-0] or a pharmaceutically acceptable salt thereof.

[0234] In a specific embodiment of the present invention, the LSD1 inhibitor is (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine [CAS Registry No. 1431304-21-0] or its hydrochloride salt.

[0235] In a specific embodiment of the invention, the LSD1 inhibitor is (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine bishydrochloride [CAS Registry No. 1431303-72-8].

[0236] Combination therapy

[0237] Therapeutic combinations can be used to treat hyperproliferative diseases or disorders, including tumors, cancers and tumor tissues, as well as pre-malignant and non-tumor or non-malignant hyperproliferative disorders. In certain embodiments, the combination of the present invention is combined in a dosing regimen as a combination therapy with another compound that has anti-hyperproliferative properties or can be used to treat hyperproliferative disorders. The additional compounds of the dosing regimen preferably have complementary activities to the combination so that they do not adversely affect each other. These compounds can be administered in an amount effective for the intended purpose. In one embodiment, the therapeutic combination is administered by a dosing regimen in which a therapeutically effective amount of an LSD1 inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof is administered in the range of twice daily to once every three weeks (q3wk), and one or more active pharmaceutical ingredients, a therapeutically effective amount of a compound of Table 2 and a pharmaceutically acceptable salt thereof is selected and administered in the range of twice daily to once every three weeks.

[0238] Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations. Co-administration includes co-administration, using separate formulations and continuous administration in any order, wherein preferably there is a period of time while both (or all) active agents simultaneously exert their biological activity.

[0239] In one specific aspect of the invention, the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, can be administered within a period of about 1 to about 10 days after the start of administration of one or more active pharmaceutical ingredients selected from the compounds of Table 2 and pharmaceutically acceptable salts thereof. In another specific aspect of the invention, the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, can be administered for a period of about 1 to 10 days prior to the administration of one or more active pharmaceutical ingredients selected from the compounds of Table 2 and pharmaceutically acceptable salts thereof. In another specific aspect of the invention, administration of the LSD1 inhibitor, or a pharmaceutically acceptable salt thereof, and one or more active pharmaceutical ingredients selected from the compounds of Table 2 and pharmaceutically acceptable salts thereof are initiated on the same day.

[0240] In one specific aspect of the invention, one or more active pharmaceutical ingredients selected from the compounds of Table 2 and pharmaceutically acceptable salts thereof can be administered within a period of about 1 to about 10 days after the start of administration of the LSD1 inhibitor or a pharmaceutically acceptable salt thereof. In another specific aspect of the invention, one or more active pharmaceutical ingredients selected from the compounds of Table 2 and pharmaceutically acceptable salts thereof can be administered within a period of about 1 to 10 days before the start of administration of the LSD1 inhibitor or a pharmaceutically acceptable salt thereof. In another specific aspect of the invention, administration of one or more active pharmaceutical ingredients selected from the compounds of Table 2 and pharmaceutically acceptable salts thereof and administration of the LSD1 inhibitor or a pharmaceutically acceptable salt thereof are initiated on the same day.

[0241] Suitable dosages for any of the above co-administered agents are those currently used and may be lowered due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or treatments, e.g., to increase the therapeutic index or reduce toxicity or other side effects or consequences.

[0242] In certain embodiments of anticancer therapy, the therapeutic combination can be combined with surgical therapy and radiation therapy. The amounts of the combination and the relative timing of administration will be selected to achieve the desired combined therapeutic effect.

[0243] In a specific embodiment of the invention, SCLC cells are sensitized by administering a LSD1 inhibitor prior to administering the therapeutic combination described herein.

[0244] In a specific embodiment of the invention, SCLC cells are sensitized by administration of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof prior to administration of the therapeutic combination described herein.

[0245] In a specific embodiment of the invention, SCLC cells are sensitized by administration of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof, prior to administration of a therapeutic combination as described herein, following a five day / two day rest (5 / 2) cycle for three weeks.

[0246] In a specific embodiment of the invention, SCLC cells are sensitized by administration of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, or a pharmaceutically acceptable salt thereof, at a dose of 40 μg / kg (upk) 5 days / 2 days (5 / 2) for three weeks prior to administration of the therapeutic combination described herein.

[0247] In a specific embodiment of the present invention, SCLC cells are sensitized by administration of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, or a pharmaceutically acceptable salt thereof, at a dose of 40 μg / kg (upk) 5 days on / 2 days off (5 / 2) for 3 weeks, followed by administration of a therapeutic combination comprising etoposide, carboplatin, and (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, or a pharmaceutically acceptable salt thereof.

[0248] In a specific embodiment of the invention, SCLC cells are sensitized by administration of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, or a pharmaceutically acceptable salt thereof, at a dose of 40 μg / kg (upk) 5 days on / 2 days off (5 / 2) for 3 weeks, followed by administration of a therapeutic combination comprising etoposide at a dose of 5 mg / kg (mpk) daily for 5 days (qdx5), carboplatin at a dose of 100 mpk weekly for 3 weeks, and (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, or a pharmaceutically acceptable salt thereof, at a dose of 20 upk 5 days on / 2 days off (5 / 2) for 3 weeks.

[0249] A particular embodiment of the present invention relates to a method for treating a neoplastic disease, which method comprises sensitization by administration of an LSD1 inhibitor followed by administration of an effective amount of a therapeutic combination as described herein to a human or animal.

[0250] A specific embodiment of the present invention relates to a method for treating tumor diseases, which comprises sensitizing a human or animal by administering (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof, and then administering an effective amount of a therapeutic combination as described herein to the human or animal.

[0251] A specific embodiment of the present invention relates to a method for treating a tumor disease, which comprises sensitizing by administering (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof, 5 days of treatment / 2 days of rest (5 / 2) for 3 weeks, and then administering to a human or animal an effective amount of a therapeutic combination as described herein.

[0252] A specific embodiment of the present invention relates to a method for treating tumor diseases, which comprises sensitizing by administering (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof at a dose of 40 μg / kg (upk), 5 days of treatment / 2 days of rest (5 / 2) for 3 weeks, and then administering to a human or animal an effective amount of a therapeutic combination as described herein.

[0253] A specific embodiment of the present invention relates to a method for treating a tumor disease, which comprises sensitizing by administering (trans)-N1-((1R, 2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof, at a dose of 401 μg / kg (upk), 5 days of treatment / 2 days of rest (5 / 2), for 3 weeks, and then administering to a human or animal an effective amount of a therapeutic combination as described herein, which comprises etoposide, carboplatin and (trans)-N1-((1R, 2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine.

[0254] A specific embodiment of the present invention relates to a method for treating a tumor disease, which comprises sensitizing the human or animal by administering (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof at a dose of 401 μg / kg (upk), 5 days of treatment / 2 days of rest (5 / 2), for 3 weeks, and then administering to the human or animal an effective amount of a therapeutic combination as described herein, which comprises etoposide at a dose of 5 mg / kg (mpk) per day for 5 days (qdx5), carboplatin at a dose of 100 mpk per week for 3 weeks (qwkx3) and (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine at a dose of 20 upk, 5 days of treatment / 2 days of rest for 3 weeks.

[0255] Pharmaceutical composition

[0256] Another embodiment provides a pharmaceutical composition or medicament comprising a therapeutic combination as described herein and a pharmaceutically acceptable excipient.

[0257] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration regimen, and other factors known to medical professionals.

[0258] Therapeutic combinations as described herein can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and if desired for local treatment, for intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0259] The therapeutic combinations described herein can be administered in any convenient administration form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like. Such compositions may contain ingredients commonly used in pharmaceutical preparations, such as diluents, carriers, pH regulators, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, antioxidants, and other active agents. They may also contain other therapeutically valuable substances.

[0260] Typical formulations are prepared by mixing a therapeutic combination as described herein with a pharmaceutically acceptable excipient. Suitable excipients are well known to those skilled in the art and are described, for example, in Ansel HC et al. 103 , Gennaro AR et al. 104 With Rowe R.C. 105 The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (i.e., a drug).

[0261] The dosage of the administered therapeutic combinations as described herein can vary within wide limits and will, of course, be tailored to the individual requirements in each particular case.

[0262] An example of a suitable oral dosage form is a tablet comprising about 0.01 mg to 10 mg of a therapeutic combination as described herein mixed with about 90 to 30 mg of anhydrous lactose, about 5 to 40 mg of croscarmellose sodium, about 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg of magnesium stearate. The powder ingredients are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment.

[0263] An example of an aerosol formulation can be prepared by dissolving a therapeutic composition as described herein (e.g., 0.1 to 100 mg) in a suitable buffer solution, such as a phosphate buffer, with the addition of a tonicity adjuster, such as a salt, such as sodium chloride, if necessary. The solution can be filtered, for example, using a 0.2 μm filter, to remove impurities and contaminants.

[0264] Another embodiment relates to pharmaceutical compositions comprising a therapeutic combination as described herein and one or more pharmaceutically acceptable excipients.

[0265] Products

[0266] In another embodiment of the present invention, an article of manufacture or "kit" is provided comprising the combination for treating the above-mentioned diseases and disorders.

[0267] In one embodiment, the kit comprises a container and a therapeutic combination as described herein.

[0268] One embodiment of the present invention provides an article of manufacture comprising a therapeutic combination as described herein for use in treating a neoplastic disease.

[0269] The kit may also include a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products, which contain information about the indications, usage, dosage, administration, contraindications and / or warnings for the use of these therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container can be formed from a variety of materials, such as glass or plastic. The container can hold a composition or its formulation that is effective in treating a condition and can have a sterile access port (for example, the container can be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). The label or package insert indicates that the composition is used to treat a selected condition, such as cancer. In one embodiment, the label or package insert indicates that the composition comprising the combination can be used to treat disorders caused by abnormal cell growth. The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively, or in addition, the product may also include a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may also include other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0270] The kit may further comprise instructions for co-administration, if present, of a second pharmaceutical formulation. For example, if the kit comprises a first composition comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a second pharmaceutical formulation comprising one or more active pharmaceutical ingredients selected from the group consisting of compounds listed in Table 2 and pharmaceutically acceptable salts thereof, the kit may further comprise instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially, or separately to a patient in need thereof.

[0271] In another embodiment, the medicine box is used to deliver a solid oral form of the combination, such as a tablet or capsule. Such medicine boxes preferably include a plurality of unit doses. Such test kits may include a card with a dosage directed in the order of its intended use. An example of such medicine box is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid may be provided, such as in the form of numbers, letters or other markings or with a calendar insert, specifying the date in the treatment regimen to which the dosage may be applied.

[0272] According to one embodiment, the kit may comprise (a) a first container containing an LSD1 inhibitor or a pharmaceutically acceptable salt thereof; (b) a second container having one or more active pharmaceutical ingredients selected from the group consisting of compounds of 2 and pharmaceutically acceptable salts thereof; and (c) a third container containing a third pharmaceutical formulation, wherein the third pharmaceutical formulation comprises another compound having anti-hyperproliferative activity. Alternatively, or in addition, the kit may comprise another container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may also include other materials required from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0273] When the kit comprises an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients, which are selected from the group consisting of compounds listed in Table 2 and pharmaceutically acceptable salts thereof, the kit may comprise containers for containing the individual compositions, such as divided bottles or divided foil packets, however, the individual compositions may also be contained in a single, undivided container. Typically, the kit includes instructions for administering the individual components. The kit format is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosage intervals, or when the prescribing physician requires that the individual components of the combination be titrated.

[0274] Medical uses and treatments

[0275] Another embodiment relates to the therapeutic combination as described herein for use as therapeutically active substances.

[0276] Another embodiment relates to a therapeutic combination as described herein for use in the treatment of a neoplastic disease.

[0277] Another embodiment relates to a method for treating a neoplastic disease, comprising administering to a human or animal an effective amount of a therapeutic combination as described herein.

[0278] Another embodiment relates to the use of a therapeutic combination as described herein for the treatment of a neoplastic disease.

[0279] Another embodiment relates to the use of a therapeutic combination as described herein for the preparation of a medicament for the treatment of a neoplastic disease.

[0280] In a specific embodiment of the invention, the therapeutic combination as described herein is administered orally, eg, by oral administration, eg, an oral solution, to a patient in need thereof.

[0281] In a specific embodiment of the present invention, the neoplastic disease that can be potentially treated by the therapeutic combination as described herein is cancer, in particular a cancer selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer (i.e. including colon cancer and rectal cancer), pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, hematological malignancies, melanoma and sarcoma.

[0282] In a specific embodiment of the invention, the cancer potentially treatable by the therapeutic combination as described herein is selected from the group consisting of hematological malignancies, neuroendocrine cancers, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, melanoma and lung cancer.

[0283] In a specific embodiment of the present invention, the tumor disease is selected from cancer, which is selected from blood cancer or lung cancer, more specifically acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0284] In a specific embodiment of the present invention, the tumor disease is a blood cancer or lung cancer, which is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0285] In a specific embodiment of the present invention, the tumor disease is a cancer selected from the group consisting of acute myeloid leukemia (AML), non-Hodgkin's lymphoma, small cell lung cancer (SCLC), thyroid cancer and melanoma.

[0286] In a specific embodiment of the present invention, the tumor disease is cancer selected from acute myeloid leukemia (AML), thyroid cancer or small cell lung cancer (SCLC).

[0287] In a specific embodiment of the present invention, the tumor disease is a cancer selected from acute myeloid leukemia (AML) and small cell lung cancer (SCLC).

[0288] In a specific embodiment of the present invention, the tumor disease is neuroendocrine cancer.

[0289] In a specific embodiment of the present invention, the tumor disease is a solid tumor.

[0290] In a specific embodiment of the present invention, the tumor disease is a malignant solid tumor selected from the group consisting of sarcoma, carcinoma and lymphoma.

[0291] In a specific embodiment of the present invention, the tumor disease is lung cancer.

[0292] In a specific embodiment of the present invention, the tumor disease is small cell lung cancer (SCLC).

[0293] In a specific embodiment of the present invention, the tumor disease is small cell lung cancer (SCLC), wherein the SCLC cells are sensitive to LSD1 inhibitor-based therapy.

[0294] In a specific embodiment of the present invention, the tumor disease is small cell lung cancer (SCLC), wherein the SCLC cells are sensitive to LSD1 inhibitor-based therapy, wherein the sensitivity to LSD1 inhibitor-based therapy is assessed based on the predictive mRNA expression level as described herein.

[0295] In a specific embodiment of the present invention, the tumor disease is small cell lung cancer (SCLC), wherein the SCLC cells are sensitive to an LSD1 inhibitor-based therapy, wherein the sensitivity to the LSD1 inhibitor-based therapy is assessed using an in vitro method comprising:

[0296] a) determining the level of a gene set in a sample from a patient, wherein the gene set comprises one or more genes selected from responder genes and non-responder genes;

[0297] b) calculating a marker score based on the measured genomic level;

[0298] c) comparing the calculated marker score to a threshold level; and

[0299] d) identifying the patient as more likely to respond to a therapy comprising a LSD1 inhibitor when the marker score is above a threshold level.

[0300] In a specific embodiment of the present invention, the tumor disease is small cell lung cancer (SCLC), wherein the SCLC cells appear to be responsive to single agent treatment with a LSD1 inhibitor.

[0301] In a specific embodiment of the present invention, the neoplastic disease is small cell lung cancer (SCLC), wherein the SCLC cells exhibit a single agent response to treatment with a LSD1 inhibitor, wherein the single agent response to treatment with the LSD1 inhibitor is assessed based on the predictive mRNA expression level as described herein.

[0302] In a specific embodiment of the present invention, the neoplastic disease is small cell lung cancer (SCLC), wherein the SCLC cells exhibit a single agent response to treatment with a LSD1 inhibitor, wherein the single agent response to treatment with the LSD1 inhibitor is assessed using an in vitro method comprising:

[0303] a) determining the level of a gene set in a sample from a patient, wherein the gene set comprises one or more genes selected from responder genes and non-responder genes;

[0304] b) calculating a marker score based on the measured genomic level;

[0305] c) comparing the calculated marker score to a threshold level; and

[0306] d) When the marker score is above a threshold level, the marker is identified as more likely to contain LSD1

[0307] Patients who respond to inhibitor therapy.

[0308] Genomic and mRNA markers

[0309] Table 3 provides a list including descriptions of genes useful in the present invention.

[0310]

[0311]

[0312]

[0313]

[0314] Table 3. Description of genes used in the present invention (*http: / / www.ensembl.org / , Cunningham F. et al. 100 ).

[0315] The present invention identifies gene sets (also referred to as "multigene sets," "gene expression sets," or "gene sets") whose mRNA expression signatures, based on in vitro data, can be used to identify patients most likely to respond to treatment regimens containing LSD1 inhibitors. The genes listed are characteristic of the classic SCLC phenotype (genetic of neuroendocrine origin) and exclude cell lines with "variant" phenotypes. The expression of these genes may have predictive value in identifying responding patients in other histological subtypes and in other tumor tissues.

[0316] It has been found that mRNA signatures are characterized by Respondent Highly expressed genes: ASCL1, HOXA10, NCAM1, NCAM2, NEUROD1, DDC, GRP, KRT8, ENO2, AVP, OXT, SYP, CHGA, CHGB, SOX21, and BCL2.

[0317] It was also found that Non-respondents The lines may be characterized by high levels of the oncogene MYC.

[0318] Baseline expression levels of the responder and non-responder genes listed herein can be used alone or in combination with one another to generate a composite score that distinguishes cell lines and patient-derived clinical specimens that are resistant to treatment and identifies those that are sensitive (responsive) to therapy with an LSD1 inhibitor.

[0319] Thus, higher levels of expression of responder genes and / or lower levels of expression of non-responder genes indicate a response to treatment with an LSD1 inhibitor. Combining the expression levels of several responder and / or non-responder genes can provide a multi-gene signature with improved confidence in responsiveness compared to readouts from the expression levels of individual genes.

[0320] The present invention identifies mRNAs that are associated with LSD1 inhibition and are used to identify mRNAs that are responsive to LSD1 inhibition.

[0321] The present invention also relates to methods for identifying cells susceptible to LSD1 inhibitor-based therapies.

[0322] The present invention also relates to the use of genomics in determining a patient's response to a neoplastic disease when the patient is treated with a therapy based on an LSD1 inhibitor.

[0323] The present invention also identifies mRNA expression that is useful for monitoring neoplastic disease in patients treated with LSD1 inhibitors.

[0324] The present invention also provides predictive mRNA values ​​in determining the effectiveness of LSD1 inhibitor-based therapies for neoplastic diseases.

[0325] One embodiment of the present invention provides an in vitro method for identifying a patient suffering from a neoplastic disease as potentially responsive to a therapy comprising an LSD1 inhibitor, the method comprising:

[0326] a) determining the level of a gene set in a sample from a patient, wherein the gene set comprises one or more genes selected from responder genes and non-responder genes;

[0327] b) comparing the genomic level determined in a) to a reference level; and

[0328] c) identifying a patient who is more likely to respond to a therapy comprising an LSD1 inhibitor when the level of a responder gene from the gene set determined in a) in a sample from the patient is above a reference level and / or when the level of a non-responder gene from the gene set determined in a) in a sample from the patient is below a reference level.

[0329] One embodiment of the present invention provides a method for identifying in vitro a patient suffering from a neoplastic disease as being likely to respond to a therapy comprising an LSD1 inhibitor, the method comprising:

[0330] a) determining the level of a gene set in a sample from a patient, wherein the gene set comprises one or more genes selected from responder genes and non-responder genes;

[0331] b) calculating marker scores from the genomic assay level;

[0332] c) comparing the calculated marker score to a threshold level; and

[0333] d) Identifying patients who are more likely to respond to a therapy comprising an LSD1 inhibitor when the marker score is above a threshold level.

[0334] Another embodiment of the present invention provides an in vitro method for identifying a patient suffering from a neoplastic disease as potentially responsive to a therapy comprising an LSD1 inhibitor, the method comprising:

[0335] a) determining the level of a gene set in a sample from a patient, wherein the gene set comprises one or more genes selected from responder genes and non-responder genes;

[0336] b) comparing the genomic levels determined in a) with a reference level;

[0337] c) identifying a patient who is more likely to respond to a therapy comprising an LSD1 inhibitor when the level of responder genes from the gene set determined in a) in a sample from the patient is above a reference level and / or when the level of non-responder genes from the gene set determined in a) in a sample from the patient is below a reference level; and

[0338] d) administering an effective amount of a LSD1 inhibitor.

[0339] One embodiment of the present invention provides an in vitro method for identifying a patient suffering from a neoplastic disease as potentially responsive to a therapy comprising an LSD1 inhibitor, the method comprising:

[0340] a) determining the level of a gene set in a sample from a patient, wherein the gene set comprises one or more genes selected from responder genes and non-responder genes;

[0341] b) calculating marker scores from the assayed genomic level;

[0342] c) comparing the calculated marker score to a threshold level;

[0343] d) identifying patients who are more likely to respond to a therapy comprising an LSD1 inhibitor when the marker score is above a threshold level; and

[0344] e) administering an effective amount of a LSD1 inhibitor.

[0345] Another embodiment of the present invention provides a method for monitoring the efficacy of a therapy comprising an LSD1 inhibitor in a patient suffering from a neoplastic disease in vitro, the method comprising:

[0346] a) determining the level of a gene set in a sample from the patient before initiating the therapy, wherein the gene set comprises one or more genes selected from responder genes and non-responder genes;

[0347] b) calculating a marker score for the patient using the genomic levels determined in a), and then initiating said therapy;

[0348] c) measuring the level of the genome in a sample from the patient after initiation of therapy;

[0349] d) calculating a marker score for the patient after starting therapy using the genomic levels determined in c);

[0350] e) comparing the patient's marker score obtained in d) after initiation of therapy with the marker score obtained in b) and then initiating said therapy; and

[0351] f) Identifying a patient as responding to therapy when the marker score obtained in d) after initiation of therapy is higher than the marker score obtained in b) before initiation of therapy.

[0352] In this application, the term "read level" refers to a value that can be measured in any form of mRNA expression, such as example expression levels from RNA sequencing, such as normalized reads and RPKM (reads per million mapped reads); RT-qPCR; or microarray.

[0353] In this application, the term "normalized reads" refers to reads obtained directly from an RNA sequencing experiment and normalized to make them comparable across experiments.

[0354] In this application, the term "normalized expression level" refers to the value obtained in a particular kind of expression measurement and normalized to make it comparable across experiments (e.g., normalized expression from microarray, normalized expression from RNA sequencing).

[0355] In one aspect of the invention, the normalized expression level is a normalized readout.

[0356] In one aspect of the invention, the level determined is the mRNA expression level.

[0357] In one aspect of the invention, the levels determined are mRNA expression levels derived from RNA sequencing, RT-qPCR or microarray.

[0358] In one aspect of the invention, the reference level is a standard value from patients suffering from the same neoplastic disease.

[0359] In another embodiment, the reference level is the median mRNA expression determined in a population of patients with the same tumor disease.

[0360] In one aspect of the invention, the reference levels of certain genes of the genome are as follows (as shown by normalized read counts): ASCL1 (4515.83); DDC (2005.02); GRP (426.01); HOXA10 (10.04).

[0361] The reference levels reported above were obtained by selecting two small cell lung cancer cell lines C s and C R The lower normalized read count of the corresponding gene in C s is the most sensitive cell line with the lowest expression of the selected gene, and C R is the resistant cell line with the highest expression of the selected gene.

[0362] The signature score used herein is a gene-based algorithm-derived score (polygenic signature) composed of values ​​indicating upregulation of responder genes and downregulation of nonresponder genes or copy number changes of nonresponder genes.

[0363] A marker score greater than a threshold level predicts a response to a therapy comprising an LSD1 inhibitor. The higher the threshold level selected for predicting response for the marker score, the higher the specificity achieved. The lower the threshold level selected for predicting response for the marker score, the higher the sensitivity achieved.

[0364] In one embodiment of the invention, the threshold level corresponds to a marker score of 0.4 to 0.6, particularly 0.5 ± 20%, most particularly 0.5, wherein the marker score is obtained by partial least squares (PLS) analysis using the second principal component:

[0365] Marker score 1 = 0.0900693 + (normalized expression level of ASCL1) × 0.00000211296 + (normalized expression level of DDC) × 0.000000536658 + (normalized expression level of GRP) × 0.00000297345 + (normalized expression level of HOXA10) × 0.000234721 - (change in copy number of MYC) × 0.0537056.

[0366] In one embodiment of the invention, the threshold level corresponds to a marker score 2 of 0.4 to 0.6, particularly 0.5 ± 20%, most particularly 0.5, wherein the marker score is obtained by partial least squares (PLS) analysis using the first principal component:

[0367] Marker score 2 = 0.483918 + (normalized expression level of ASCL1) × 0.00000188066 + (normalized expression level of DDC) × 0.00000188066 + (normalized expression level of GRP) × 0.00000352033 - (copy number change of MYC) × 0.0407898.

[0368] In one embodiment of the invention, the threshold level corresponds to a marker score 3 of 0.4 to 0.6, particularly 0.5 ± 20%, most particularly 0.5, wherein the marker score is obtained by partial least squares (PLS) analysis using the first principal component:

[0369] Marker score 3 = 0.393569 + (normalized expression level of ASCL1) x 0.00000182731 + (normalized expression level of DDC) x 0.00000189664 + (normalized expression level of GRP) x 0.00000342046.

[0370] Marker scores above a threshold level indicate a high likelihood of response to treatment with an LSD1 inhibitor, while marker scores below that level indicate a low likelihood of response to such treatment. Higher scores were associated with higher mRNA expression of ASCL1, DDC, GRP, and HOXA10, and lower copy number variation in MYC.

[0371] In one embodiment of the invention, the reference level is a threshold level for a marker score.

[0372] In one embodiment of the present invention, a marker score for predicting response to a therapy comprising an LSD1 inhibitor can be obtained by performing the following steps:

[0373] a. Select a gene set comprising m genes, wherein m is an integer greater than 1, selected from the genes disclosed in Table 9 and optionally HOXA10 and MYC.

[0374] b. Select a panel of one or more sensitive and one or more resistant cancer cell lines, particularly derived from neuroendocrine tumors, such as small cell lung cancer (SCLC), for example as described in Table 6. Alternatively, select a panel of one or more typical and one or more variant small cell lung cancer cell lines.

[0375] c. Generate an nxm matrix, where m is as defined above and n is the total number of selected small cell lung cancer cell lines. The matrix contains the expression levels of the selected genes (and / or the copy number variation in the case of MYC). Gene expression levels can be reported as RPKM or as calibrated read counts.

[0376] d. Generate a response vector of size n that describes each cell line as sensitive ("S") or resistant ("R"), as defined in Table 6. Alternatively, the vector can describe each cell line as a "classical" (C") or "variant" (V") subtype.

[0377] e. Apply a machine learning algorithm to classify the above matrix in point c. Examples of such machine learning algorithms include, but are not limited to, decision trees, support vector machines, neural networks, nearest neighbor analysis, Bayes, random forest, partial least squares, etc.

[0378] f. Perform appropriate cross-validation using cell lines included in the analysis and / or cell lines not included in the analysis to optimize the predictive power of the model.

[0379] g. If appropriate, select a function f(x) based on the selected machine learning algorithm to obtain a marker score y (y = f(x)). The function f(x) includes a set of coefficients a1...ap (where p is the number of coefficients selected by the given algorithm) calculated by the machine learning algorithm and the gene expression levels (x1...xm) of the selected genes.

[0380] h. Select thresholds based on recommendations from machine learning methods to determine whether the marker score predicts sensitivity or resistance to LSD1 inhibition therapy.

[0381] In a specific embodiment of the present invention, the genome comprises one or more genes selected from ASCL1, MYC, HOXA10, DDC, GRP, NCAM1, NCAM2, NEUROD1, KRT8, ENO2, AVP, OXT, SYP, CHGA, CHGB, SOX21 and BCL2.

[0382] In a specific embodiment of the present invention, the genome comprises one or more genes selected from the group consisting of ASCL1, MYC, HOXA10, DDC, GRP, NCAM1, NCAM2, NEUROD1, SOX21 and BCL2.

[0383] In a specific embodiment of the present invention, the genome comprises 2, 3, 4 or 5 genes selected from ASCL1, MYC, HOXA10, DDC, GRP, NCAM1, NCAM2, NEUROD1, SOX21 and BCL2.

[0384] In a specific embodiment of the present invention, the genome comprises one or more genes selected from the group consisting of ASCL1, MYC, HOXA10, DDC and GRP.

[0385] In a specific embodiment of the present invention, the genome comprises 2, 3, 4 or 5 genes selected from ASCL1, MYC, HOXA10, DDC and GRP.

[0386] In a specific embodiment of the present invention, the genome comprises one or more genes selected from the group consisting of ASCL1, MYC and HOXA10.

[0387] In a specific embodiment of the present invention, the genome comprises the ASCL1 gene.

[0388] In a specific embodiment of the present invention, the genome comprises the MYC gene.

[0389] In a specific embodiment of the present invention, the genome comprises the HOXA10 gene.

[0390] In a specific embodiment of the present invention, the genome comprises the DDC gene.

[0391] In a specific embodiment of the present invention, the genome comprises a GRP gene.

[0392] In a specific embodiment of the present invention, the genome consists of 1, 2, 3, 4 or 5 genes.

[0393] In a specific embodiment of the present invention, the genome consists of 2, 3 or 4 genes.

[0394] In a specific embodiment of the present invention, the responder gene is selected from ASCL1, HOXA10, DDC, GRP, NCAM1, NCAM2, NEUROD1, KTR8, ENO2, AVP, OXT, SYP, CHGA, CHGB, SOX21 and BCL2.

[0395] In a specific embodiment of the present invention, the non-responder gene is selected from MYC. BRIEF DESCRIPTION OF THE DRAWINGS

[0396] Figure 1: The in vitro activity of LSD1 inhibitors (i.e., (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine) in a panel of SCLC cell lines treated for 7 days was variable. "Classical" neuroendocrine cell lines that maintain a high level of sensitivity, such as NCI-H1876 ( Figure 1A ) and NCI-H510( Figure 1B ).

[0397] Figure 2: LSD1 inhibitors (i.e., (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine) improve the in vivo SCLC standard of care (SOC) response to etoposide and carboplatin ( Figure 2A ) and in mice ( Figure 2B )’s effectiveness and duration.

[0398] Figure 3 ： The principal component analysis score plots for principal component 1 (t[1], x-axis) and principal component 2 (t[2], y-axis) according to Example 5 separate typical cell lines (C, black) from variant cell lines (V, gray).

[0399] Figure 4 ： A heatmap of mRNA expression (as z-scores) for the gene set of Example 6, comprising genes from Table 8, Table 6, and MYC, is shown. These genes best predicted response to LSD1 inhibition therapy in the 19 cell lines from Table 6. Higher z-scores correlated with better sensitivity.

[0400] Figure 5 ： A heat map is shown of the mRNA expression (as z-scores) of the neuroendocrine genes of Example 7 in the 19 cell lines of Table 6. Sensitive cell lines showed stronger expression (higher z-scores) of these neuroendocrine markers.

[0401] Figure 6 ： Marker scores obtained by PLS analysis using the second principal component according to Example 8. Cell lines with a score of _1>0.5 are more likely to be sensitive to LSD1 inhibition therapy.

[0402] Figure 7 ： Marker scores obtained by PLS analysis using the first principal component according to Example 8. Cell lines with a score of _2>0.5 are more likely to be sensitive to LSD1 inhibition therapy.

[0403] Figure 8 ： Marker scores obtained by PLS analysis using the first principal component according to Example 8. Cell lines with a score of _3>0.45 are more likely to be sensitive to LSD1 inhibition therapy.

[0404] Figure 9 ： In vivo tumor growth inhibition by (trans)-N1-((1R,2S)-2-phenylcyclopropyl))cyclohexane-1,4-diamine in the representative (C) cell line H-510A.

[0405] Figure 10: Heatmap showing the pattern of mRNA expression (as z-scores) in SCLC patient samples. Example

[0406] The following Examples 1 to 9 are provided to illustrate the present invention. They should not be considered as limiting the scope of the invention, but merely as representative thereof.

[0407] method

[0408] Expression data

[0409] Expression data were obtained by whole transcriptome RNA sequencing (RNA-seq) by Illumina, Inc. (San Diego, CA). The Illumina HiSeq machine generates raw base calls for reads of 50 or 100 bp in length, which are then subjected to multiple data analysis steps. RNA-seq is performed at 40 to 50 million reads per sample. This number provides relatively high sensitivity for detecting lowly expressed genes while allowing cost-effective multiplexing of samples. RNA was prepared using a standard kit and RNA libraries using the polyA TruSeq Illumina kit. 100 ng of mRNA from each cell line was used for each RNA-seq reaction. A number of quality control procedures were applied to the RNA-seq data for each sample. The Illumina HiSeq software reports the total number of clusters (DNA fragments) loaded in each lane, the percentage that passed the sequencing quality filter (identifying errors due to overloading and sequencing chemistry), the phred quality score for each base of each sequence read, the overall average phred score per sequencing cycle, and the overall percentage error (based on alignment with the reference genome). For each RNA-seq sample, the percentage of reads containing mitochondrial and ribosomal RNA was calculated. The FASTQC package was used to provide additional QC metrics (base distribution, sequence repeats, overrepresented sequences, and enriched kmers) and graphical summaries. Raw reads were aligned to the human genome (hg19) using GSNAP and recommended options for RNASeq data. In addition to the genomic sequence, GSNAP also provides a database of human splice junctions and transcripts based on Ensemblv73. The resulting SAM files were then converted to sorted BAM files using Samtools. Gene expression values ​​were calculated as RPKM values ​​and read counts following (Mortazavi et al.). Aligned read counts were obtained using the R package DESeq2.

[0410] Copy number variation (CNV)

[0411] To obtain copy number variation data, genomic DNA was extracted and array CGH analysis was performed by Roche NimbleGen (Madison, WI) using their standard protocol. Normalized signal intensity and copy number variation were obtained using the segMNT algorithm. CGH microarrays contain isothermal 45-85mer oligonucleotide probes synthesized directly on a silica surface using light-guided photochemistry (Selzer et al. 108 ). The genomic DNA sample is randomly fragmented into lower molecular weight species and differentially labeled with fluorescent dyes.

[0412] Main component analysis

[0413] Principal component analysis was performed using Simca v 14 (Umetrics AB, Umea, Sweden).

[0414] Differential gene expression analysis

[0415] The differential gene expression analysis used to generate the data in Table 9 was performed using the R package DESeq2 starting from the raw read counts of the 19 cell lines.

[0416] Heatmap of cell lines

[0417] Gene pattern v 3.9.4 (Reich M. et al. 101 ) to generate a heat map of cell lines (e.g. Figure 4 and 5 1.5 dfs (Figure 10) show the gene expression levels of color coding. The logarithm of the gene pattern input calibration read count (as described in Table 10) plus 1 and the standardization based on the row is applied, which includes the z-scores of all expression levels of a given gene in the cell line of the calculation test. The z-score 0 corresponds to the mean value of the distribution, and the positive or negative value represents the standardized gene expression level higher or lower than the mean value, respectively. The color mapping limits the z-score range to between -1.5 and +1.5, that is, the z-score higher than +1.5 is shown in black, and the z-score lower than -1.5 is white. The median value is shown in different shades of gray. The gene pattern performs hierarchical clustering to group and sort the cell lines according to the gene expression profile of the cell line.

[0418] Example 1 - Differential activity of LSD1 inhibitors in SCLC cell lines

[0419] The differential activity of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine in SCLC cell lines is shown in Figures 1A-1B The activity of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine was evaluated in vitro in a panel of SCLC cell lines treated for 7 days. Cell lines characterized as "typical" neuroendocrine lineages, such as NCI-H1876 ( Figure 1A ) and NCI-H510( Figure 1B ) maintains a high level of sensitivity to (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine.

[0420] Compound potency assays were performed by culturing small cell lung cancer cell lines in the presence of 15 serial dilutions of the indicated concentrations of (trans)-N1-((1R,2S)-2)-phenylcyclopropyl)cyclohexane-1,4-diamine for 7 days in a humidified incubator at 37°C with 5% CO2. Each cell line was propagated and tested in a different optimized culture medium as recommended by the ATCC or cell line source.

[0421] Cells were thawed from liquid nitrogen storage. Screening began once cells were expanded and split at the expected doubling time. Cells were seeded at 500 cells per well in growth medium in black 384-well tissue culture-treated plates (except where noted on the analyzer). Cells were equilibrated in the assay plates by centrifugation and placed in an incubator connected to the dosing module at 37°C for 24 hours prior to treatment. At the time of treatment, one set of assay plates (not receiving treatment) was collected and ATP levels were measured by adding ATPLite (Perkin Elmer). These Tzero (T0) plates were read using ultrasensitive luminescence on Envision Plate Readers. Treated assay plates were incubated with (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine for 168 hours. After 186 hours, plates were developed using ATPLite for endpoint analysis. All data points were collected through automated processes, quality controlled, and analyzed using Horizon CombinatoRx proprietary software. Assay plates were accepted if they passed the following quality control criteria: relative luciferase values ​​were consistent across the experiment, Z-factor scores were greater than 0.6, and untreated / vehicle controls appeared consistent across the plate.

[0422] Horizon Discovery utilizes growth inhibition (GI) as a measure of cell viability. Cell viability was measured at the time of dosing (T0) and after 168 hours (T168) for vehicle. A GI reading of 0% indicates no growth inhibition - matched for cells treated with (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine and T168 vehicle signal. A GI of 100% represents complete growth inhibition - matched for cells treated with compound and T0 vehicle signal. There was no increase in cell number during treatment in wells with a GI of 100% and may indicate a cytostatic effect of the compound that plateaued at this effect level. G1200% indicates complete cell death in all cells in the culture well. Compounds that reach a GI 200% activity plateau are considered cytotoxic. Horizon CombinatoRx calculates the GI by applying the following test and equation:

[0423] If T <V0:

[0424] If T ≥ V0:

[0425] Where T is the signal measurement of the test article, V is the vehicle-treated control measurement, and Vo is the vehicle control measurement at time zero. This formula is derived from the growth inhibition calculation used in the National Cancer Institute's NCI-60 high-throughput screen.

[0426] Example 2 - Synergistic Effects of Combinations of LSD1 Inhibitors with Additional Active Pharmaceutical Ingredients

[0427] Table 4 provides a heat map of synergy scores, which represent the strength of the synergistic effect. Synergy scores > 6.4 were considered significant and require further validation. Cell lines were sensitive to the effects of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine (NCI-H187, NCI-H1417, NCI-H1876, NCI-H510) across a wide range of drug classes, including HDAC and BET inhibitors, DNA alkylating agents, topoisomerase inhibitors, antimitotics, Aurora kinase inhibitors, BCL2 family inhibitors, and Chk inhibitors. Similar synergy was not observed in cell lines that were insensitive to (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine (NSCLC cells) (NSCLC cell lines and SCLC cell lines NCI-H1048, NCI-H446, and SBC-5). These data suggest that LSD1 inhibition can broadly sensitize SCLC cell lines to chemotherapeutic and targeted therapy intervention.

[0428] Thaw cells from liquid nitrogen storage and expand until they reach the expected doubling time. Propagate and test each cell line in different optimized media as recommended by the ATCC or cell line source.

[0429] Cells were seeded at the indicated density in 384-well assay plates (determined during the optimization phase). Cells were then equilibrated by centrifugation for 24 hours in an incubator connected to a dosing module and then pre-treated with (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine. The assay plates were then treated with the indicated concentrations of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine (determined during the optimization phase).

[0430] Upon treatment with (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, one set of assay plates (no compound treatment) were harvested and ATP levels were measured by adding ATPLite (Perkin Elmer). These Tzero (T0) plates were read on Envision PlateReaders to measure luminescence. The treated assay plates were incubated with (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine for 96 hours and then treated with the second compound. Thereafter, the assay plates were then treated with an 8-point serial dilution of the enhancer compound in a 9x9 extension matrix and harvested after an additional 72 hours of incubation. After a total of 168 hours from the initial (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine treatment time, the plates were developed for endpoint analysis using ATPLite. All data points were collected through automated processes; quality controlled; and analyzed using Horizon CombinatoRx proprietary software. Assay plates were accepted if they passed the following quality control criteria: relative luciferase values ​​were consistent across the experiment, a Z-factor score was greater than 0.6, and untreated / vehicle controls performed consistently across the plate.

[0431] Horizon Discovery utilizes growth inhibition (GI) as a measure of cell viability. Cell viability is measured at the time of dosing (T0) and after 168 hours (T168) with vehicle. A GI reading of 0% indicates no growth inhibition - cells treated with compound and vehicle signals at T168 are matched. A GI of 100% represents complete growth inhibition - cells treated with compound and vehicle signals at T0 are matched. There was no increase in cell number during treatment in wells with a GI of 100% and may indicate a cytostatic effect of the compound that plateaued at this level of effect. A GI of 200% indicates complete cell death in all cells in the culture well. Compounds that reach a GI 200% activity plateau are considered cytotoxic. Horizon CombinatoRx calculates the GI by applying the following test and equation:

[0432] If T <V0:

[0433] If T ≥ V0:

[0434] Where T is the signal measurement of the test article, V is the vehicle-treated control measurement, and Vo is the vehicle control measurement at time zero. This formula is derived from the growth inhibition calculation used in the National Cancer Institute's NCI-60 high-throughput screen.

[0435] The Loewe additivity model is dose-based and applies only to activity levels achieved by a single agent. The Loewe volume is used to assess the overall magnitude of combinatorial interactions that exceed the Loewe additivity model. The Loewe volume is particularly useful when distinguishing synergistic increases in phenotypic activity (positive Loewe volume) from synergistic antagonism (negative Loewe volume). When antagonism is observed, as in the current dataset, the Loewe volume should be assessed to examine whether there is any correlation between the antagonism and specific drug target activity or cellular genotype. The model defines additivity as a non-synergistic combinatorial interaction where the combination dose matrix should be surface indistinguishable from any drug hybridizing with itself. The calculation of additivity is:

[0436] I Loewe Satisfy (X / X I )+(Y / Y I )=1

[0437] where X I and Y I is the effective concentration of the single agents at which the combined effect I is observed. For example, if 50% inhibition is achieved by 1 mM drug A or 1 mM drug B, respectively, then the combination of 0.5 mM A and 0.5 mM B should also inhibit by 50%.

[0438] To measure the effect of the combination beyond Loewe additivity, the Horizon Discovery platform was used. This approach devised a scalar measure to characterize the strength of the synergistic interaction called the Synergy score. The Synergy score is calculated as follows:

[0439] Synergy score = log f X log f Y ∑max(0,I 数据 )(I 数据 -I Loewe )

[0440] The score inhibition of each component reagent and combination point in the matrix is ​​calculated relative to the median of the control wells treated with all vehicles. The synergistic scoring equation integrates the experimentally observed active volume at each point in the matrix, exceeding the model surface derived from the component reagent activity mathematically using the Loewe model additivity. The additional term in the synergistic scoring equation (above) is used to standardize the various dilution factors for each reagent and allows comparison of synergistic scores across the experiment.

[0441] The activity of Loewe additivity is most easily calculated using a simple volume fraction, where V Loewe =log f X log f Y ∑(I 数据-I Loewe ), summing all non-single agent concentration pairs, where log f X，Y is the natural logarithm of the dilution factor for each single active agent used. This effectively calculates the volume between the measured values ​​and the Loewe additive response surface, corrected for the different dilution factors. This volume fraction emphasizes the overall synergistic or antagonistic effects of the combination, minimizing the influence of outlying data peaks and identifying combinations with strong synergy across a wide range of concentrations and high potency levels. Loewe It is positive for most synergistic combinations and negative for antagonistic effects. I and standard error propagation to calculate uncertainty σ V .

[0442] "Synergy score" S = f cov ln f X ln f Y ∑max(0,I 数据 )max(0,I 数据 -I Loewe ), which is a positive gate that suppresses the weighted volume beyond Loewe additivity. This provides additional prioritization, favoring combinations whose synergy occurs at high effect levels, ignoring the antagonistic part of the response surface. Here f X，Y is the dilution factor for each single active agent, and the coverage factor f cov To account for missing data, the score is inflated by the ratio of total / tested combined dose matrix points. S is always positive and its uncertainty σ S The error σ can be calculated based on the measurement I and standard error propagation. An alternative to the synergy score is the “hit score” H = f COV log f X log f Y ∑max(0,I 数据 )max(0,I 数据 -I HSA ), which refers to the HSA model. The key difference between S and H lies in the different underlying models and how the individual active agents are used in the model calculations. In the Chalice analyzer, the HSA model is calculated directly from the responses of the individual agents at the corresponding concentrations, while the Loewe additivity model is derived from a sigmoidal fit of the response curves of the individual active agents.

[0443] To prioritize the hits, the distribution of the scores (S or H) and their errors can be used to define an appropriate selection cutoff. For example, assuming normal error, with S > 3σ SThe combination of the two drugs was "individually significant" at a confidence level of 99%. To estimate the systematic experimental error that did not pass the replicate plate test, the distribution of synergy scores for any drug in combination with itself obtained during the experiment can be used to determine a plausible range for non-detection. Alternatively, the distribution of scores for the entire experiment can be used to identify outliers at a selected confidence level.

[0444] Example 3 - In vitro synergistic effects of LSD1 inhibitors in combination with other active pharmaceutical ingredients for SCLC

[0445] Table 5 provides a heat map of synergy scores, which represent the strength of the synergistic effect. Synergy scores > 6.4 were considered significant and require further validation. Based on the observed level of synergy and the potential clinical application of the compounds in SCLC treatment regimens, a group of drug classes were prioritized for further evaluation in an expanded panel of SCLC cell lines. Targeted therapies and chemical probes inhibiting epigenetic regulators BET (particularly Brd4) ((+)-JQ1, CPI-203, MS436, GSK1324726A, GSK1210151A, and OTX015) and the anti-apoptotic regulator BCL2 (Obakra, ABT-199, ABT-737, and TW-37) were highly synergistic with LSD1 inhibition. Synergy was also observed with other epigene regulators EZH2 (e.g., CPI-169, EPZ005687, EPZ-6438, GSK126, GSK343) and DOT1L (e.g., EPZ-5676, SGC 0946), although at low levels compared with BET (particularly BRD4) and BCL2 inhibitors.

[0446] Inhibitors of the Notch, Hedgehog, or Smoothened pathways had no synergistic effect with (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine treatment, indicating that LSD1 inhibition sensitized cell lines to select compounds and drug classes, including HDAC and BET inhibitors, DNA alkylating agents, topoisomerase inhibitors, antimitotics, Aurora kinase inhibitors, BCL2 family inhibitors, EZH2, DOT1L, and Chk inhibitors.

[0447] Cells were processed and data analyzed as described in Example 2 above.

[0448] Table 4. Synergistic Effects of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine in Combination with a Group of Suitable Active Pharmaceutical Ingredients (APIs)

[0449]

[0450] Table 5. In vitro synergistic effects of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine in combination with a panel of suitable active pharmaceutical ingredients (APIs) in SCLC cell lines.

[0451]

[0452] Example 4. LSD1 inhibitors improve SCLC-SOC efficacy and duration in vivo

[0453] In vivo, the effect of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine treatment synergistically with etoposide and carboplatin to induce cytotoxic responses can be seen from Figure 2A Clinically, one standard of care (SOC) for SCLC is the combination of etoposide and carboplatin.

[0454] In vivo, the combination of etoposide and carboplatin promoted rapid tumor regression during dosing in the NCI-H526 model. Figure 2B Addition of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine to SOC prolonged tumor regression and significantly delayed tumor regrowth by 30 days after drug withdrawal. Together, these data suggest that LSD1 inhibition can sensitize cells to chemotherapeutic agents and targeted drugs in vitro and in vivo.

[0455] NCI-H526 Model:

[0456] 8-12 week old nu / nu mice were injected with 100 μL of 1:1 suspension of 1×107 H526 cells or 5×106 SHP-77 cells in a mixture of PBS and PBS. 3 Animals were graded and assigned to dosing groups. (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine was administered at a dose of 40 μg / kg (upk) for 5 days on / 2 days off (5 / 2) for three weeks. Etoposide was administered ip at a dose of 5 mg / kg (mpk) per day for 5 days (qdx5). Carboplatin was administered ip at a dose of 100 mpk per week for three weeks (qwkx3). In combination with etoposide and carboplatin, (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine was administered at a dose of 20 upk for 5 days on / 2 days off for three weeks. Tumor volume was measured every two weeks using a digital caliper. The endpoint of the experiment was a tumor volume of 1000 mm 3 or 90 days, whichever comes first. Statistical analysis was performed using unpaired t-test and Gehan-Breslow-Wilcoxon test.

[0457] Example 5. Cellular Response to LSD1 Inhibition

[0458] Compound potency assays were performed by culturing 19 small cell lung cancer cell lines (various tumor origins) in the presence of serially diluted (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine dihydrochloride at 37°C, 5% CO2 in a humidified incubator for 4 days.

[0459] As a positive control for cytotoxicity, the Hsp90 inhibitor 17-N-allylamino-17-demethylgeldanamycin (17-AAG, a geldanamycin analog) was used as a positive control for serial dilutions. Each cell line was propagated and tested in different optimized media according to the recommendations of the ATCC or the cell line source.

[0460] Small cell lung cancer cell lines can be classified as “classical” or “variant” based on their enzymatic activity, cell morphology, and growth phenotype (Desmond et al. 102 ., Shoemaker RH 103 Classical cell lines express elevated levels of L-dopa decarboxylase, bombesin-like immunoreactivity, neuron-specific enolase, and the brain isoenzyme of creatine kinase; variant cell lines continue to express the brain isoenzymes of neuron-specific enolase and creatine kinase but have variable expression levels of L-dopa decarboxylase and bombesin-like immunoreactivity. Unlike classical cell lines, some variant cell lines are amplified and have increased expression of the c-myc (MYC) oncogene.

[0461] Some cell lines exhibit characteristics specific to both classical and variant subtypes. For example, SHP-77 has biochemical characteristics typical of SCLC (e.g., elevated L-dopa decarboxylase levels and bombesin-like immunoreactivity) but exhibits variant morphology. Based on the literature, SHP-77 is considered classical based on its biochemical characteristics but variable based on its morphology and growth characteristics.

[0462] For NCI-H2029 and SBC-5, subtypes were not reported in the literature, but their trans-fragmentation profiles (mRNA expression levels of DDC / GRP) clearly showed their class membership, which is provided in parentheses in Table 6.

[0463] Based on their response to (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine bishydrochloride, cell lines were classified as “sensitive” [S], defined as having an EC50 < 0.05 μM, or “resistant,” defined as having an EC50 >= 0.05 μM [R].

[0464] Classical SCLC cell lines showed a higher cellular response to (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine dihydrochloride compared to variant SCLC cell lines (p value 0.0055 Table 6). Of the 19 SCLC cell lines tested, 9 of the 11 classical cell lines [C] were sensitive [S] and 7 of the 8 variant cell lines [V] were resistant [R] (Table 7).

[0465] The variant and typical subtypes predicted response to LSD1 inhibitor treatment with 82% sensitivity and 88% specificity.

[0466] Higher copy number variations (CNVs) in the MYC gene (Ensemble gene ID: ENSG00000136997) are associated with variant subtype (V) of small cell lung cancer (Am J Path 01. 1988 Jul; 132(1): 13-17). Indeed, among the 19 cell lines described here, high copy number variations in the MYC gene (CNV>>2) were found only in cell lines with variant subtype (NCI-H2171, NCI-H446, NCI-H82, see Table 6). Furthermore, all three cell lines with high copy number MYC variants were resistant to LSD1 inhibition, indicating that the presence of MYC amplification can predict resistance to LSD1 inhibition therapy (R).

[0467] Principal component analysis of the RNA-seq data from the cell lines in Table 6 surprisingly revealed that classical and variant SCLC cell lines formed distinct clusters. Figure 3 ).

[0468]

[0469] Table 6. Cell-based responses to (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine bishydrochloride in a typical SCLC cell line [C] compared to a variant SCLC cell line [V].

[0470]

[0471] Table 7. Contingency matrix showing the number of typical and variant cell lines that are sensitive or resistant to LSD1 inhibition therapy.

[0472] Example 6. Gene Sets Predicting Response to LSD1 Inhibition

[0473] Differential gene expression analysis between two resistant cell lines with typical subtypes (SHP-77 and NCI-2029) and typical and variant cell line characteristics was sensitive (NCI-H1876, NCI-H69, NCI-H510A, NCI-H146, NCI-H187, NCI-H2081, NCI-H345, NCI-H526, NCI-H748) interestingly revealed that lower mRNA expression levels of HOXA10 were associated with resistance to LSD1 inhibition therapy (Table 8). This suggests that low levels of HOXA10 mRNA may predict resistance to LSD1 inhibition therapy even in the presence of a typical phenotype.

[0474] A predictive mRNA expression signature for response to LSD1 inhibition therapy was defined by selecting the top differentially expressed genes between classical and variant cell lines (Table 9). Based on adjusted p-values, DDC (adjusted p-value 4.37E-23), encoding an immunoreactive peptide similar to bombesin, which encodes L-dopa decarboxylase, and GRP (adjusted p-value 5.19E-14), ranked second and sixth most differentially expressed genes. The most differentially expressed gene was ASCL1 (adjusted p-value 2.6E-23). ​​ASCL1 is a transcription factor required for the normal development of lung neuroendocrine cells and is essential for the survival of most lung cancers (Augustyn et al. 104 ).

[0475] As discussed above in Example 5, MYC amplification is predictive of resistance to LSD1 inhibition therapy.

[0476] Table 10 lists the calibrated readouts for DDC, GRP, and ASCL1 for the 19 cell lines described in Table 6, while Table 11 lists the corresponding z-scores.

[0477] Figure 4 The heat maps visually show that sensitive cell lines can be distinguished from resistant cell lines based on the mRNA expression levels of the genes listed in Table 9 and based on the expression levels of HOXA10 and copy number variations of MYC.

[0478] <![CDATA[Ensembl gene ID ＊ > Gene Baseline average log2 fold change p-value ENSG00000253293 HOXA10 2717.58 8.21 7.45E-023

[0479] Table 8. Principal component analysis of HOXA10 based on RNA-seq data for selected cell lines ( ＊ http: / / www.ensembl.org / , Cunningham F. et al. 100 )

[0480]

[0481]

[0482] Table 9. Genes filtered by p-value obtained by principal component analysis based on RNA-seq data of selected cell lines ( ＊ http: / / www.ensembl.org / , Cunningham F. et al. 100 ).

[0483] cell lines ASCL1 DDC GRP HOXA10 NCI-H1417 42666.4 16161.1 10935.2 3327.72 NCI-H1876 34116.3 986.718 43.7461 2779.5 NCI-H69 19902.1 25773.6 3256.24 4271.2 NCI-H510A 79879.7 19456.3 27861 2730.12 NCI-H2227 4515.83 2005.02 645.86 2.59381 NCI-H2029 127171 39070.6 1800.43 10.0396 NCI-H146 59238.2 45308.8 426.015 2126.39 NCI-H187 71323.6 4363.62 130.681 2448.85 NCI-H2081 69670.9 29683.5 2.97459 3423.76 NCI-H345 81805.8 16935.7 30601.3 263.11 SHP-77 115523 71808.9 39002.6 4.72759 NCI-H748 122007 27938.7 12773.8 3940.53 DMS-114 59.1696 16.3227 12.242 1462.92 NCI-H1048 38.9626 90.2292 0 1168.88 NCI-H2171 1115.78 368.976 0 1248.61 NCI-H446 13.1805 32.0098 11.2976 2818.75 NCI-H82 577.05 486.304 9.30725 221.047 SBC5 4.51028 13.5308 0 617.908 NCI-H526 11.9576 38.2644 4.78305 4091.9

[0484] Table 10: Corrected read counts from mRNA expression levels.

[0485] cell lines ASCL1 DDC GRP HOXA10 NCI-H1417 0.63 0.69 1.09 0.67 NCI-H1876 0.57 -0.24 -0.34 0.6 NCI-H69 0.42 0.85 0.78 0.78 NCI-H510A 0.8 0.76 1.34 0.59 NCI-H2227 0.02 0 0.35 -2.31 NCI-H2029 0.93 0.99 0.62 -1.82 NCI-H146 0.72 1.04 0.25 0.48 NCI-H187 0.77 0.26 -0.06 0.54 NCI-H2081 0.77 0.9 -0.98 0.69 NCI-H345 0.81 0.71 1.36 -0.43 SHP-77 0.9 1.19 1.43 -2.11 NCI-H748 0.92 0.88 1.13 0.75 DMS-114 -1.16 -1.59 -0.66 0.32 NCI-H1048 -1.27 -1.04 -1.34 0.22 NCI-H2171 -0.36 -0.57 -1.34 0.25 NCI-H446 -1.55 -1.38 -0.68 0.6 NCI-H82 -0.54 -0.48 -0.73 -0.51 SBC5 -1.81 -1.65 -1.34 -0.06 NCI-H526 -1.58 -1.32 -0.88 0.76

[0486] Table 11: Z-scores generated by mRNA read counts from calibration.

[0487] Example 7. Neuroendocrine Gene Set Predicting Response to LSD1 Inhibition

[0488] The mRNA expression levels of the second group of genes according to Table 12 (NCAM1, NCAM2, NEUROD1, KRT8, ENO2, AVP, OXT, SYP, CHGA, CHGB, SOX21, BCL2), including genes representing neuroendocrine phenotype and used as immunohistochemical markers for diagnosing lung neuroendocrine tumors, were significantly downregulated in the resistant cell lines DMS114, SBC5 and NCI-H1048, as shown in Table 12. Figure 5 This is consistent with our hypothesis that LSD1 inhibition therapy blocks cell growth in tumors of neuroendocrine origin.

[0489] Tables 13A and 14B list the normalized read counts for the genes in Table 12 in the 19 cell lines in Table 6.

[0490]

[0491]

[0492] Table 12. Genes of the second neuroendocrine gene group ( ＊ http: / / www.ensembl.org / , Cunningham F. et al. 100 ).

[0493] cell lines NCAM1 NCAM2 NEUROD1 KRT8 ENO2 AVP NCI-H1417 52961.1 230.0 257.7 32261.1 32287.3 5.8 NCI-H1876 12131.4 111.0 143.4 36460.8 37021.4 33.2 NCI-H69 53702.4 16861.8 295.0 28560.6 28765.0 18.6 NCI-H510A 21010.6 197.4 255.2 67662.7 11901.4 1.7 NCI-H2227 42956.2 32469.4 1273.6 181.6 35558.6 2.6 NCI-H2029 37343.8 70.3 244.3 76401.1 22753.0 0.0 NCI-H146 39176.8 1929.1 173.4 50190.4 32430.6 5.5 NCI-H187 47022.6 8.5 31.3 61809.4 32195.9 2.8 NCI-H2081 37569.1 1279.1 2427.3 26842.7 32137.5 0.0 NCI-H345 62260.5 131.6 96.7 46256.4 32848.5 45.6 SHP-77 21787.1 990.4 0.0 35148.0 8851.6 0.0 NCI-H748 21844.8 892.7 12.1 1508.8 44468.6 0.9 DMS-114 95.9 512.1 18.4 377.5 3260.5 0.0 NCI-H1048 14740.2 760.8 0.0 12726.4 38304.4 0.0 NCI-H2171 16524.2 35.4 60402.8 26223.8 212034.0 0.0 NCI-H446 79657.4 3747.0 19164.5 45.2 36229.5 0.0 NCI-H82 20878.5 437.4 34283.3 27.9 22702.7 0.0 SBC-5 130.8 19026.6 9.0 640.5 160.1 0.0 NCI-H526 44561.3 0.0 23.9 38233.3 24912.5 0.0

[0494] Table 13A. Corrected read counts from mRNA expression levels.

[0495]

[0496]

[0497] Table 13B. Corrected read counts from mRNA expression levels.

[0498] Example 8. Marker Scores for Predicting Response to LSD1 Inhibition

[0499] Normalized expression levels (Norm_read_count) of ASCL1, DDC, GRP, and HOXA10 and MYC copy number variation (Copy_number_variation) were used to generate a gene signature to predict response to LSD1 inhibition therapy as follows:

[0500] The scores were generated according to the following equation, obtained by partial least squares (PLS) analysis using the second principal component:

[0501] Marker score 1 = 0.0900693 + (ASCL1-calibrated expression level) × 0.00000211296 + (DDC-calibrated expression level) × 0.000000536658 + (GRP-calibrated expression level) × 0.00000297345 + (HOXA10-calibrated expression level) × 0.000234721 - (copy number change of MYC) × 0.0537056

[0502] A marker score of 1>0.5 predicted response to LSD1 inhibition therapy (Fisher's exact test two-tailed p < 0.0001, sensitivity 90%, specificity 100%), as Figure 6 As shown in .

[0503] Alternatively, the scores are generated according to the following equation, obtained by partial least squares using the first principal component:

[0504] Marker score 2 = 0.483918 + (ASCL1-calibrated expression level) × 0.00000188066 + (DDC-calibrated expression level) × 0.00000188066 + (GRP-calibrated expression level) × 0.00000352033 - (copy number change of MYC) × 0.0407898

[0505] A marker score 2 > 0.5 predicted response to LSD1 inhibition therapy (Fisher's exact test two-tailed p < 0.0055, sensitivity 90%, specificity 77.8%), as Figure 7 As shown in .

[0506] Furthermore, the score is generated according to the following equation, obtained by partial least squares using the first principal component:

[0507] Marker score 3 = 0.393569 + (ASCL1-calibrated expression level) × 0.00000182731 + (DDC-calibrated expression level) × 0.00000189664 + (GRP-calibrated expression level) × 0.00000342046

[0508] Marker score 3>0.45 predicted response to LSD1 inhibition therapy (Fisher's exact test two-tailed p 0.0055, sensitivity 90%, specificity 77.8%), as Figure 8 As shown in .

[0509] Marker scores above the reference level indicate a high likelihood of response to treatment with an LSD1 inhibitor, while marker scores below that level indicate a low likelihood of response to such treatment. Higher scores were associated with ASCL1, DDC, GRP, Higher mRNA expression of HOXA10 was associated with lower copy number variation in MYC.

[0510] Example 9. In vivo tumor growth inhibition

[0511] NCI-H510A Model:

[0512] 7-8 week old athymic nude mice were injected with 100 μL of 1:1 suspension. Matrix (Corning Inc., Tewksbury / MA, CS Hughes et al. 105 ) and PBS in a 1:1 mixture of 5x10 6 H510A cells. Tumors were grown at 200-300 mm 3 Animals were graded and assigned to treatment groups. (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine was administered at a dose of 40 μg / kg (upk) for 5 days followed by two rest days until the end of the study. Tumor volume was measured every two weeks using a digital caliper. When the average tumor volume in the control group reached 2000 mm 3 The study was terminated at 28 days after the initial phase. Statistical analysis was performed using unpaired t-test.

[0513] NCI-H526 and SHP-77 models:

[0514] 8-12 week old nu / nu mice were injected with 1x10 7 H526 cells were resuspended in 100 μL of 1:1 and 5x10 in a PBS mixture 6 SHP-77. The tumor was 100-150 mm 3Animals were graded and assigned to dosing groups. (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine was administered at a dose of 40 UPK for 5 days / two days until the end of the study. Tumor volume was measured every two weeks using a digital caliper. When the average tumor volume in the control group reached 2000 mm 3 The study was terminated at 28 days after the initial phase. Statistical analysis was performed using unpaired t-test.

[0515] The in vitro activity of the LSD1 inhibitor (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine inhibited the growth of the H510A xenograft model in vivo, e.g. Figure 9 As shown. In the "response marker"-positive cell line H510A model, treatment with (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine resulted in a modest but measurable 34% tumor growth inhibition compared to untreated controls after 21 days of dosing. These results suggest that the 15-gene signature defined previously can predict sensitivity to (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine in vivo. The in vivo activity of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine was also evaluated in the "response marker"-positive SHP-77 and "response marker-negative" H526 xenografts to validate the predictive power of the gene signature from in vitro results.

[0516] Example 10. Expression patterns in SCLC patient samples

[0517] Gene expression patterns in a panel of SCLC patient samples were found to be similar to those observed in SCLC cell lines (Example 6, Figure 4 ), which suggests that the use of LSD1 inhibitor-responsive gene signatures, particularly (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine-responsive gene signatures may increase the likelihood of identifying patients who will clinically benefit from LSD1 inhibitor-based therapies, particularly from (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine-based therapies.

[0518] Figure 10 provides a heat map showing the mRNA expression (as z-scores) patterns in SCLC patient samples comprising the genes of Tables 8 and 9 and MYC. Higher z-scores are associated with better sensitivity.

[0519] The dataset used corresponds to the dataset EGAD00001000223 from the European Genome-phenome Archive (EGA) of the European Bioinformatics Institute, Part of the European Molecular Biology Laboratory (EMBL-EBI, Hinxton / UK, https: / / www.ebi.ac.uk / ega / datasets / EGAD00001000223 ). The patient ID (SAMxxxxxx) is equivalent to the ID used in this dataset.

Claims

1. A therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients selected from the group consisting of a BCL2 inhibitor, a BET inhibitor, an EZH2 inhibitor, a DOT1L inhibitor, a Chk inhibitor, a DNA alkylating agent, an HDAC inhibitor, a topoisomerase inhibitor, an antimitotic drug, an Aurora kinase inhibitor, and pharmaceutically acceptable salts thereof.

2. A therapeutic combination comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and one or more active pharmaceutical ingredients selected from ABT-199, ABT-263, ABT-737, ABT-888, ACY-1215, belinostat, bendamustine, BGJ398, BMS-906024, carboplatin, CGK 733, cisplatin, CPI-169, CPI-203, docetaxel, doxorubicin, EPZ-004777, EPZ005687, EPZ-5676, EPZ-6438, erlotinib, etoposide, FLI 06, fluorouracil, GDC-0449, gemcitabine, GSK-126, GSK-1324, GSK-1343, GSK-1326A, GSK-1343, and GSK-247. 1015lA, irinotecan, (+)-JQ1, lapatinib, LDE225, LY2603618, LY-3039478, menadione, methotrexate, MK-0752, MLN8237, MS 436, Nutlin-3A, obaclava, OTX015, paclitaxel, panobinostat, pemetrexed, PF-04217903, PF-3084014, SAHA, SGC0946, SNDX-275, Taladegib, temozolomide, topotecan, TW-37, vincristine, and pharmaceutically acceptable salts thereof.

3. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor or a pharmaceutically acceptable salt thereof.

4. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor selected from the group consisting of ABT-199, ABT-263, ABT-737, Obakola, TW-37 and pharmaceutically acceptable salts thereof.

5. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a BET inhibitor or a pharmaceutically acceptable salt thereof.

6. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a BET inhibitor selected from the group consisting of CPI-203, GSK1324726A, GSK12 10151A, (+)-JQ1, MS 436, OTX015 and pharmaceutically acceptable salts thereof.

7. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an EZH2 inhibitor or a pharmaceutically acceptable salt thereof.

8. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an EZH2 inhibitor selected from the group consisting of CPI-169, EPZ005687, EPZ-6438, GSK126, GSK343 ​​and pharmaceutically acceptable salts thereof.

9. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a DOT1L inhibitor or a pharmaceutically acceptable salt thereof.

10. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a DOT1L inhibitor selected from EPZ-004777, EPZ-5676, SGC 0946 and pharmaceutically acceptable salts thereof.

11. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a Chk inhibitor or a pharmaceutically acceptable salt thereof.

12. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a Chk inhibitor selected from LY2603618 and a pharmaceutically acceptable salt thereof.

13. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a DNA alkylating agent or a pharmaceutically acceptable salt thereof.

14. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a DNA alkylating agent selected from bendamustine, carboplatin, cisplatin, temozolomide and pharmaceutically acceptable salts thereof.

15. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an HDAC inhibitor or a pharmaceutically acceptable salt thereof.

16. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an HDAC inhibitor selected from the group consisting of ACY-1215, belinostat, panobinostat, SAHA, SNDX-275 and pharmaceutically acceptable salts thereof.

17. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

18. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor selected from the group consisting of etoposide, irinotecan, topotecan and pharmaceutically acceptable salts thereof.

19. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an Aurora kinase inhibitor or a pharmaceutically acceptable salt thereof.

20. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an Aurora kinase inhibitor selected from MLN8237 and a pharmaceutically acceptable salt thereof.

21. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an antimitotic drug or a pharmaceutically acceptable salt thereof.

22. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof and an antimitotic drug selected from the group consisting of docetaxel, paclitaxel, vincristine and pharmaceutically acceptable salts thereof.

23. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof, a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, and a DNA alkylating agent or a pharmaceutically acceptable salt thereof.

24. The therapeutic combination according to claim 1 or 2, comprising an LSD1 inhibitor or a pharmaceutically acceptable salt thereof, etoposide or a pharmaceutically acceptable salt thereof, and carboplatin or a pharmaceutically acceptable salt thereof.

25. The therapeutic combination according to any one of claims 1 to 24, wherein the LSD1 inhibitor is selected from: 4-[[4-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]-1-piperidinyl]methyl]-benzoic acid (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, (R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine, 4-(aminomethyl)-N-((trans)-2-phenylcyclopropyl)cyclohexylamine, N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine, N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine, N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine, N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine, N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine, N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine, N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine, N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine, N1-(2-(naphthalene-2-yl)cyclopropyl)cyclohexane-1,4-diamine, N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide, N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine, and pharmaceutically acceptable salts thereof.

26. The therapeutic combination according to any one of claims 1 to 25, wherein the LSD1 inhibitor is (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising a therapeutic combination according to any one of claims 1 to 26 and one or more pharmaceutically acceptable excipients.

28. A preparation comprising a therapeutic combination according to any one of claims 1 to 26 for use in the treatment of a neoplastic disease.

29. Therapeutic combination according to any one of claims 1 to 26 for use as therapeutically active substances.

30. Therapeutic combination according to any one of claims 1 to 26 for use in the treatment of a neoplastic disease.

31. A method for treating a neoplastic disease, which method comprises administering to a human or animal an effective amount of a therapeutic combination according to any one of claims 1 to 26.

32. A method for treating a tumor disease, which method comprises sensitization by administration of an LSD1 inhibitor and then administration of an effective amount of a therapeutic combination according to any one of claims 1 to 26 to a human or animal.

33. A method for treating a tumor disease, which comprises sensitizing a human or animal by administering (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine or a pharmaceutically acceptable salt thereof, and then administering an effective amount of a therapeutic combination according to any one of claims 1 to 26.

34. Use of a therapeutic combination according to any one of claims 1 to 26 in the treatment of a neoplastic disease.

35. Use of a therapeutic combination according to any one of claims 1 to 26 for the preparation of a medicament for the treatment of a neoplastic disease.

36. The preparation according to claim 28, for use in a therapeutic combination according to claim 29 or 30, the method according to claims 31 to 33 or the use according to claim 34 or 35, wherein the neoplastic disease is cancer.

37. The preparation according to claim 28, for use in the therapeutic combination according to claim 29 or 30, the method according to claims 31 to 33 or the use according to claim 34 or 35, wherein the tumor disease is breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, hematological malignancies, melanoma and sarcoma.

38. The preparation according to claim 28, for use in a therapeutic combination according to claim 29 or 30, the method according to claims 31-33 or the use according to claim 34 or 35, wherein the neoplastic disease is a solid tumor.

39. The preparation according to claim 28, for use in a therapeutic combination according to claim 29 or 30, the method according to claims 31-33 or the use according to claim 34 or 35, wherein the tumor disease is small cell lung cancer (SCLC).

40. The invention as hereinbefore described.

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