WO2021252900A1 - Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un myélome multiple - Google Patents

Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un myélome multiple Download PDF

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WO2021252900A1
WO2021252900A1 PCT/US2021/037017 US2021037017W WO2021252900A1 WO 2021252900 A1 WO2021252900 A1 WO 2021252900A1 US 2021037017 W US2021037017 W US 2021037017W WO 2021252900 A1 WO2021252900 A1 WO 2021252900A1
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ncbi gene
alkyl
subject
heteroaryl
gene
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PCT/US2021/037017
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Christopher Walker
Mariano Javier Alvarez
Yosef Landesman
Andrea Califano
Yao Shen
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Karyopharm Therapeutics Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • MM Multiple Myeloma
  • MM is a hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, or M protein in the serum or urine, bone disease, kidney disease, and immunodeficiency.
  • MM is the second most common hematological malignancy (after non- Hodgkin’s lymphoma), representing 1% of all cancers and 2% of all cancer deaths.
  • MM has improved in the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation, the introduction of immunomodulatory agents, such as thalidomide, lenalidomide, and pomalidomide, and the proteasome inhibitors, bortesomib and carfilzomib.
  • immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide
  • proteasome inhibitors such as thalidomide, lenalidomide, and pomalidomide
  • bortesomib and carfilzomib the proteasome inhibitors
  • the present invention is a method of treating a patient suffering from multiple myeloma, comprising determining a plurality of protein activity values in the subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; determining a classification of the subject as a responder or non-responder to a therapy by a compound represented by structural formula (I); and administering a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to be responder.
  • MM myeloma
  • the values and preferred values of the variables in structural formula (I) are defined herein.
  • the present invention is a method of treating a subject suffering from multiple myeloma, comprising administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject suffering from multiple myeloma, wherein the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject.
  • the values and preferred values of the variables in structural formula (I) are defined herein.
  • the present invention is a method of treating a subject suffering from multiple myeloma, comprising selecting the subject suffering from multiple myeloma only if the subject is determined to be a responder to a therapy by a compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof [0006]
  • the present invention is a method of treating a subject suffering from multiple myeloma, comprising receiving information of a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof only if the subject is determined to be
  • the present invention is a method of treating a subject suffering from multiple myeloma (MM), comprising the steps of obtaining a sample of from the subject; determining a sequence of one or more of the following genes in the sample ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I) to the subject determined to have a mutation in one or more of the genes.
  • the values and preferred values of the variables in structural formula (I) are defined herein.
  • the present invention is a method of treating multiple myeloma in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound represented by structural formula (I) [0009] to the subject, wherein the subject is determined to have determined to have a mutation in one or more of the following genes ZNF518A, DE8A, HNRNPULl , GRIA2, ADGRV1, and NOTCH3.
  • the values and preferred values of the variables in structural formula (I) are defined herein.
  • the present invention is a method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of selecting the subject only if the subject has been determined to have a mutation in at least one of the following genes ZNF518A, DE8A, HNRNPULl, GRIA2, ADGRV1, and NOTCH3; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I):
  • the present invention is a method of treating a patient suffering from a multiple myeloma, comprising the steps of receiving information about a mutation in one or genes present in the patient: ZNF518A, DE8A, HNRNPULl, GRIA2, ADGRV1, and NOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I) to the patient only if the subject has a mutation in one or more of the genes.
  • the values and preferred values of the variables in structural formula (I) are defined herein.
  • the present invention is a method of identifying a subject as a responder or a non-responder, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof; and obtaining from the classifier a classification of the subject as a responder or non-responder,
  • MM myeloma
  • the present invention is a computer program product for identifying responders and non-responders
  • the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder,
  • MM myeloma
  • FIG.1 A and IB illustrate analysis of 35 available interactomes based on tissue lineage supervised classification and network representation. Identification of the most appropriate tissue context-specific interactomes for MM was based on the likelihood predicted by a tissue-type classifier based on gene expression (FIG. 1 A), and the Network Score (FIG. IB), representing how well each evaluated interactome can explain the transcriptional state of the MM samples.
  • FIG. 2A and 2B show heatmaps of eltanexor and selinexor responder patients, constructed using protein activity signatures estimated from RNA sequencing data. Colors in the heatmap indicate the level of correlation among the proteins (by Pearson’s correlation analysis).
  • FIG. 3 A and FIG. 3B illustrate gene set enrichment analysis (GSEA) comparing selinexor and eltanexor response signatures 1 and 2.
  • GSEA gene set enrichment analysis
  • FIG. 3 A illustrates comparisons between signature 1 and signature 2.
  • FIG. 3B illustrates comparisons between eltanexor and selinexor treated patients.
  • FIG. 4 shows protein activity heatmaps according to meta VIPER algorithm described herein. The protein activity signatures were computed for each patient and then integrated across all responders and all non-responders taking the average Z-scores.
  • FIG. 5 is a schematic of an example of a computing node
  • Targeting exportin 1 is a promising therapeutic option for patients with multiple myeloma (MM).
  • Exemplary XPOl inhibitors useful for practicing the present invention are compounds represented by structural formula (I): [0025] In structural formula (I):
  • Ring A is phenyl or pyridyl
  • X is -N- or -C(H)-;
  • each R 1 is independently selected from -CN, halo, - OH, C1-C3 alkyl, C3-C 6 cycloalkyl, C 3 -C12 heterocycloalkyl, halo-Ci-C 3 alkyl, -NH2, -NO2, -NH(CI-C3 alkyl), -N(Ci- C3 alkyl)(Ci-C 3 alkyl), -C(0)OH, -C(0)0-(Ci-Ce alkyl), -C(0)-(Ci-C 3 alkyl), -0-(Ci-C 3 alkyl), -0-(Ci-C 3 haloalkyl), and -S-( C1-C 3 alkyl);
  • R 2 is selected from -C(0)-0-R 3 , -C(0)-N(R 5 )(R 6 ), -C(0)-N(R 7 )-N(R 5 )(R 6 ),
  • R a is hydrogen and R b is selected from hydrogen, -C(0)-0-R 3 ,
  • R 3 and R 3 are each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 3 -C18 carbocyclyl, C 6 -C18 aryl, C 3 -C18 heterocyclyl and C5-C18 heteroaryl;
  • R 5 , R 5 , R 6 and R 6 are each independently selected from hydrogen, C1-C4 alkyl,
  • R 5 and R 6 or R 5 and R 6 are each independently taken together with the nitrogen atom to which they are commonly attached to form a C 3 -C18 heterocyclyl or C5-C18 heteroaryl;
  • each R 7 and R 7 are each independently hydrogen or C1-C4 alkyl; and [0037] n is 0, 1, 2, 3, 4 or 5;
  • each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
  • aliphatic or “aliphatic group,” as used herein, denotes a monovalent hydrocarbon radical that is straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclic).
  • An aliphatic group can be saturated or can contain one or more units of unsaturation, but is not aromatic.
  • aliphatic groups contain 1-6 carbon atoms. However, in some embodiments, an aliphatic group contains 1-10 or 2-8 carbon atoms. In some embodiments, aliphatic groups contain 1- 4 carbon atoms and, in yet other embodiments, aliphatic groups contain 1-3 carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • An aliphatic group can be optionally substituted as described herein.
  • alkyl as used herein, means a saturated, straight-chain or branched aliphatic group. In one aspect, an alkyl group contains 1-6 or 1-4 carbon atoms.
  • Alkyl includes, but is not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, and the like.
  • An alkyl group can be optionally substituted as described herein.
  • an alkenyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like.
  • alkenyl encompasses radicals having carbon-carbon double bonds in the “cis” and “trans” or, alternatively, the ⁇ ” and “Z” configurations. If an alkenyl group includes more than one carbon-carbon double bond, each carbon-carbon double bond is independently a cis or trans double bond, or a mixture thereof.
  • An alkenyl group can be optionally substituted as described herein.
  • alkynyl means a straight-chain or branched aliphatic radical having one or more carbon-carbon triple bonds (i.e., -CoC-).
  • an alkyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, 1-propynyl (propargyl), 1-butynyl and the like.
  • An alkynyl group can be optionally substituted as described herein.
  • cycloaliphatic refers to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein.
  • a cycloaliphatic group has 3-6 carbon atoms.
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • cycloaliphatic also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane. These aliphatic rings can be optionally substituted as described herein.
  • cycloalkyl means a saturated cyclic aliphatic monocyclic or bicyclic ring system having from 3-18, for example 3-12 members.
  • a cycloalkyl can be optionally substituted as described herein.
  • a cycloalkyl has 3-6 carbons.
  • a cycloalkyl group can be optionally substituted as described herein.
  • heterocyclyl means a saturated or unsaturated aliphatic ring system having from 3 to 18, for example 3-12 members in which at least one carbon atom is replaced with a heteroatom selected from N, S and O.
  • a heterocyclyl can contain one or more rings, which may be attached together in a pendent manner or may be fused.
  • a heterocyclyl is a three- to seven-membered ring system and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.
  • a heterocyclyl group can be optionally substituted as described herein.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, and includes any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen; and a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • alkoxy means -O-alkyl.
  • Alkoxy can include a straight-chained or branched alkyl.
  • alkoxy has from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
  • An alkoxy group can be optionally substituted as described herein.
  • halo or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.
  • haloalkyl means an alkyl group that is substituted with one or more halogen atoms. In some embodiments, haloalkyl refers to a perhalogenated alkyl group. In some embodiments, haloalkyl refers to an alkyl group which is substituted with one or more halogen atoms.
  • haloalkyl groups include -CF3, -CF2H, -CCI3, - CF2CH3, -CH2CF3, -CH2(CF 3)2, -CF2(CF 3 )2, and the like.
  • Preferred haloalkyl groups include -CF3 and -CF2H.
  • a preferred haloalkyl group is -CF3.
  • alkylene means a bivalent branched or unbranched saturated hydrocarbon radical.
  • alkylene has one to six carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like. An alkylene group can be optionally substituted as described herein.
  • alkenylene has two to six carbon atoms, and includes, for example, and without being limited thereto, ethenylene, n-propenylene, n-butenylene and the like.
  • An alkenylene group can be optionally substituted as described herein.
  • alkynylene means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon triple bonds (i.e., -CoC-).
  • alkynylene has two to six carbon atoms, and includes, for example, and without being limited thereto, ethynylene, n-propynylene, n-butynylene and the like.
  • An alkynylene group can be optionally substituted as described herein.
  • aryl alone or in combination, as used herein, means a carbocyclic aromatic system containing one or more rings, which may be attached together in a pendent manner or may be fused. In some embodiments, an aryl has one, two or three rings. In one aspect, the aryl has six to twelve ring atoms.
  • aryl encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl and acenaphthyl.
  • An “aryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
  • heteroaryl alone or in combination, as used herein, means an aromatic system wherein at least one carbon atom is replaced by a heteroatom selected from N, S and O.
  • a heteroaryl can contain one or more rings, which may be attached together in a pendent manner or may be fused.
  • a heteroaryl has one, two or three rings.
  • the heteroaryl has five to twelve ring atoms.
  • heteroaryl encompasses heteroaromatic groups such as triazolyl, imidazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, oxadiazolyl, isoxazolyl, and the like.
  • a “heteroaryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
  • substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted group” can have a suitable substituent at each substitutable position of the group and, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • an “optionally substituted group” can be unsubstituted.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o- 2 R*, -(haloR*), -(CH 2 )o- 2 OH, -(CH 2 )o- 2 OR*, -(CH 2 )o- 2 CH(OR*) 2 ; -0(haloR ⁇ ), -CN, -Ns, -(CH 2 )o- 2 C(0)R*, -(CH 2 )o- 2 C(0)OH, -(CH 2 )o- 2 C(0)OR ⁇ , -(CH 2 )O- 2 SR*, -(CH 2 )O- 2 SH, -(CH 2 )O- 2 NH 2 , -(CH 2 )O- 2 NHR ⁇ , -(CH 2 )O- 2 NR* 2 , - N0 2 , -SiR
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -0(CR * 2 ) 2-3 0-, wherein each independent occurrence of R * is selected from hydrogen, Ci- 6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, - R ⁇ , -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , NHR*, -NRN, and -N0 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C i—i aliphatic, -CHzPh, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted group” include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , - S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , and -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CHzPh, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Example embodiments of compounds of structural formula (I) are selinexor, eltanexor, and vedinexor.
  • Eltanexor is a compound represented by the following structural formula
  • Eltanexor is a second-generation oral selective inhibitor of nuclear export (SINE) that binds to XPOl and prevents it from shuttling its cargo from the nucleus to the cytoplasm, resulting in nuclear accumulation of tumor suppressor proteins and oncogene mRNAs.
  • the first generation XPOl inhibitor selinexor compound represented by the following structural formula, is approved in the USA for treatment of patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, 2 immunomodulatory agents and an anti-CD38 monoclonal antibody.
  • Verdinexor represented by structural formula (3), is an oral inhibitor or XPOl also described in WO2013/019548.
  • Eltanexor has demonstrated potent anti-cancer activity in cell line and murine models of multiple solid tumor and hematologic malignancies.
  • RNA expression profiles (approximately 23,000 genes) were used to estimate the relative activity of 5,451 regulatory proteins was for each sample using the meta VIPER algorithm, using acute myeloid leukemia and thymoma context-specific models of transcriptional regulation (interactomes).
  • the VIPER algorithm is described, for example, in W02017/040311 Al, the entire teachings of which are incorporated herein by reference.
  • Table 1 describes the MM patients treated with Eltanexor selected for the molecular markers analysis.
  • Table 1 Treatment and Responses for Patient Subset Used for Molecular Marker Analyses
  • the entries marked (*) represent refractory MM to at least one proteasome inhibitor and one immunomodulatory agent; the entries marked ( ⁇ ) represent refractory MM to at least one proteasome inhibitor, one immunomodulatory agent, and an anti-CD38 monoclonal antibody; the entries marked ( * ) represents that Eltanexor was administered in 28 day cycles on days 1-5, 8-12, 15-19, and 22-26, unless otherwise specified; and the entries marked ( ⁇ ) represent that Dexamethasone was administer at 20mg on days 1, 3, 8, 10, 15, 17, 22 and 24.
  • Zinc finger protein 518A likely a nuclear transcriptional regulator ( ZNF518A , NCBI Gene ID: 9849), High Affinity CAMP-Specific And IBMX-Insensitive 3',5'-Cyclic Phosphodiesterase 8A ( PDE8A , NCBI Gene ID: 5151), Notch Receptor 3 NOTCH3 , NCBI Gene ID: 4854), Heterogeneous Nuclear Ribonucleoprotein U-like 1 (HNRNPUL1, Gene ID: 11100), Glutamate Ionotropic Receptor AMPA-type Subunit 2 ( GRIA2 , Gene ID: 2891), and Adhesion G-protein-coupled Receptor VI ( ADGRVl , Gene ID: 84059).
  • ZNF518A likely a nuclear transcriptional regulator
  • NCBI Gene ID: 9849 High Affinity CAMP-Specific And IBMX-Insensitive 3',5'-Cyclic Phosphodiesterase 8A
  • PDE8A NCBI Gene ID: 5151
  • RNAseq was used to infer master regulator protein activities for eltanexor treated patients as was previously done with selinexor-treated patients with RRMM (Chari P et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. NEngl J Med 2019; 381:727-738).
  • the term “signature” refers to a set of proteins with a characteristic pattern of activities that is reflective of the underlying biologic state of the population of cells that exhibit the signature and that can be causally associated with specific properties of the cells such as response to drug treatment
  • FIG. 2A and FIG. 2B depict heatmaps showing the similarity between individual eltanexor responder signatures and selinexor responder signatures based on gene expression signatures or MR protein activity signatures.
  • Red, white, and blue colors in the heatmap indicate whether samples are similar, independent or different to each other, based on Pearson’s correlation analysis.
  • the top orange/green or yellow/black bar indicate two different clusters for each drug.
  • the samples were sorted according to unsupervised hierarchical cluster analysis, using on Pearson’s correlation as similarity metric and simple linkage.
  • GSEA reciprocal gene set enrichment analysis
  • activated proteins in cluster 1 were hematopoietic regulators RARA and MAFB, and inactivated proteins included general regulators of RNA transcription NOLC1, POLR2I, TAF9, and TOP2A.
  • Cluster 2 was hallmarked by altered MYC signaling, with inactivation of MYB and MYCBP, and activation of ZBTB17 (MIZ-1).
  • the positive MRs for the selinexor responder cluster- 2 were significantly and negatively enriched in the protein activity signature for the selinexor responder cluster- 1 (p ⁇ 10 4 ).
  • the negative MRs - the 25 most inactivated proteins in the group of patients evaluated - of each of the selinexor responder clusters was significantly, albeit borderline, enriched in the protein activity signature for the other selinexor responder cluster (p ⁇ 0.05 and p ⁇ 0.01 for the negative MRs of cluster-1 and -2, respectively).
  • the inverse activity of the MRs between clusters is even stronger for the eltanexor cohort, with strong negative enrichment for the MRs of eltanexor responder cluster- 1 on the protein activity signature for eltanexor responder cluster-2 (p ⁇ 10 23 ), with both positive and negative MRs showing a significant enrichment (p ⁇ 10 25 and p ⁇ 10 4 , respectively); and strong negative enrichment for the MRs of eltanexor responder cluster-2 on the protein activity signature for eltanexor responder cluster- 1 (p ⁇ 10 22 ), with both positive and negative MRs showing a significant enrichment (p ⁇ 10 21 and p ⁇ 10 5 , respectively).
  • both positive and negative MRs for each of the eltanexor clusters were significantly enriched on the protein activity signatures for the corresponding selinexor clusters.
  • the selinexor cluster- 1 positive MRs were significantly and negatively enriched on the eltanexor responder cluster-2 protein activity signature (p ⁇ 10 14 ), while no significant enrichment was observed for the selinexor responder cluster- 1 negative MRs on the eltanexor responder cluster-2 protein activity signature, as well as for the eltanexor responder cluster-2 MRs on the selinexor responder cluster- 1 protein activity signature.
  • FIG. 4 depicts heatmaps that show the activities of the top up and down regulated protein activities in responders in the eltanexor signature 1 proteins (top) and eltanexor signature 2 proteins (bottom).
  • the protein activity signatures were computed for each patient and then integrated across all responders and all non responders taking the average Z-scores.
  • the following four MR proteins can be used as biomarkers of Selinexor response in MM patients.
  • SLC11A1 (NCBI Gene ID: 6556), NACC2 (NCBI Gene ID: 138151), BCL6 (NCBI Gene ID: 604), CD86 (NCBI Gene ID: 942), BAZ2A (NCBI Gene ID: 11176), ZDHHC7 (NCBI Gene ID: 55625), KLF13 (NCBI Gene ID: 51621), RC3H1 (NCBI Gene ID: 149041), MAFB (NCBI Gene ID: 9935), RARA (NCBI Gene ID: 5914), ZSWIM6 (NCBI Gene ID: 57688), ZBTB7B (NCBI Gene ID: 51043), TADA2B (NCBI Gene ID: 93624), TRAFD1 (NCBI Gene ID: 10906), NOTCH1 (NCBI Gene ID: 4851), AKNA (NCBI Gene ID: 80709), MTF1 (NCBI Gene ID: 4520), CAMTA2 (NCBI Gene ID: 23125), RC3H2 (NCBI Gene ID: 54542), Z
  • the MRs predictive of the response of an MM patient to eltanexor are PHB, GMNN, MRPL12, C1QBP, RUVBL2, SLC11 Al, NACC2, BCL6, CD86, and BAZ2A.
  • ZNF22 (NCBI Gene ID: 7570), MYCBP (NCBI Gene ID: 26292), ATF1 (NCBI Gene ID: 466), C1D (NCBI Gene ID: 10438), TDP2 (NCBI Gene ID: 51567), ZHX1 (NCBI Gene ID: 11244), ZCRB1 (NCBI Gene ID: 85437), ASF1A (NCBI Gene ID: 25842), BTF3 (NCBI Gene ID: 689), NAA15 (NCBI Gene ID: 80155), HDAC2 (NCBI Gene ID: 3066), TAF12 (NCBI Gene ID: 6883), ZFANDl (NCBI Gene ID: 79752), ZNF146 (NCBI Gene ID: 7705), TRIAPl (NCBI Gene ID: 51499), PTGES3 (NCBI Gene ID: 10728), NDUFS4 (NCBI Gene ID: 4724), RPL22 (NCBI Gene ID: 6146), NUFIP1 (NCBI Gene ID: 26747), Z
  • NCBI Gene ID: 4034 AKNA
  • TFE3 NCBI Gene ID: 7030
  • CRTC2 NCBI Gene ID: 200186
  • CCNL2 NCBI Gene ID: 81669
  • CHMP1A NCBI Gene ID: 5119
  • CIC NCBI Gene ID: 23152
  • PTOV1 NCBI Gene ID: 53635
  • CNOT3 NCBI Gene ID: 4849
  • SPI1 NCBI Gene ID: 6688
  • SUPT5H NCBI Gene ID: 6829
  • ZBTB17 NCBI Gene ID: 7709
  • MED22 NCBI Gene ID: 6837
  • TYK2 NCBI Gene ID: 7297
  • SLC11A1 NCBI Gene ID: 6556
  • SBN02 NCBI Gene ID: 22904
  • FLYWCH1 NCBI Gene ID: 84256
  • NACC2 NCBI Gene ID: 138151
  • E4F1 NCBI Gene ID: 1877
  • the MRs predictive of an MM patient response to eltanexor are MED 15, ZNF335, CAMTA2, RHOT2, HGS, ZNF22, MYCBP, ATF1, C1D and TDP2.
  • protein activity is determined for one or more subjects based on genetic data. Protein activity for a population of subjects is used to identify MR proteins as described above, and to train classifiers based on sets of known responders and non-responders. Similarly, protein activity for an individual subject is used to classify that subject as a responder or non-responder. In particular, a feature vector is constructed for a given subject that comprises protein activity values for one or more proteins.
  • VIPER provides protein activity values in terms of normalized enrichment scores, which express activity for all the regulatory proteins in the same scale.
  • alternative methods of determining protein activity provide alternative measures of protein activity values, for example, absolute or relative abundance in a sample, or absolute enrichment.
  • Various embodiments described herein employ the VIPER algorithm to determine protein activity in the form of normalized enrichment scores for a plurality of proteins based on a predetermined model of transcriptional regulation.
  • the VIPER algorithm is described further in PCT Pub. No. W02017040311 Al, which is hereby incorporated by reference in its entirety.
  • ChEA ChlP- X Enrichment Analysis
  • ChEA3 transcription factor enrichment analysis by orthogonal omics integration. Nucleic Acids Res. 47, W212-W224 (2019); TFEA.ChIP, which is described further in Puente-Santamaria, L., Wasserman, W. W. & Del Peso, L. TFEA.ChIP: a tool kit for transcription factor binding site enrichment analysis capitalizing on ChIP-seq datasets.
  • Biochemical approaches can be used to estimate abundance of the proteins included in a given biomarker, such us immunostaining (immunofluorescence or immunochemistry) of tissue samples followed by histological examination, flow cytometry, mass cytometry or cytometric bead arrays, reverse-phase protein arrays, bead-based IVD assays such as Luminex and mass spectrometry.
  • a set of MR proteins may be determined by a variety of methods, including those described in connection with the examples below.
  • cluster analysis may be performed with or without separate dimensionality reduction in order to determine the heterogeneity of responder and non-responder clusters in an «-dimensional vector space, with n corresponding to a number of proteins considered.
  • methods are available for dimensionality reduction, including unsupervised dimensionality reduction techniques such as principal component analysis (PCA), random projection, and feature agglomeration analysis.
  • PCA principal component analysis
  • cluster analysis methods are available, including hierarchical clustering and &-means clustering.
  • a variety of statistical methods are available for determining the correlation of a given protein value to the classification as a responder or non-responder.
  • the DarwinOncoTargetTM system is used to identify and rank potential protein predictors of responsiveness and non-responsiveness.
  • the top proteins showing differential activity between responder and non-responder patients can be sorted by the False Discovery Rate (FDR)-corrected p-value.
  • FDR False Discovery Rate
  • a subset of proteins is selected by performing a cross- validation process such as leave-one-out cross validation.
  • a model is trained on all data except for one point and a prediction is made for that point.
  • cross-validation may be used to optimize the selection of proteins and/or the number of proteins.
  • repeated application of cross-validation may be employed with multiple models in order to select an optimal pairing of model and proteins.
  • a variable number of proteins may be selected for training a classifier as set out herein. It will be appreciated that while there may be computational advantages to reduction in the number of MR proteins used to train a given classifier, a classifier may be trained with all or some of the potential proteins while still arriving at a trained classifier suitable for identification of responders and non-responders. In particular, while inclusion of additional low value proteins may increase training time, a given classifier will de-emphasize low value proteins while emphasizing high value proteins by virtue of the training process. In some embodiments, a predetermined number of proteins having the highest differential activity between responder and non-responder patients are selected.
  • a training set including responders and non-responders is determined by RNA sequencing of a plurality of subjects.
  • Normalized enrichment scores are determined for a plurality of proteins across the training set.
  • normalized enrichment scores are determined by application of VIPER.
  • protein activity scores for responsive and non-responsive subjects are determined as set forth above.
  • a feature vector is constructed for each of the responsive and non-responsive subjects, and provided to a classifier.
  • the classifier comprises a SVM.
  • the classifier comprises an artificial neural network.
  • the classifier comprises a random decision forest. It will be appreciated that a variety of other classifiers are suitable for use according to the present disclosure, including linear classifiers, support vector machines (SVM), Linear Discriminant Analysis (LDA), Logistic regression, Random Forest, Ridge regression methods, or neural networks such as recurrent neural networks (RNN).
  • SVM support vector machines
  • LDA Linear Discriminant Analysis
  • Logistic regression Random Forest
  • Ridge regression methods or neural networks such as recurrent neural networks (RNN).
  • RNN recurrent neural networks
  • an ensemble model of any of the forgoing may also be employed. For example, a combination of any of the models can be used and the outputs of each model averaged (integrated).
  • Suitable artificial neural networks include but are not limited to a feedforward neural network, a radial basis function network, a self-organizing map, learning vector quantization, a recurrent neural network, a Hopfield network, a Boltzmann machine, an echo state network, long short term memory, a bi-directional recurrent neural network, a hierarchical recurrent neural network, a stochastic neural network, a modular neural network, an associative neural network, a deep neural network, a deep belief network, a convolutional neural networks, a convolutional deep belief network, a large memory storage and retrieval neural network, a deep Boltzmann machine, a deep stacking network, a tensor deep stacking network, a spike and slab restricted Boltzmann machine, a compound hierarchical-deep model, a deep coding network, a multilayer kernel machine, or a deep Q-network.
  • the classifier is trained to classify a subject as either responsive or non-responsive.
  • a protein activity of a given subject is determined.
  • the protein activity values are provided as a feature vector to a trained classifier, which provides an output classification as either a responder or a non responder.
  • the output of a classifier is a probability that the subject being classified will respond to the therapy described herein.
  • a “responder” is a subject whose probability to respond is at least 0.5 (0.5-1), for example, at least 0.6 (0.6-1), at least 0.7 (0.7-1), at least 0.8 (0.8-1), at least 0.9 (0.9-1).
  • subject to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g.,
  • subjects are humans, such as adult humans.
  • the subject is an adult human.
  • the adult human subject is suffering from relapsed refractory multiple myeloma.
  • the adult human subject has received at least four prior therapies to treat the relapsed refractory multiple myeloma.
  • the adult human subject has received at least four prior therapies to treat the relapsed refractory multiple myeloma and the relapsed refractory multiple myeloma is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
  • treating means to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease. Treatment includes treating a symptom of a disease, disorder or condition.
  • combination therapy or “co-administration” embraces the administration of the XPOl inhibitors of the present invention and an additional therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of each.
  • the XPOl inhibitors of the present invention and an additional therapeutic agent can be formulated as separate compositions. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” or “co-administration” is intended to embrace administration of these therapeutic agent (the XPOl inhibitors of the present invention and an additional therapeutic agent) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence wherein the therapeutic agents are administered is not narrowly critical.
  • “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different therapeutic agent) and non drug therapies (e.g surgery or radiation).
  • dexamethasone is co administered with the XPOl inhibitors of the present invention.
  • the dexamethasone is administered at 20 mg per administration.
  • combination treatment comprises the administration of the XPOl inhibitors of the present invention in combination with at least one (e.gANC 1, 2 or 3) of the following: lenalidomide, pomalidomide, carfilzomib, bortezomib or duratumumab and optionally dexamethasone.
  • the combination administration of this embodiment can be twice a week (e.g., Days 1 and 3) or once per week.
  • the treatment comprises administering a combination of the XPOl inhibitors of the present invention, bortezomib and optionally dexamethasone.
  • the subject has not been previously treated with a proteasome inhibitor (PI naive).
  • selinexor is administered on Days 1, 8, 15, 22, and 29 of a 35-day cycle (e.g., at 100 mg per dose); bortezomib is administered on Days 1, 8, 15, and 22 of a 35- day cycle (e.g., at 1,3 mg/m2) and dexamethasone is administered Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle at 20 mg per dose.
  • the length of the cycle can be adjusted accordingly, maintaining the once weekly administration for selinexor and bortezomib and the twice weekly administration of dexamethasone.
  • the XPOl inhibitors of the present invention can be present in the form of pharmaceutically acceptable salt.
  • the salts of the XPOl inhibitors of the present invention refer to non-toxic “pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable acidic/anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulf
  • the XPOl inhibitors of the present invention can be administered orally, nasally, ocularly, transdermally, topically, intravenously (both bolus and infusion), and via injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally) either as alone or as part of a pharmaceutical composition comprising the XPOl inhibitors of the present invention and a pharmaceutically acceptable excipient.
  • the composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository.
  • a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository.
  • compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions.
  • prior therapies refers to known therapies for multiple myeloma involving administration of a therapeutic agent.
  • Prior therapies can include, but are not limited to, treatment with proteasome inhibitors (PI), Immunomodulatory agents, anti-CD38 monoclonal antibodies or other agents typically used in the treatment of multiple myeloma such as glucocorticoids.
  • Specific prior therapies can include bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, glucocorticoids or an alkylating agent.
  • the present invention is a method of treating a patient suffering from multiple myeloma, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; determining a classification of the subject as a responder or non-responder to a therapy by a compound represented by structural formula (I); and administering a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to be responder.
  • MM myeloma
  • the present invention is a computer- assisted method of treating a subject suffering from multiple myeloma, comprising: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a treatment of MM with a compound of formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder; and administering to the responder a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof.
  • MM myeloma
  • the present invention is a method of treating a subject suffering from multiple myeloma, comprising administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject suffering from multiple myeloma, wherein the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject.
  • the present invention is a computer-assisted method of treating a subject suffering from multiple myeloma, comprising: administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject suffering from multiple myeloma, wherein the subject is determined to be a responder to treatment by the compound represented by structural formula (I) by: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder.
  • MM myeloma
  • the present invention is a method of treating a subject suffering from multiple myeloma, comprising selecting the subject suffering from multiple myeloma only if the subject is determined to be a responder to a therapy by a compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is a computer-assisted method of treating a subject suffering from multiple myeloma, comprising: selecting the subject suffering from multiple myeloma only if the subject is determined to be a responder to treatment by a compound represented by structural formula (I), wherein the subject is determined to be a responder by: determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof.
  • MM myeloma
  • each protein activity value corresponding to one of a set of proteins in the
  • the present invention is a method of treating a subject suffering from multiple myeloma, comprising receiving information of a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof only if the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on said plurality of protein activity values.
  • MM myeloma
  • the present invention is a computer-assisted method of treating a subject suffering from multiple myeloma, comprising: receiving information of a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder, and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof only if the subject is determined to be a responder.
  • MM myeloma
  • the present invention is a method of treating a subject suffering from multiple myeloma (MM), comprising the steps of obtaining a sample of from the subject; determining a sequence of one or more of the following genes in the sample: ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I) to the subject determined to have a mutation in one or more of the genes.
  • MM multiple myeloma
  • the present invention is a method of treating multiple myeloma in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound represented by structural formula (I) to the subject, wherein the subject is determined to have determined to have a mutation in one or more of the following genes: ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3.
  • the present invention is a method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of selecting the subject only if the subject has been determined to have a mutation in at least one of the following genes ZNF518A, DE8A, HNRNPUL1, GRIA2, ADGRV1, and NOTCH3; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I).
  • MM multiple myeloma
  • the present invention is a method of treating a patient suffering from a multiple myeloma, comprising the steps of receiving information about a mutation in one or genes present in the patient: ZNF518A, DE8A, HNRNPIJL1, GRIA2, ADGRV1, and NOTCH3; and administering a therapeutically effective amount of a compound represented by structural formula (I) to the patient only if the subject has a mutation in one or more of the genes.
  • any of the first through fourth example embodiments and their alternatives can include any one or more of the following aspects.
  • the set of proteins can consist of proteins having at least a pre-determined value of differential protein activity between responders and non-responders.
  • the protein activity value can be a normalized enrichment score.
  • Determining the plurality of protein activity values can comprise applying VIPER algorithm to gene expression data of the subject.
  • the trained classifier can comprise one or more of a support vector machine, an artificial neural network, a random forest, a linear classifier, linear discriminant analysis, logistic regression, or ridge regression.
  • Any of the first through eighth example embodiments can include any one or more of the following aspects.
  • the XPOl inhibitors can be represented by the following structural formula: [00154]
  • the set of proteins can be SLC11 A1 (NCBI Gene ID: 6556), NACC2 (NCBI Gene ID: 138151), BCL6 (NCBI Gene ID: 604), CD86 (NCBI Gene ID: 942), BAZ2A (NCBI Gene ID: 11176), ZDHHC7 (NCBI Gene ID: 55625), KLF13 (NCBI Gene ID:
  • NCBI Gene ID: 149041 MAFB (NCBI Gene ID: 9935), RARA (NCBI Gene ID: 5914), ZSWIM6 (NCBI Gene ID: 57688), ZBTB7B (NCBI Gene ID: 51043), TADA2B (NCBI Gene ID: 93624), TRAFD1 (NCBI Gene ID: 10906), NOTCH1 (NCBI Gene ID: 4851), AKNA (NCBI Gene ID: 80709), MTF1 (NCBI Gene ID: 4520), CAMTA2 (NCBI Gene ID: 23125), RC3H2 (NCBI Gene ID: 54542), ZMYND15 (NCBI Gene ID: 84225), RALGAPB (NCBI Gene ID: 57148), IL10 (NCBI Gene ID: 3586), ZZEF1 (NCBI Gene ID: 23140), ASH1L (NCBI Gene ID: 55870), ZNF710 (NCBI Gene ID: 374655),
  • NCBI Gene ID: 114803 MY SMI (NCBI Gene ID: 114803), PRMTl (NCBI Gene ID: 3276), CENPK (NCBI Gene ID: 64105), HPRT1 (NCBI Gene ID: 3251), TFAP4 (NCBI Gene ID: 7023), TRIM28 (NCBI Gene ID: 10155), TRIP 13 (NCBI Gene ID: 9319), TFDP1 (NCBI Gene ID: 7027), TOP2A (NCBI Gene ID:), PTTG1 (NCBI Gene ID: 9232), GGCT (NCBI Gene ID: 79017), FOXM1 (NCBI Gene ID: 2305), HDAC2 (NCBI Gene ID: 3066), TAF9 (NCBI Gene ID: 6880), ZMYND19 (NCBI Gene ID: 116225), RUVBL1 (NCBI Gene ID: 8607), POLR2I (NCBI Gene ID: 5438), NOLC1 (NCBI Gene ID: 9221), PRMT5 (NCBI Gene ID: 10419), ILF
  • the set of proteins is PHB, GMNN, MRPL12, C1QBP, RUVBL2, SLC11 Al, NACC2, BCL6, CD86, and BAZ2A.
  • the set of proteins is ZNF22 (NCBI Gene ID: 7570), MYCBP (NCBI Gene ID: 26292), ATF1 (NCBI Gene ID: 466), C1D (NCBI Gene ID: 10438), TDP2 (NCBI Gene ID: 51567), ZHX1 (NCBI Gene ID: 11244), ZCRB1 (NCBI Gene ID: 85437), ASF1A (NCBI Gene ID: 25842), BTF3 (NCBI Gene ID: 689), NAA15 (NCBI Gene ID: 80155), HDAC2 (NCBI Gene ID: 3066), TAF12 (NCBI Gene ID: 6883), ZFANDl (NCBI Gene ID: 79752), ZNF146 (NCBI Gene ID: 7705), TRIAPl (NCBI Gene ID:
  • the set of proteins is MED 15, ZNF335, CAMTA2, RHOT2, HGS, ZNF22, MYCBP, ATF1, C1D and TDP2.
  • the methods of any of the example embodiments can further comprise collecting a bone marrow sample from the subject; separating CD131+ cells in the bone marrow sample; and identifying the activity pattern of the MR proteins in the CD131+ cells.
  • Multiple myeloma is a relapsed or refractory multiple myeloma.
  • the subject could have received from 1 to 7 prior therapies.
  • the subject could have received at least two, at least three, at least four prior therapies.
  • the subject could be a human, for example an adult human.
  • the XPOl inhibitors of the invention could be administered orally.
  • Multiple myeloma can be refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
  • the methods of any of the example embodiments could comprise administering at least one additional therapeutic agent.
  • the additional therapeutic agent can be dexamethasone.
  • the dexamethasone can be orally administered at an amount of 20 mg/day.
  • the methods of any one of the example embodiments can further comprise administering bortezomib.
  • Multiple myeloma can be relapsed or refractory multiple myeloma, the subject could be an adult human who has received at least four prior therapies and the multiple myeloma could be refractory to at least two proteasome inhibitors, at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.
  • the XPOl inhibitor of the invention can be administered at 80 mg/per day on days 1 and 3 of each week of treatment.
  • An additional therapeutic agent can be administered.
  • the additional therapeutic agent can be dexamethasone.
  • Dexamethasone can be administered at 20 mg/day on days 1 and 3 of each week of treatment.
  • Multiple myeloma can be relapsed or refractory multiple myeloma, the subject can be an adult human who has received from 1 to 3 prior therapies.
  • the XPOl inhibitor if the invention can be administered at 100 mg once a week.
  • At least one additional therapeutic agent can be administered.
  • the additional therapeutic agents can be bortezomib administered at 1.3 mg/m2 once a week and dexamethasone administered twice a week at 20 mg per administration.
  • the present invention is a computer program product for identifying responders and non-responders
  • the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non- responders to a therapy by the XPOl inhibitors of the present invention; and obtaining from the classifier a classification of the subject as a responder or non-responder.
  • MM myeloma
  • FIG. 5 a schematic of an example of a computing node is shown.
  • Computing node 10 is only one example of a suitable computing node and is not intended to suggest any limitation as to the scope of use or functionality of embodiments described herein. Regardless, computing node 10 is capable of being implemented and/or performing any of the functionality set forth hereinabove.
  • computing node 10 there is a computer system/server 12, which is operational with numerous other general purpose or special purpose computing system environments or configurations.
  • Examples of well-known computing systems, environments, and/or configurations that may be suitable for use with computer system/server 12 include, but are not limited to, personal computer systems, server computer systems, thin clients, thick clients, handheld or laptop devices, multiprocessor systems, microprocessor-based systems, set top boxes, programmable consumer electronics, network PCs, minicomputer systems, mainframe computer systems, and distributed cloud computing environments that include any of the above systems or devices, and the like.
  • Computer system/server 12 may be described in the general context of computer system-executable instructions, such as program modules, being executed by a computer system.
  • program modules may include routines, programs, objects, components, logic, data structures, and so on that perform particular tasks or implement particular abstract data types.
  • Computer system/server 12 may be practiced in distributed cloud computing environments where tasks are performed by remote processing devices that are linked through a communications network.
  • program modules may be located in both local and remote computer system storage media including memory storage devices.
  • computer system/server 12 in computing node 10 is shown in the form of a general-purpose computing device.
  • the components of computer system/server 12 may include, but are not limited to, one or more processors or processing units 16, a system memory 28, and a bus 18 that couples various system components including system memory 28 to processor 16.
  • Bus 18 represents one or more of any of several types of bus structures, including a memory bus or memory controller, a peripheral bus, an accelerated graphics port, and a processor or local bus using any of a variety of bus architectures.
  • bus architectures include Industry Standard Architecture (ISA) bus, Micro Channel Architecture (MCA) bus, Enhanced ISA (EISA) bus, Video Electronics Standards Association (VESA) local bus, Peripheral Component Interconnect (PCI) bus, Peripheral Component Interconnect Express (PCIe), and Advanced Microcontroller Bus Architecture (AMBA).
  • Computer system/server 12 typically includes a variety of computer system readable media. Such media may be any available media that is accessible by computer system/server 12, and it includes both volatile and non-volatile media, removable and non removable media.
  • System memory 28 can include computer system readable media in the form of volatile memory, such as random access memory (RAM) 30 and/or cache memory 32.
  • Computer system/server 12 may further include other removable/non-removable, volatile/non-volatile computer system storage media.
  • storage system 34 can be provided for reading from and writing to a non-removable, non-volatile magnetic media (not shown and typically called a "hard drive").
  • a magnetic disk drive for reading from and writing to a removable, non-volatile magnetic disk (e.g ., a "floppy disk")
  • an optical disk drive for reading from or writing to a removable, non-volatile optical disk such as a CD-ROM, DVD-ROM or other optical media
  • each can be connected to bus 18 by one or more data media interfaces.
  • memory 28 may include at least one program product having a set (e.g., at least one) of program modules that are configured to carry out the functions of embodiments of the disclosure.
  • Program/utility 40 having a set (at least one) of program modules 42, may be stored in memory 28 by way of example, and not limitation, as well as an operating system, one or more application programs, other program modules, and program data. Each of the operating system, one or more application programs, other program modules, and program data or some combination thereof, may include an implementation of a networking environment.
  • Program modules 42 generally carry out the functions and/or methodologies of embodiments as described herein.
  • Computer system/server 12 may also communicate with one or more external devices 14 such as a keyboard, a pointing device, a display 24, etc.; one or more devices that enable a user to interact with computer system/server 12; and/or any devices (e.g, network card, modem, etc.) that enable computer system/server 12 to communicate with one or more other computing devices. Such communication can occur via Input/Output (I/O) interfaces 22. Still yet, computer system/server 12 can communicate with one or more networks such as a local area network (LAN), a general wide area network (WAN), and/or a public network (e.g ., the Internet) via network adapter 20.
  • LAN local area network
  • WAN wide area network
  • public network e.g ., the Internet
  • network adapter 20 communicates with the other components of computer system/server 12 via bus 18. It should be understood that although not shown, other hardware and/or software components could be used in conjunction with computer system/server 12. Examples, include, but are not limited to: microcode, device drivers, redundant processing units, external disk drive arrays, RAID systems, tape drives, and data archival storage systems, etc.
  • the present disclosure may be embodied as a system, a method, and/or a computer program product.
  • the computer program product may include a computer readable storage medium (or media) having computer readable program instructions thereon for causing a processor to carry out aspects of the present disclosure.
  • the computer readable storage medium can be a tangible device that can retain and store instructions for use by an instruction execution device.
  • the computer readable storage medium may be, for example, but is not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing.
  • a non- exhaustive list of more specific examples of the computer readable storage medium includes the following: a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), a static random access memory (SRAM), a portable compact disc read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanically encoded device such as punch-cards or raised structures in a groove having instructions recorded thereon, and any suitable combination of the foregoing.
  • RAM random access memory
  • ROM read-only memory
  • EPROM or Flash memory erasable programmable read-only memory
  • SRAM static random access memory
  • CD-ROM compact disc read-only memory
  • DVD digital versatile disk
  • memory stick a floppy disk
  • mechanically encoded device such as punch-cards or raised structures in a groove having instructions recorded thereon
  • a computer readable storage medium is not to be construed as being transitory signals per se, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through a waveguide or other transmission media (e.g., light pulses passing through a fiber-optic cable), or electrical signals transmitted through a wire.
  • Computer readable program instructions described herein can be downloaded to respective computing/processing devices from a computer readable storage medium or to an external computer or external storage device via a network, for example, the Internet, a local area network, a wide area network and/or a wireless network.
  • the network may comprise copper transmission cables, optical transmission fibers, wireless transmission, routers, firewalls, switches, gateway computers and/or edge servers.
  • a network adapter card or network interface in each computing/processing device receives computer readable program instructions from the network and forwards the computer readable program instructions for storage in a computer readable storage medium within the respective computing/processing device.
  • Computer readable program instructions for carrying out operations of the present disclosure may be assembler instructions, instruction-set-architecture (ISA) instructions, machine instructions, machine dependent instructions, microcode, firmware instructions, state-setting data, or either source code or object code written in any combination of one or more programming languages, including an object oriented programming language such as Smalltalk, C++ or the like, and conventional procedural programming languages, such as the “C” programming language or similar programming languages.
  • the computer readable program instructions may execute entirely on the user’s computer, partly on the user’s computer, as a stand-alone software package, partly on the user’s computer and partly on a remote computer or entirely on the remote computer or server.
  • the remote computer may be connected to the user’s computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).
  • electronic circuitry including, for example, programmable logic circuitry, field-programmable gate arrays (FPGA), or programmable logic arrays (PLA) may execute the computer readable program instructions by utilizing state information of the computer readable program instructions to personalize the electronic circuitry, in order to perform aspects of the present disclosure.
  • These computer readable program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.
  • These computer readable program instructions may also be stored in a computer readable storage medium that can direct a computer, a programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having instructions stored therein comprises an article of manufacture including instructions which implement aspects of the function/act specified in the flowchart and/or block diagram block or blocks.
  • the computer readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.
  • each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s).
  • the functions noted in the block may occur out of the order noted in the figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved.
  • the present invention is a method of identifying a subject as a responder or a non-responder, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder.
  • MM myeloma
  • the set of proteins can be SLC11 A1 (NCBI Gene ID: 6556), NACC2 (NCBI Gene ID: 138151), BCL6 (NCBI Gene ID: 604), CD86 (NCBI Gene ID: 942), BAZ2A (NCBI Gene ID: 11176), ZDHHC7 (NCBI Gene ID: 55625), KLF13 (NCBI Gene ID:
  • NCBI Gene ID: 149041 MAFB (NCBI Gene ID: 9935), RARA (NCBI Gene ID: 5914), ZSWIM6 (NCBI Gene ID: 57688), ZBTB7B (NCBI Gene ID: 51043), TADA2B (NCBI Gene ID: 93624), TRAFD1 (NCBI Gene ID: 10906), NOTCH1 (NCBI Gene ID: 4851), AKNA (NCBI Gene ID: 80709), MTF1 (NCBI Gene ID: 4520), CAMTA2 (NCBI Gene ID: 23125), RC3H2 (NCBI Gene ID: 54542), ZMYND15 (NCBI Gene ID: 84225), RALGAPB (NCBI Gene ID: 57148), IL10 (NCBI Gene ID: 3586), ZZEF1 (NCBI Gene ID: 23140), ASH1L (NCBI Gene ID: 55870), ZNF710 (NCBI Gene ID: 374655),
  • NCBI Gene ID: 114803 MY SMI (NCBI Gene ID: 114803), PRMTl (NCBI Gene ID: 3276), CENPK (NCBI Gene ID: 64105), HPRT1 (NCBI Gene ID: 3251), TFAP4 (NCBI Gene ID: 7023), TRIM28 (NCBI Gene ID: 10155), TRIP 13 (NCBI Gene ID: 9319), TFDP1 (NCBI Gene ID: 7027), TOP2A (NCBI Gene ID:), PTTG1 (NCBI Gene ID: 9232), GGCT (NCBI Gene ID: 79017), FOXM1 (NCBI Gene ID: 2305), HDAC2 (NCBI Gene ID: 3066), TAF9 (NCBI Gene ID: 6880), ZMYND19 (NCBI Gene ID: 116225), RUVBL1 (NCBI Gene ID: 8607), POLR2I (NCBI Gene ID: 5438), NOLC1 (NCBI Gene ID: 9221), PRMT5 (NCBI Gene ID: 10419), ILF
  • the set of proteins can be PHB, GMNN, MRPL12, C1QBP, RUVBL2, SLC11A1, NACC2, BCL6, CD86, and BAZ2A.
  • the set of proteins can be ZNF22 (NCBI Gene ID: 7570), MYCBP (NCBI Gene ID: 26292), ATF1 (NCBI Gene ID: 466), C1D (NCBI Gene ID: 10438), TDP2 (NCBI Gene ID: 51567), ZHX1 (NCBI Gene ID: 11244), ZCRB1 (NCBI Gene ID: 85437), ASF1A (NCBI Gene ID: 25842), BTF3 (NCBI Gene ID: 689), NAA15 (NCBI Gene ID: 80155), HDAC2 (NCBI Gene ID: 3066), TAF12 (NCBI Gene ID: 6883), ZFANDl (NCBI Gene ID: 79752), ZNF146 (NCBI Gene ID: 7705), TRIAPl (NCBI Gene ID: 51499), PTGES3 (NCBI Gene ID: 10728), NDUFS4 (NCBI Gene ID: 4724), RPL22 (NCBI Gene ID: 6146), NUFIP1 (NCBI Gene ID: 107
  • the set of proteins can be MED15, ZNF335, CAMTA2, RHOT2, HGS, ZNF22, MYCBP, ATF1, C1D and TDP2.
  • the set of proteins is selected by cross-validation.
  • the set of proteins consists of proteins can have at least a pre determined value of differential protein activity between responders and non-responders.
  • the protein activity value can be a normalized enrichment score.
  • Determining the plurality of protein activity values can comprise applying VIPER algorithm to gene expression data of the subject.
  • the trained classifier can comprise a support vector machine, an artificial neural network, a random forest, a linear classifier, linear discriminant analysis, logistic regression, or ridge regression.
  • the present invention is a computer program product for identifying responders and non-responders
  • the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non- responders to a therapy by a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof and obtaining from the classifier a classification of the subject as a responder or non-responder.
  • MM myeloma
  • EXAMPLE 1 NCT02649790 STUDY
  • CRC colorectal cancer
  • mCRPC metastatic castration resistant prostate cancer
  • MDS myelodysplastic syndrome
  • QDx5/week once daily for 5 days per week
  • QoDx3 once daily for 3 days per week
  • dex dexamethasone
  • RRMM relapsed/refractory multiple myeloma.
  • Parts A and B up to 10 patients may be treated at any dose cohort to evaluate safety, tolerability, and efficacy to inform dose selection for Parts C-F. These 10 patients include the patients evaluated for dose limiting toxicity (DLT) during 3+3 dose escalation.
  • DLT dose limiting toxicity
  • Part A2 KPT-8602 Single Agent; QoDx3/Week
  • Part A2 Patients in Part A2 will receive KPT-8602 single agent QoDx3/week. The starting dose for Part A2 will be informed by Part Al. Initially, approximately 3 patients will be enrolled in Part A2.
  • Part B KPT-8602 with Low Dose Dexamethasone; QDx5/Week [00219] Patients will receive KPT-8602 for 5 consecutive days (QDx5/week) in combination with low dose dexamethasone (20 mg on Days 1, 3, 8, 10, 15, 17, 22, and 24 of each 28-day cycle). Initially, approximately 3 patients will be enrolled in Part B, but additional patients may be added as needed to more completely evaluate preliminary safety, tolerability, and efficacy.
  • Example 2 Biomarkers for Eltanexor Response in MM
  • Example 2 Selection of MRs predictive of Eltanexor response in MM patients.
  • the predictor MRs were selected using reciprocal gene set enrichment analysis of the 25 most activated and 25 most inactivated eltanexor signature 1 MRs onto selinexor signature 1 (and separately the top 25 activated and top 25 inactivated selinexor 1 MRs onto eltanexor 1). Any MRs that showed similar activation/inactivation in the GSEA were selected for the final model (technically, these were the proteins that had an absolute enrichment score greater than the absolute maximum running enrichment score for either the top activated or inactivated proteins, in the reciprocal GSEA.)

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Abstract

L'invention concerne un procédé mis en oeuvre par ordinateur pour traiter un patient souffrant de myélome multiple, consistant : à déterminer si le patient est un répondeur sur la base d'une sortie d'un classificateur, l'entrée du classificateur étant un vecteur de caractéristiques comprenant des valeurs d'activité de protéines correspondant à un ensemble de protéines chez le sujet ; et à administrer au répondeur une quantité thérapeutiquement efficace du composé représenté par la formule structurale (I) ou un sel pharmaceutiquement acceptable de celui-ci. Les valeurs et les valeurs préférées des variables de formule structurale (I) sont définies dans la description.
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