WO2024148008A1 - Traitement du cancer de la prostate neuroendocrinien - Google Patents

Traitement du cancer de la prostate neuroendocrinien Download PDF

Info

Publication number
WO2024148008A1
WO2024148008A1 PCT/US2024/010041 US2024010041W WO2024148008A1 WO 2024148008 A1 WO2024148008 A1 WO 2024148008A1 US 2024010041 W US2024010041 W US 2024010041W WO 2024148008 A1 WO2024148008 A1 WO 2024148008A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
subject
acceptable salt
pharmaceutically acceptable
agents
Prior art date
Application number
PCT/US2024/010041
Other languages
English (en)
Inventor
Anneleen Daemen
Melissa R. JUNTTILA
Lori S. Friedman
Natalie YUEN
Original Assignee
Oric Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oric Pharmaceuticals, Inc. filed Critical Oric Pharmaceuticals, Inc.
Publication of WO2024148008A1 publication Critical patent/WO2024148008A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Prostate cancer is the second leading cause of cancer-related death in men in the US. Androgen deprivation therapy (ADT) and blockade are commonly used to treat prostate cancer. However, relapse occurs with subsequent progression to metastatic castration-resistant prostate cancer (mCRPC) after treatment with androgen biosynthesis inhibitors or androgen receptor (AR) antagonists through multiple acquired resistance mechanisms. While some mechanisms of resistance are androgen receptor (AR) dependent, and can be treated with other hormonal therapies, like AR antagonists such as enzalutamide, other mechanisms of resistance occur by trans-differentiation of adenocarcinoma cells into neuroendocrine prostate cancer (NEPC).
  • ADT Androgen deprivation therapy
  • mCRPC metastatic castration-resistant prostate cancer
  • AR androgen receptor
  • NEPC neuroendocrine prostate cancer
  • NEPC is distinct from prostate adenocarcinoma and is an aggressive form of prostate cancer that is resistant to current therapies used in the context of advanced prostate adenocarcinoma.
  • NEPC displays high proliferative rates and tumor dissemination to visceral organs such as lung and liver.
  • NEPC is a significant problem with recent evidence indicating that approximately twenty percent of subjects with progressive hormone-resistant prostate cancer suffer from NEPC, and data demonstrates that subjects determined to suffer from NEPC have a median time of survival of less than a year. Thus, there remains a need to develop new methods of treating subjects determined to have NEPC.
  • Z is O or S
  • X is O, CR 5 , CR 5 OH, or C(R 5 )2, wherein: when X is O, - is a single bond; when X is C(R 5 )2, - is a single bond; when X is CR 5 OH, - is a single bond; or when X is CR 5 , - is a double bond;
  • R 1 is aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl is optionally substituted with one or more R 4 ;
  • R 2 is cyano, -COOR 5 , -C(O)N(R 5 )2, or -C(O)N(R 5 )2 wherein each R 5 taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R 4 ; each R 3 is independently C1-C3 alkyl or halogen; each R 4 is independently oxo, cyano, halogen, -POsiCi-C, alkyl):.
  • L is a bond or C1-C4 alkylene
  • Y 1 is a bond, -C(O)-, or -NHC(O)-;
  • Y 2 is a bond, -S-, -SO-, -SO 2 -, or -NR 5 SO 2 -, each R 5 is hydrogen or C1-C3 alkyl;
  • R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R 7 is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R 5 )2, Ci-Ce alkyl or -Y’-heterocyclyl; and n is 1 or 2.
  • n 1
  • R 2 is cyano. In other embodiments, R 2 is - COOR 5 or -C(O)N(R 5 )2. In other embodiments, R 2 is -COOR 5 . In other embodiments, R 2 is -C(O)N(R 5 )2. [0007] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof, R 3 is halogen. In some embodiments R 3 is fluorine.
  • X is C(R 5 )2 and - is a single bond.
  • X is CR 5 and - is a double bond.
  • X is O and - is a single bond.
  • R 1 is aryl optionally substituted with one or more R 4 .
  • the aryl is phenyl optionally substituted with one or more R 4 .
  • the phenyl is substituted with one, two or three R 4 .
  • the one, two or three R 4 are each independently halogen, -PCffC i-C alkyl)2, hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, - COOR 5 , -Y’-Ci-Ce alkyl, Y 2 -CI-C 6 alkyl, -L-N(R 5 ) 2 , -O-L-N(R 5 ) 2 , -C(CF 3 )N(R 5 ) 2 , -Y’-N(R 5 ) 2 , -Y 2 -N(R 5 ) 2 , Y 2 -haloalkyl, -L-heteroaryl, -L-heterocyclyl, or -Y 1 -heterocyclyl, wherein the heterocyclyl portion of the - L-heterocyclyl or -Y 1 -heterocyclyl is optionally substituted with one or more R 7
  • R 4 is -Y’-Ci-Ce alkyl and Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl, isopropyl, butyl or pentyl.
  • R 4 is -Y 2 -Ci-Ce alkyl and Y 2 is a -SO2- and the Ci-Ce alkyl is methyl.
  • R 4 is -Y 2 -haloalkyl and Y 2 is -S- or -SO2- and the haloalkyl is trifluoromethyl.
  • R 4 is -L-N(R 5 )2 and L is a bond and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
  • R 4 is -L-N(R 5 )2 and L is methylene or ethylene and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
  • R 4 is -Y’-N(R 5 )2, Y 1 is -C(O)- and each R 5 independently is hydrogen, each R 5 is independently methyl or one R 5 is methyl and one R 5 is hydrogen.
  • R 4 is -Y 2 -N(R 5 )2, Y 2 is -SO2- and each R 5 independently is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is independently hydrogen.
  • R 4 is -Y 1 -heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the L- heterocyclyl is piperazinyl or 4-methyl-piperazinyl.
  • R 4 is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3/. 2 -azabicyclo
  • R 4 is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L- heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R 7 selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen.
  • R 4 is -Y 1 - heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the Y’-heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.
  • R 4 is -L-heteroaryl optionally substituted with one or more R 7 .
  • the -L-heteroaryl is tetrazolyl.
  • R 4 is -POsfCi-Cs alkyl)2.
  • R 4 is -COOR 5 .
  • R 4 is hydroxyalkyl.
  • R 4 is -O-L-N(R 5 )2.
  • R 4 is aralkyl.
  • heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, each optionally substituted with one or more R 4 .
  • the heteroaryl is substituted with one or more R 4 ; wherein each R 4 is independently cyano, halogen, -Y’-Ci-Ce alkyl, -Y 2 -Ci-Ce alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R 5 )2, -Y'-N(R 5 )2, -L-heteroaryl, -L-heterocyclyl, or -Y 1 - heterocyclyl, wherein the heteroaryl of the -L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl, or Y 1 -heterocyclyl is optionally substituted with one or more R 7 .
  • the heteroaryl is pyrazolyl optionally substituted with one R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L- heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R 7 .
  • R 4 is -L-heteroaryl and L is methylene wherein the heteroaryl is pyridyl optional substituted with one or more R 7 .
  • R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl or 4-methylpiperazinyl.
  • R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl or 4-methylpiperazinyl.
  • R 4 is -L-N(R 5 )2 where L is methylene and each R 5 is independently hydrogen, each R 5 is independently C1-C3 alkyl or one R 5 is C1-C3 alkyl and one R 5 is hydrogen.
  • R 4 is -Y’-Ci-Ce alkyl where Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl or isopropyl.
  • the heteroaryl is pyrazolyl optionally substituted with two R 4 groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y’-Ci-Ce alkyl.
  • heteroaryl is pyridyl optionally substituted with one R 4 independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, -Y’-N(R 5 )2, -L-cycloalkyl, or -L- heterocyclyl optionally substituted with one or more R 7 .
  • R 1 is -L-cycloalkyl optionally substituted with one or more R 4 .
  • R 1 is -L-heterocyclyl optionally substituted with one or more R 4 .
  • L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.
  • n is 2.
  • prostate cancer in a subject, wherein the prostate cancer has been determined to comprise neuroendocrine prostate cancer, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • Formula (I) is Compound (Compound 1), or a pharmaceutically acceptable salt thereof.
  • Formula (I) is Compound (Compound 3), or a pharmaceutically acceptable salt thereof.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 9.8° ⁇ 0.2° 2-theta, 15.2° ⁇ 0.2° 2-theta, and 17.7° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of about 172 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 205 °C to about 210 °C.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C, or from about 207 °C to about 210 °C, or from about 208 °C to about 210 °C, or from about 209 °C to about 210 °C.
  • the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 °C to a temperature prior to melting.
  • the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 °C to about 380 °C.
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ⁇ 0.2° 2-theta, 8.6° ⁇ 0.2° 2-theta, 15.9° ⁇ 0.2° 2-theta, 19.9° ⁇ 0.2° 2-theta, and 24.1° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ⁇ 0.2° 2-theta, 11.0° ⁇ 0.2° 2-theta, 15.4° ⁇ 0.2° 2- theta, 21.0° ⁇ 0.2° 2-theta, and 26.3° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further a peak in an x-ray powder diffraction (XRPD) pattern at 15.4° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further a peak in an x-ray powder diffraction (XRPD) pattern at 19.2° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ⁇ 0.2° 2-theta, 8.6° ⁇ 0.2° 2- theta, 15.9° ⁇ 0.2° 2-theta, 19.9° ⁇ 0.2° 2-theta, and 24.1° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ⁇ 0.2° 2-theta, 11.0° ⁇ 0.2° 2-theta, 21.0° ⁇ 0.2° 2-theta, and 26.3° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C.
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) patern at 5.5° ⁇ 0.2° 2-theta, 8.6° ⁇ 0.2° 2- theta, 15.9° ⁇ 0.2° 2-theta, 19.9° ⁇ 0.2° 2-theta, and 24.1° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) patern at 10.6° ⁇ 0.2° 2-theta, 11.0° ⁇ 0.2° 2-theta, 21.0° ⁇ 0.2° 2-theta, and 26.3° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry patern of from about 203 °C to about 210 °C.
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry patern of from about 206 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits peaks in an x-ray powder diffraction (XRPD) patern at 9.6° ⁇ 0.2° 2-theta, 5.7° ⁇ 0.2° 2-theta, 19.7° ⁇ 0.2° 2-theta, and 22.0° ⁇ 0.2° 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta, 13.7° ⁇ 0.2° 2-theta, and 19.2° ⁇ 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits less than about 10% degradation when the crystalline forms are stored at 40 °C and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 8. 1° ⁇ 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits (a) peaks in an x- ray powder diffraction (XRPD) pattern at 9.6° ⁇ 0.2° 2-theta, 5.7° ⁇ 0.2° 2-theta, 19.7° ⁇ 0.2° 2-theta, and 22.0° ⁇ 0.2° 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x- ray powder diffraction
  • crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 60 °C for at least one week.
  • Formula (I) is Compound 12: (Compound 12), or a pharmaceutically acceptable salt thereof.
  • the methods disclosed herein wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is selected from (a) luteinizing hormone -releasing hormone (LHRH) agonists, (b) luteinizing hormone-releasing hormone (LHRH) antagonists, (c) androgen receptor inhibitors, (d) inhibitors of cytochrome P450 17A1, and/or (e) antiandrogens.
  • the neuroendocrine prostate cancer in the subject has been determined to be progressing following the administration to the subject of the one or more first agents.
  • the neuroendocrine prostate cancer in the subject has been determined to comprise visceral metastases or lung metastases.
  • the visceral metastases comprise liver metastases.
  • the neuroendocrine prostate cancer in the subject has been determined to comprise bulky lymphadenopathy or a pelvic mass.
  • the pelvic mass is 5 cm or more in size.
  • the neuroendocrine prostate cancer in the subject has been determined to comprise bone metastases.
  • the neuroendocrine prostate cancer in the subject has been determined to comprise 20 or more bone metastases.
  • the bone metastases are lytic bone metastases.
  • the methods disclosed herein wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is a luteinizing hormone-releasing hormone (LHRH) agonist.
  • the luteinizing hormone-releasing hormone (LHRH) agonist is selected from goserelin, histrelin, leuprolide, and triptorelin.
  • the luteinizing hormone -releasing hormone (LHRH) agonist is goserelin.
  • the luteinizing hormone -releasing hormone (LHRH) agonist is histrelin.
  • the luteinizing hormone -releasing hormone (LHRH) agonist is leuprolide.
  • the luteinizing hormone- releasing hormone (LHRH) agonist is triptorelin.
  • the methods disclosed herein wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is an inhibitor of cytochrome P450 17A1.
  • the one or more inhibitors of cytochrome P450 17A1 is abiraterone acetate.
  • a biological sample obtained from the subject has been determined to exhibit one or more biological markers prior to the administration of the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more biological markers are selected from synaptophysin (SYP), chromogranin A (CGA), insulinoma-associated protein 1 (INSMI), syntaxin 1 (STX1), ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSMI), secretagogin (SECG), neural cell adhesion molecule 1 (NCAM1;
  • the biological sample obtained from the subject has been determined to exhibit synaptophysin (SYP) prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the biological sample obtained from the subject has been determined to exhibit chromogranin A (CGA) prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the biological sample obtained from the subject has been determined to exhibit insulinoma-associated protein 1 (INSMI) prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • INSMI insulinoma-associated protein 1
  • the biological sample obtained from the subject has been determined to exhibit secretagogin (SECG) prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the biological sample obtained from the subject has been determined to exhibit neural cell adhesion molecule 1 (NCAM1; CD56) prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the biological sample obtained from the subject has been determined to exhibit neuronspecific enolase (NSE) prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the biological sample obtained from the subject has been determined to exhibit an amount of the one or more biological markers that exceeds 2.5 times the upper limit of normal. In some embodiments, the biological sample obtained from the subject has been determined to exhibit an amount of the one or more biological markers that exceeds 2.75 times the upper limit of normal. In some embodiments, the biological sample obtained from the subject has been determined to exhibit an amount of the one or more biological markers that exceeds 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, or 20 times the upper limit of normal.
  • the biological sample obtained from the subject is blood, and the biological sample has been determined to exhibit an amount of chromogranin A (CGA) that exceeds 101 ng/mL prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • CGA chromogranin A
  • more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, or more than 90% of cells in the biologic sample demonstrate staining for syntaxin 1 (STX1) prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • STX1 syntaxin 1
  • the one or more additional therapeutic agents are selected from chemotherapeutic agents.
  • the chemotherapeutic agents are selected from actinomycin, azacytidine, azathioprine, bleomycin, bortezomib, chlorambucil, cyclophosphamide, daunorubicin, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, idarubicin, irinotecan, lurbinectedin, mechlorethamine, mitoxantrone, teniposide, topotecan, valrubicin, vemurafenib, vinblastine, vincristine, and vindesine.
  • the chemotherapeutic agent is actinomycin. In some embodiments, the chemotherapeutic agent is azacytidine. In some embodiments, the chemotherapeutic agent is azathioprine. In some embodiments, the chemotherapeutic agent is bleomycin. In some embodiments, the chemotherapeutic agent is bortezomib. In some embodiments, the chemotherapeutic agent is chlorambucil. In some embodiments, the chemotherapeutic agent is cyclophosphamide. In some embodiments, the chemotherapeutic agent is daunorubicin. In some embodiments, the chemotherapeutic agent is doxifluridine.
  • the chemotherapeutic agent is teniposide. In some embodiments, the chemotherapeutic agent is topotecan. In some embodiments, the chemotherapeutic agent is valrubicin. In some embodiments, the chemotherapeutic agent is vemurafenib. In some embodiments, the chemotherapeutic agent is vinblastine. In some embodiments, the chemotherapeutic agent is vincristine. In some embodiments, the chemotherapeutic agent is vindesine.
  • the one or more additional therapeutic agents are selected from antimetabolites.
  • the one or more antimetabolites are selected from azacytidine, 6- mercaptopurine, capecitabine, hydroxyurea, cladribine, pralatrexate, thioguanine, decitabine, clofarabine, nelarabine, fludarabine, 5 -fluorouracil, gemcitabine, cytarabine, pemetrexed, and methotrexate, cytarabine (Ara-C), floxuridine, fludarabine, pentostatin, and trifluridine/tipiracil combination.
  • the antimetabolite is 5 -fluorouracil. In some embodiments, the antimetabolite is gemcitabine. In some embodiments, the antimetabolite is cytarabine. In some embodiments, the antimetabolite is pemetrexed. In some embodiments, the antimetabolite is and methotrexate. In some embodiments, the antimetabolite is cytarabine (Ara-C). In some embodiments, the antimetabolite is floxuridine. In some embodiments, the antimetabolite is fludarabine. In some embodiments, the antimetabolite is pentostatin. In some embodiments, the antimetabolite is a trifluridine/tipiracil combination.
  • the platinum -based agent is triplatin tetranitrate. In further embodiments, the platinum-based agent is pheanthriplatin. In further embodiments, the platinum -based agent is picoplatin. In further embodiments, the platinum -based agent is satraplatin.
  • the one or more additional therapeutic agents are selected from N- terminal domain inhibitors of androgen receptor.
  • the N-terminal domain inhibitor of androgen receptor is selected from EPI-001, EPI-002 (ralaniten), EPI-506, and EPI-7386.
  • the N-terminal domain inhibitor of androgen receptor is EPI-001.
  • the N-terminal domain inhibitor of androgen receptor is EPI-002 (ralaniten).
  • the N- terminal domain inhibitor of androgen receptor is EPI-506.
  • the N-terminal domain inhibitor of androgen receptor is EPI-7386.
  • the methods disclosed herein wherein the one or more additional therapeutic agents are selected from poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors.
  • PARP poly(adenosine diphosphate-ribose) polymerase
  • the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are selected from olaparib, niraparib, rucaparib, talazopari, veliparib, pamiparib, CEP-9722, and E7016.
  • the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is olaparib.
  • the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is niraparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is rucaparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is talazopari. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is veliparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is pamiparib.
  • the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is CEP-9722. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is E7016.
  • the methods disclosed herein wherein the one or more additional therapeutic agents are selected from inhibitors of CYP17.
  • the inhibitor of CYP17 is galeterone.
  • aralkyl and arylalkyl as used herein mean an aryl group covalently linked to an alkylene group wherein the moiety is linked to another group via the alkyl moiety.
  • An exemplary aralkyl group is -(Ci-C6)alkyl(Ce-Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity non-polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • the pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • the pharmaceutically acceptable formulations of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of from about 0.5 w/w % to about 95 w/w %, or from about 1 w/w % to about 95 w/w %, or from about 1 w/w % to about 75 w/w %, or from about 5 w/w % to about 75 w/w %, or from about 10 w/w % to about 75 w/w %, or from about 10 w/w % to about 50 w/w %.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount between about 150 mg to about 350 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 160 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg per day.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in 28-day cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in multiple 28-day cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof for at least one 28-day cycle. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof on each day of each 28-day cycle.
  • the methods described herein comprise administering the compositions and formulations comprising the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, to the subject or subject in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle.
  • treatment given for one week followed by three weeks of rest is one treatment cycle.
  • the length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks.
  • the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.
  • the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and/or pharmaceutical formulations comprising them that corresponds to such an amount varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.
  • the GnRH antagonist is degarelix. In some embodiments, the GnRH antagonist is elagolix. In some embodiments, the GnRH antagonist is ganirelix. In some embodiments, the GnRH antagonist is linzagolix. In some embodiments, the GnRH antagonist is relugolix.
  • the prostate cancer in the subject has progressed after having been administered at least one androgen receptor antagonist.
  • the at least one androgen receptor antagonist is selected from abiraterone, enzalutamide, apalutamide, and darolutamide.
  • the prostate cancer in the subject has progressed after having been administered abiraterone.
  • the prostate cancer in the subject has progressed after having been administered enzalutamide.
  • the prostate cancer in the subject has progressed after having been administered apalutamide.
  • the prostate cancer in the subject has progressed after having been administered darolutamide.
  • prostate cancer in the subject exhibits evidence of progressive disease by the Prostate Cancer Working Group 3 (PCWG3) criteria, comprising one or more of (a) 2 or more rising levels of prostate specific antigen (PSA) a minimum of one week apart with the latest result being at least 2.0 ng/mL, (b) 1.0 ng/mL PSA rise, (c) confirmation of 2 new bone lesions on last systemic therapy, and (d) soft tissue progression according to RECIST 1.1 guidelines.
  • PCWG3 Prostate Cancer Working Group 3
  • ANC ANC >1500 cells/mm 3 (1.5 x 103 cells/mm 3 );
  • platelets >100,000 /pL (100 x 109 /L);
  • hemoglobin >9.0 g/dL (90 g/L);
  • AST SGOT
  • ALT ALT
  • bilirubin ⁇ 1.5 x ULN;
  • QTcF QTcF ⁇ 470 msec.
  • [00161] Disclosed herein are methods comprising: (a) providing a biologic sample obtained from a subject having prostate cancer; (b) assaying to detect in the biologic sample obtained from the subject a presence or absence of a biomarker; (c) detecting the presence or absence of the biomarker in the biologic sample using the methods described herein; and (d) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, if the biomarker is present in the biological sample.
  • the presence of one or more biomarkers described herein indicate the prostate cancer in the subject is neuroendocrine prostate cancer.
  • a biomarker such as synaptophysin (SYP), chromogranin A (CGA), insulinoma-associated protein 1 (INSMI), syntaxin 1 (STX1), ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSM1), secretagogin (SECG), neural cell adhesion molecule 1 (NCAM1; CD56), neuron-specific enolase (NSE), and gastrin-releasing peptide (GRP).
  • a biological sample obtained from the subject has been determined to exhibit a biomarker that may comprise one or more alterations in one or more genes selected from TP53, RBI, and PTEN.
  • the presence, absence, or level, of such biomarkers may be measured, collectively or individually, in a biological sample obtained from a subject, such as a sample of a solid tumor, such as a neuroendocrine prostate cancer, or from a sample of a relevant biological fluid, such as a blood sample.
  • a biological sample obtained from a subject such as a sample of a solid tumor, such as a neuroendocrine prostate cancer, or from a sample of a relevant biological fluid, such as a blood sample.
  • the one or more biomarkers are detected in plasma or serum that is derived from a blood sample obtained from the subject.
  • the methods of detection disclosed herein are useful for predicting a therapeutic response to a therapy described herein (e.g., the administration to a subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof), monitor the treatment using the therapy of, and treating with the therapy, a proliferative disease or condition described herein in a subject.
  • a therapy described herein e.g., the administration to a subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • the expression of a biomarker in a biological sample from a subject is measured by use of immunohistochemistry (IHC) assays.
  • a biomarker such as synaptophysin (SYP), chromogranin A (CGA), insulinoma-associated protein 1 (INSMI), syntaxin 1 (STX1), ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSMI), secretagogin (SECG), neural cell adhesion molecule 1 (NCAM1; CD56), neuron-specific enolase (NSE), and gastrin-releasing peptide (GRP), is measured by use of immunohistochemistry (IHC) assays.
  • immunohistochemistry (IHC) assays are commercially available, or may be developed and utilized according to methods known to those having ordinary skill in the art.
  • Immunohistochemistry techniques utilize an antibody to probe and visualize cellular antigens in situ, generally by chromogenic or fluorescent methods.
  • antibodies or antisera, polyclonal antisera, or monoclonal antibodies specific for each marker are used to detect expression.
  • the antibodies can be detected by direct labeling of the antibodies themselves, for example, with radioactive labels, fluorescent labels, hapten labels such as, biotin, or an enzyme such as horse radish peroxidase or alkaline phosphatase.
  • unlabeled primary antibody is used in conjunction with a labeled secondary antibody, comprising antisera, polyclonal antisera, or a monoclonal antibody specific for the primary antibody.
  • Immunohistochemistry protocols and kits are well known in the art and are commercially available.
  • Two general methods of IHC are generally available; direct and indirect assays.
  • binding of antibody to the target antigen is determined directly.
  • This direct assay uses a labeled reagent, such as a fluorescent tag or an enzyme -labeled primary antibody, which can be visualized without further antibody interaction.
  • a labeled reagent such as a fluorescent tag or an enzyme -labeled primary antibody, which can be visualized without further antibody interaction.
  • unconjugated primary antibody binds to the antigen and then a labeled secondary antibody binds to the primary antibody.
  • a chromagenic or fluorogenic substrate is added to provide visualization of the antigen. Signal amplification occurs because several secondary antibodies may react with different epitopes on the primary antibody.
  • the primary and/or secondary antibody used for immunohistochemistry typically will be labeled with a detectable moiety.
  • Numerous labels are available which can be generally grouped into the following categories.
  • the antibody can be labeled with the radioisotope using the techniques described in Current Protocols in Immunology, Volumes 1 and 2, Coligen et al., Ed. Wiley-Interscience, New York, N.Y., Pubs. (1991) for example and radioactivity can be measured using scintillation counting.
  • colloidal gold particles are colloidal gold particles.
  • the enzyme generally catalyzes a chemical alteration of the chromogenic substrate that can be measured using various techniques.
  • the enzyme may catalyze a color change in a substrate, which can be measured spectrophotometrically.
  • the enzyme may alter the fluorescence or chemiluminescence of the substrate. Techniques for quantifying a change in fluorescence are described above.
  • the chemiluminescent substrate becomes electronically excited by a chemical reaction and may then emit light which can be measured (using a chemiluminometer, for example) or donates energy to a fluorescent acceptor.
  • Examples of enzymatic labels include luciferases (e.g., firefly luciferase and bacterial luciferase; U.S. Pat.
  • luciferin 2,3- dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, P-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like.
  • HRPO horseradish peroxidase
  • alkaline phosphatase P-galactosidase
  • glucoamylase lysozyme
  • saccharide oxidases e.g., glucose oxidase, galactose oxidase, and glucose-6-
  • DAB 3,3 -Diaminobenzidine
  • AP alkaline phosphatase
  • P-D-Gal P-D-galactosidase
  • a chromogenic substrate e.g., p-nitrophenyl-p-D-galactosidase
  • Anorogenic substrate e.g., 4-methylumbelliferyl-P-D-galactosidase
  • the label is indirectly conjugated with the antibody.
  • the antibody can be conjugated with biotin and any of the four broad categories of labels mentioned above can be conjugated with avidin, or vice versa. Biotin binds selectively to avidin and thus, the label can be conjugated with the antibody in this indirect manner.
  • the antibody is conjugated with a small hapten and one of the different types of labels mentioned above is conjugated with an anti-hapten antibody.
  • indirect conjugation of the label with the antibody can be achieved.
  • Biological samples obtained from subjects comprising tissue samples may be prepared according to protocols commonly used in the art.
  • sections of paraffin-embedded cells or tissues are obtained by (1) preserving tissue in fixative, (2) dehydrating the fixed tissue, (3) infiltrating the tissue with fixative, (4) orienting the tissue such that the cut surface accurately represents the tissue, (5) embedding the tissue in paraffin (making a paraffin block), (6) cutting tissue paraffin block with a microtome in sections of 4-5 picometers, and (7) mounting sections onto slides.
  • the slides may then be read by a pathologist or the like assessing for the presence or absence of a biomarker, or of abnormal or normal cells or a specific cell type and provides the loci of the cell types of interest.
  • a pathologist or the like would review the slides and identify normal cells and abnormal cells (such as abnormal or tumor cells).
  • Any means of defining the loci of the cells of interest may be used (e.g., coordinates on an X-Y axis.
  • tissue section prior to, during or following IHC may be desired.
  • epitope retrieval methods such as heating the tissue sample in citrate buffer may be carried out [see, e.g., Leong et al. Appl.
  • tissue section is exposed to primary antibody for a sufficient period of time and under suitable conditions such that the primary antibody binds to the target protein antigen in the tissue sample. Appropriate conditions for achieving this can be determined by routine experimentation.
  • the label is an enzymatic label (e.g. HRPO) which catalyzes a chemical alteration of the chromogenic substrate such as 3,3 ’-diaminobenzidine chromogen.
  • the enzymatic label is conjugated to antibody which binds specifically to the primary antibody (e.g. the primary antibody is rabbit polyclonal antibody and secondary antibody is goat anti -rabbit antibody). Specimens thus prepared may be mounted and coverslipped. Slide evaluation is then determined, e.g. using a microscope.
  • IHC may be combined with morphological staining, either prior to or thereafter.
  • the sections mounted on slides may be stained with a morphological stain for evaluation.
  • the morphological stain to be used provides for accurate morphological evaluation of a tissue section.
  • the section may be stained with one or more dyes each of which distinctly stains different cellular components.
  • hematoxylin is use for staining cellular nucleic of the slides. Hematoxylin is widely available. An example of a suitable hematoxylin is Hematoxylin II (Ventana). When lighter blue nuclei are desired, a bluing reagent may be used following hematoxylin staining.
  • staining may be optimized for a given tissue by increasing or decreasing the length of time the slides remain in the dye.
  • the tissue section may be analyzed by standard techniques of microscopy. Generally, a pathologist or the like assesses the tissue for the presence of abnormal or normal cells or a specific cell type and provides the loci of the cell types of interest. Thus, for example, a pathologist or the like would review the slides and identify normal cells and abnormal cells (such as abnormal or tumor cells). Any means of defining the loci of the cells of interest may be used (e.g., coordinates on an X-Y axis).
  • the presence, or an absence, and/or a level of expression of the biomarker is detected in the sample obtained from a subject by analyzing the genetic material in the sample.
  • the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known by one of skill in the art.
  • the sample comprises circulating tumor RNA (ctRNA).
  • the sample comprises peripheral blood mononuclear cells (PBMCs).
  • the sample comprises circulating tumor cells (CTCs).
  • the genetic material is obtained from a tumor biopsy or liquid biopsy.
  • a tumor biopsy comprises a formalin-fixed paraffin embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy.
  • a liquid biopsy comprises PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). Tumor and liquid biopsies can undergo additional analytic processing for sample dissociation, cell sorting, and enrichment of cell populations of interest.
  • methods of detecting a presence, absence, or level of a biomarker in a biologic sample obtained from the subject involve detecting a nucleic acid sequence.
  • the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript.
  • the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof.
  • the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA.
  • the DNA is single -stranded DNA (ssDNA), double -stranded DNA, denaturing double -stranded DNA, synthetic DNA, and combinations thereof.
  • the circular DNA may be cleaved or fragmented.
  • the nucleic acid sequence comprises ribonucleic acid (RNA).
  • the nucleic acid sequence comprises fragmented RNA.
  • the nucleic acid sequence comprises partially degraded RNA.
  • the nucleic acid sequence comprises a microRNA or portion thereof.
  • the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (IncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell- free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.
  • miRNA microRNA
  • pre-miRNA pre-miRNA
  • a pri-miRNA a RNA
  • mRNA a pre-mRNA
  • a pri-miRNA a
  • a biomarker is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay.
  • the nucleic acid-based detection assay comprises quantitative polymerase chain reaction (qPCR), reverse transcription PCT (RT-qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunohistochemistry (IHC), immunofluorescence (IF), in situ hybridization (ISH) such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing.
  • the sequencing technique comprises next generation sequencing.
  • the methods involve a hybridization assay such as Anorogenic qPCR (e.g., TaqManTM, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence.
  • a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles.
  • the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles.
  • the probe may be a hydrolysable probe comprising a Auorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid.
  • the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles.
  • hybridization may occur at standard hybridization temperatures, e.g., between about 35 °C and about 65 °C in a standard PCR buffer.
  • An additional exemplary nucleic acid -based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi -well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence.
  • the nucleic acid probe is specific to one or more of a polynucleotide sequence that encodes a relevant biomarker as disclosed herein.
  • the nucleic acid probe specific to a biomarker comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence that encodes the relevant biomarker protein.
  • the probe comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA).
  • the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence.
  • the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane, such as nitrocellulose.
  • the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence.
  • the term “probe” with regards to nucleic acids refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence.
  • probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art.
  • the fluorescent label comprises a fluorophore.
  • the fluorophore is an aromatic or heteroaromatic compound.
  • the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin.
  • xanthene dyes include, e.g., fluorescein and rhodamine dyes.
  • Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N'-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX).
  • Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position.
  • naphthylamino compounds include l-dimethylaminonaphthyl-5 -sulfonate, l-anilino-8-naphthalene sulfonate, and 2-p-toluidinyl-6- naphthalene sulfonate, 5 -(2 '-aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS).
  • Detection of the mRNA involves amplification of the subject’s nucleic acid by the polymerase chain reaction (PCR).
  • the PCR assay involves use of a pair of primers capable of amplifying at least about 10 contiguous nucleobases within a nucleic acid sequence, thereby amplifying the one or more gene products in the biomarker.
  • Anorogenic quantitative PCR quantitation is based on amount of Huorescence signals (TaqMan and SYBR green).
  • the nucleic acid probe is conjugated to a detectable molecule.
  • the detectable molecule may be a Huorophore.
  • the nucleic acid probe may also be conjugated to a quencher.
  • the assay for detecting the presence or absence of mRNA encoding a relevant biomarker comprises reverse -transcribing the relevant mRNA molecule to produce a corresponding complementary DNA (cDNA) molecule.
  • the assay further comprises contacting the cDNA molecule with a nucleic acid probe comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of the cDNA molecule.
  • the assay comprises detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecule.
  • the hybridization product is further amplified using a pair of primers.
  • this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich.
  • the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis.
  • the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification.
  • a decrease in the quantity of ctRNA suggests the solid tumor is shrinking and treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is effective.
  • a lack of ctRNA in the bloodstream indicates that the cancer has not returned after treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a subject having neuroendocrine prostate cancer comprising: (a) providing a biologic sample obtained from a subject having prostate cancer; (b) assaying to detect in the biologic sample obtained from the subject a presence or absence of a biomarker; (c) detecting the presence or absence of the biomarker in the biologic sample using the methods described herein; and (d) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, if the biomarker is present in the biological sample.
  • expression of a biomarker is based on the expression level of the biomarker deviating from a reference expression level.
  • the expression level is high, relative to the reference expression level. In some embodiments, the expression level is low, relative to the reference expression level. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that do not have cancer. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that have cancer that does not therapeutically respond to the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the expression level deviates from the reference expression level by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.
  • the determination of expression or the presence of a biomarker is defined based on the percentage of cells that stain weakly, moderately, or strongly for the relevant biomarker, with the threshold defining the minimal percentage of cells that are required to stain positive at the various intensity levels (>a% of prostate tumor cells stain weakly, >b% of prostate tumor cells stain moderately, >c% of prostate tumor cells stain strongly, or a combination thereof).
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
  • X is O, CR 5 , CR 5 OH, or C(R 5 )2, wherein: when X is O, - is a single bond; when X is C(R 5 )2, - is a single bond; when X is CR 5 OH, - is a single bond; or when X is CR 5 , - is a double bond;
  • R 2 is cyano, -COOR 5 , -C(O)N(R 5 )2, or -C(O)N(R 5 )2 wherein each R 5 taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R 4 ; each R 3 is independently C1-C3 alkyl or halogen; each R 4 is independently oxo, cyano, halogen, -POXCi-C alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 2 -haloalkyl, -Y’-Ci-Ce alkyl, -Y 2 -Ci-Ce alkyl, -L- cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y'-hetero
  • Embodiment 6 The method of any of embodiments 1-4, wherein R 2 is -COOR 5 .
  • Embodiment 14 The method of embodiment 13, wherein the aryl is phenyl optionally substituted with one or more R 4 .
  • Embodiment 17 The method of embodiment 16, wherein R 4 is -Y'-Ci-Ce alkyl and Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl, isopropyl, butyl, or pentyl.
  • Embodiment 18 The method of embodiment 16, wherein R 4 is -Y 2 -Ci-Ce alkyl and Y 2 is a -SO 2 - and the Ci-Ce alkyl is methyl.
  • Embodiment 19 The method of embodiment 16, wherein R 4 is -Y 2 -haloalkyl and Y 2 is -S- or -SO 2 - and the haloalkyl is trifluoromethyl.
  • Embodiment 20 The method of embodiment 16, wherein R 4 is -L-N(R 5 )2 and L is a bond and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
  • Embodiment 21 The method of embodiment 16, wherein R 4 is -L-N(R 5 )2 and L is methylene or ethylene and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
  • Embodiment 22 The method of embodiment 16, wherein R 4 is -Y'-N(R 5 )2, Y 1 is -C(O)- and each R 5 independently is hydrogen, each R 5 is independently methyl or one R 5 is methyl and one R 5 is hydrogen.
  • Embodiment 23 The method of embodiment 16, wherein R 4 is -Y 2 -N(R 5 )2, Y 2 is -SO2- and each R 5 independently is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is independently hydrogen.
  • Embodiment 24 The method of embodiment 16, wherein R 4 is -Y 1 -heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl.
  • Embodiment 25 The method of embodiment 16, wherein R 4 is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3/. 2 -azabicyclo
  • Embodiment 26 The method of embodiment 16, wherein R 4 is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R 7 selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen.
  • Embodiment 27 The method of embodiment 16, wherein R 4 is -Y 1 -heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the Y 1 -heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.
  • Embodiment 28 The method of embodiment 16, wherein R 4 is -L-heteroaryl optionally substituted with one or more R 7 .
  • Embodiment 29 The method of embodiment 28, wherein the -L-heteroaryl is tetrazolyl.
  • Embodiment 31 The method of embodiment 16, wherein R 4 is -COOR 5 .
  • Embodiment 32 The method of embodiment 16, wherein R 4 is hydroxyalkyl.
  • Embodiment 34 The method of embodiment 16, wherein R 4 is aralkyl.
  • Embodiment 36 The method of embodiment 35, wherein the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[l,2- b]pyrazolyl, each optionally substituted with one or more R 4 .
  • the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl
  • Embodiment 38 The method of embodiment 37, wherein the heteroaryl is pyrazolyl optionally substituted with one R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, - L-N(R 5 )2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R 7 .
  • R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, - L-N(R 5 )2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R 7 .
  • Embodiment 40 The method of embodiment 38, wherein R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, or 4-methylpiperazinyl.
  • Embodiment 41 The method of embodiment 38, wherein R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl, or 4-methylpiperazinyl.
  • Embodiment 43 The method of embodiment 38, wherein R 4 is -Y'-Ci-Ce alkyl where Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl, or isopropyl.
  • Embodiment 50 A method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to comprise neuroendocrine prostate cancer, comprising administering to the subject a
  • Embodiment 52 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 53 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 54 The method of embodiment 51, wherein the compound is: or a pharmaceutically acceptable salt thereof.
  • Embodiment 55 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 59 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 60 The method of embodiment 51, wherein the compound is: or a pharmaceutically acceptable salt thereof.
  • Embodiment 61 The method of embodiment 51 , wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 62 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 64 The method of any one of embodiments 1-63, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and wherein the one or more first agents is selected from the group consisting of (a) luteinizing hormone -releasing hormone (LHRH) agonists, (b) luteinizing hormone -releasing hormone (LHRH) antagonists, (c) androgen receptor inhibitors, (d) inhibitors of cytochrome P450 17A1, and (e) antiandrogens.
  • LHRH luteinizing hormone -releasing hormone
  • LHRH luteinizing hormone -releasing hormone
  • LHRH luteinizing hormone -releasing hormone
  • LHRH luteinizing hormone -releasing hormone
  • LHRH luteinizing hormone -releasing hormone
  • c androgen receptor inhibitors
  • inhibitors of cytochrome P450 17A1 inhibitors of cytochrome P450 17A1
  • Embodiment 67 The method of embodiment 64, wherein (a) the neuroendocrine prostate cancer in the subject has been determined to be progressing, and (b) testosterone levels in the subject have been determined to be equal to or less than 50 mg/mL, following the administration to the subject of the one or more first agents.
  • Embodiment 68 The method of embodiment 64, wherein (a) the neuroendocrine prostate cancer in the subject has been determined to be radiographically progressing, and (b) testosterone levels in the subject have been determined to be 50 mg/mL or less following the administration to the subject of the one or more first agents.
  • Embodiment 74 The method of embodiment 73, wherein the neuroendocrine prostate cancer in the subject has been determined to comprise 20 or more bone metastases.
  • Embodiment 81 The method of embodiment 80, wherein the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
  • Embodiment 85 The method of any one of embodiments 64-75, wherein the one or more first agents is an inhibitor of cytochrome P450 17A1.
  • Embodiment 86 The method of embodiment 85, wherein the one or more inhibitors of cytochrome P450 17A1 is abiraterone acetate.
  • Embodiment 95 The method of embodiment 89 or 90, wherein the biological sample obtained from the subject is tissue, and the biological sample has been determined to exhibit a positive immunohistochemical (IHC) stain for synaptophysin (SYP).
  • IHC immunohistochemical stain for synaptophysin
  • Embodiment 112 The method of any one of embodiments 1-111, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.01 mg/kg per day to about 300 mg/kg per day.
  • Embodiment 113 The method of embodiment 112, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0. 1 mg/kg per day to about 100 mg/kg per day.
  • Embodiment 114 The method of any one of embodiments 1-113, further comprising administering to the subject one or more additional therapeutic agents.
  • Embodiment 118 The method of embodiment 115, wherein the one or more additional therapeutic agents are selected from mitotic inhibitors.
  • Embodiment 133 The method of embodiment 132, wherein the one or more heat shock protein 90 (HSP90) inhibitors are selected from tanespimycin, luminespib, alvespimycin, ganetespib, BIIB021, onalespib, geldanamycin, NVP-BEP800, SNX-2112 (PF-04928473), PF-04929113 (SNX-5422), KW-2478, XL888, TAS-116, VER-50589, CH5138303, VER-49009, NMS-E973, zelavespib (PU-H71), and HSP990 (NVP-HSP990).
  • HSP90 heat shock protein 90
  • Embodiment 141 The method of embodiment 140, wherein the anti-PD-Ll agents are selected from atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559), BMS- 935559, MSB0010718C, and MEDI4736.
  • the anti-PD-Ll agents are selected from atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559), BMS- 935559, MSB0010718C, and MEDI4736.
  • Embodiment 142 The method of embodiment 115 wherein the one or more additional therapeutic agents are selected from anti-CTLA-4 agents.
  • Embodiment 144 The method of embodiment 114, wherein the one or more additional therapeutic agents are selected from surgery, radiation, and prostate -specific membrane antigen (PSMA) targeted agents.
  • PSMA prostate -specific membrane antigen
  • Example 1 Prostate cancer cell line NCI-H660 represents neuroendocrine prostate cancer
  • RT-qPCR reactions were set up in triplicate using 3 pL of 3 ng/ pL of RNA in 7 pL of pre-mixed SensiFASTTM SYBRNo-ROX One-Step Kit reagents (BIOLINE# BIO-98005). The RT-qPCR reactions were run on a Bio-Rad CFX384 Real-Time PCR System and data was plotted with GraphPad Prism 8 software.
  • RT-qPCR was used to measure the expression levels of androgen receptor (AR), synaptophysin (SYP), and chromogranin A (CGA) in prostate cancer cell lines including VCaP, LNCaP, CWR22PC, 22Rvl, LREX’, LAPC4, H660, PC3 and DU145 (FIG. 1A, FIG. IB, FIG. 1C).
  • AR androgen receptor
  • SYP synaptophysin
  • CGA chromogranin A
  • Example 2 Administration of Compound 4 to NCI-H660 tumor-bearing male athymic nude mice [00343] NCI-H660 (ATCC® CRL-5813TM) androgen-independent neuroendocrine prostate tumor cells were inoculated into right flanks of 90 intact male athymic nude mice.
  • RNA sequencing was performed on the H660 samples obtained from mice treated with 100 mg/kg of Compound 4 or vehicle from this Example 2. Extracted RNA was process into libraries for RNA-sequencing at Q2 Solutions-EA Genomics (North Carolina, USA). RNA-sequencing data was aligned using Kallisto 0.46.1 (Bray et al, Nature Biotechnology 2016) against a combined human Gencode v38 and mouse Gencode vM27 reference of the protein coding transcripts (Frankish et al, Nucleic Acids Research 2019).
  • ASCL1 and MYCL have been associated with lineage trans-differentiation in prostate cancer (see, for example, Davies et al, Cancer Discovery 2023).
  • Example 6 Thermal gravimetric analyses and differential scanning calorimetry analyses of Form 1 and Form 2 of Compound 4

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Sont divulguées, dans la présente invention, des méthodes de traitement du cancer de la prostate neuroendocrinien chez un patient par administration au patient d'un composé de formule (I)
PCT/US2024/010041 2023-01-03 2024-01-02 Traitement du cancer de la prostate neuroendocrinien WO2024148008A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363478296P 2023-01-03 2023-01-03
US63/478,296 2023-01-03
US202363518146P 2023-08-08 2023-08-08
US63/518,146 2023-08-08

Publications (1)

Publication Number Publication Date
WO2024148008A1 true WO2024148008A1 (fr) 2024-07-11

Family

ID=91804346

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/010041 WO2024148008A1 (fr) 2023-01-03 2024-01-02 Traitement du cancer de la prostate neuroendocrinien

Country Status (1)

Country Link
WO (1) WO2024148008A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019152419A1 (fr) * 2018-01-31 2019-08-08 Mirati Therapeutics, Inc Inhibiteurs de prc2
WO2021240373A1 (fr) * 2020-05-28 2021-12-02 Novartis Ag Schémas posologiques pour la n-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine, ou un sel pharmaceutiquement acceptable de celle-ci, pour une utilisation dans le traitement de maladies ou d'affections médiées par prc2

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019152419A1 (fr) * 2018-01-31 2019-08-08 Mirati Therapeutics, Inc Inhibiteurs de prc2
WO2021240373A1 (fr) * 2020-05-28 2021-12-02 Novartis Ag Schémas posologiques pour la n-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine, ou un sel pharmaceutiquement acceptable de celle-ci, pour une utilisation dans le traitement de maladies ou d'affections médiées par prc2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EROKHIN MAKSIM, CHETVERINA OLGA, GYŐRFFY BALÁZS, TATARSKIY VICTOR V., MOGILA VLADIC, SHTIL ALEXANDER A., RONINSON IGOR B., MOREAUX: "Clinical Correlations of Polycomb Repressive Complex 2 in Different Tumor Types", CANCERS, vol. 13, no. 13, CH , pages 1 - 26, XP093196212, ISSN: 2072-6694, DOI: 10.3390/cancers13133155 *

Similar Documents

Publication Publication Date Title
US11198677B2 (en) Deoxyuridine triphosphatase inhibitors containing amino sulfonyl linkage
JP6450323B2 (ja) デオキシウリジントリホスファターゼ阻害剤
US9371567B2 (en) Methods and kits to predict therapeutic outcome of BTK inhibitors
EP3089964B1 (fr) Inhibiteurs de la désoxyuridine triphosphatase contenant un hétéroatome
US9198910B2 (en) Methods for the treatment of cancer
US20200113852A1 (en) Methods of patient selection and treating trxr- or prdx-overexpressed cancers
US20230134425A1 (en) Methods of treating glioblastoma
US10993946B2 (en) Systems and methods for treating cancer
US11471451B2 (en) Uses of crenolanib
WO2020176461A2 (fr) Méthodes et compositions pour le traitement du cancer neuroendocrinien de la prostate
US8598188B2 (en) Method for predicting therapeutic efficacy of chemotherapy on non-small-cell lung cancer
WO2024148008A1 (fr) Traitement du cancer de la prostate neuroendocrinien
JP6875410B2 (ja) 多発性骨髄腫を有する患者の識別方法、評価方法、及び治療方法
WO2024215699A1 (fr) Traitement du lymphome à lymphocytes t
WO2024123669A1 (fr) Traitement du cancer de la prostate ayant des variants du récepteur des androgènes
WO2022098712A1 (fr) Biomarqueurs pour le syndrome myélodysplasique (mds) et leurs méthodes d'utilisation
US8697681B2 (en) Method for prediction of therapeutic effect of chemotherapy employing expression level of dihydropyrimidine dehydrogenase gene as measure
WO2023131866A1 (fr) Biomarqueurs pour le syndrome myélodysplasique (mds) et leurs méthodes d'utilisation
KR20230118040A (ko) 비알코올 지방간염 환자에서 miR-4449 억제제를 유효성분으로 포함하는 간 섬유화의 예방 또는 치료용 약학적 조성물
WO2021247869A2 (fr) Signature génique de récepteur de glucocorticoïde
JP2022530390A (ja) 抗精神病剤の応答を予測するための方法
EA047764B1 (ru) Способы, системы и устройства для выбора пациента в отношении tl1a
WO2010074241A1 (fr) Méthode de prédiction de l'effet thérapeutique d'une chimiothérapie combinatoire

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24738813

Country of ref document: EP

Kind code of ref document: A1