# US 2021/0332136 A1 · Methods for diagnosing and treating cancers

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2021/0332136 A1
- Document ID: US20210332136A1
- Status: Published application
- Kind: A1
- Application number: 17/200,729
- Filed: 2021-03-12
- Published: 2021-10-28
- Earliest claimed: 2020-03-13
- Assignees: Research Development Foundation
- Applicants: Research Development Foundation
- Inventors: Tyler J. CURIEL; Anand Kornepati
- Web page: https://patentgrep.com/patent/US20210332136A1

## CPC

- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/43: Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/502: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/545: Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-A61K-0953.gif] , e.g. cephalosporins, {cefaclor, or cephalexine}
- A61K 31/546: containing further heterocyclic rings, e.g. cephalothin
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- G01N 33/68: involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)}
- A61K 2039/505: {comprising antibodies}
- C12N 15/1138: {against receptors or cell surface proteins}
- C12N 2310/20: involving clustered regularly interspaced short palindromic repeats [CRISPR]
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- G01N 2333/4703: Regulators; Modulating activity
- G01N 2800/7028: Cancer
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

Provided herein are methods for the diagnosis, assessment, and treatment of cancer. In some aspects, detection of intracellular or cytoplasmic PD-L1, or measuring the ratio of cytoplasmic to surface PD-L1, can be used to identify cancers that may respond to immunotherapies or a DDR inhibitor such as, e.g., a Chk1 inhibitor, a PARP inhibitor, an ATM inhibitor, or an ATR inhibitor.

## Claims

### Claim 1

A method of treating a cancer in a mammalian subject, comprising measuring expression of
i) cytoplasmic PD-L1 and/or
ii) one or more Lamtor proteins in the cancer;
wherein if the expression of cytoplasmic or intracellular PD-L1 or one or more LAMTOR proteins is decreased relative to a normal control, then the method comprises administering an anti-cancer therapy to the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the anti-cancer therapy is a DDR inhibitor (DDRi) or an immune blockade therapy.

### Claim 3 (depends on 1)

The method of claim 1, wherein the anti-cancer therapy is a DDR inhibitor (DDRi).

### Claim 4 (depends on 1)

The method of claim 1, wherein the DDR inhibitor is a Chk1 inhibitor (Chk1i), a PARP inhibitor (PARPi), ATM inhibitor (ATMi), or an ATR inhibitor (ATRi).

### Claim 5 (depends on 1)

The method of claim 1, wherein the PARP inhibitor is rucaprib, olaparib, or niraparib.

### Claim 6 (depends on 1)

The method of claim 1, wherein the ATM inhibitor is AZD0156 or KU-55933.

### Claim 7 (depends on 1)

The method of claim 1, wherein the ATR inhibitor is VE-821, AZD6738, or VX970.

### Claim 8 (depends on 1)

The method of claim 1, wherein the Chk1 inhibitor is MK8776 (SCH900776), LY2603618, CCT245737, or GDC-0575.

### Claim 9 (depends on 1)

The method of claim 1, wherein the immune blockade therapy is an antibody that selectively binds PD-L1 or PD-1.

### Claim 10 (depends on 9)

The method of claim 9, wherein the antibody selectively binds PD-1, wherein the antibody is cemiplimab, nivolumab, pembrolizumab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), AMP-224, or AMP-514.

### Claim 11 (depends on 9)

The method of claim 9, wherein the antibody selectively binds PD-L1, wherein the antibody is atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189.

### Claim 12 (depends on 1)

The method of claim 1, wherein the anti-cancer therapy is 9-(2-phosphonylmethoxyethyl)guanine (PMEG) or chlorambucil.

### Claim 13 (depends on 12)

The method of claim 12, wherein the anti-cancer therapy is 9-(2-phosphonylmethoxyethyl)guanine (PMEG).

### Claim 14 (depends on 12)

The method of claim 12, wherein the anti-cancer therapy is chlorambucil.

### Claim 15 (depends on 1)

The method of claim 1, wherein the anti-cancer therapy is a beta-lactam antibiotic.

### Claim 16 (depends on 15)

The method of claim 15, wherein the beta-lactam antibiotic is a penam, carbapenem, an oxapenam, a penem, a carbapenem, a monobactam, a cephem, a carbacephem, or an oxacephem.

### Claim 17 (depends on 16)

The method of claim 16, wherein the beta-lactam antibiotic is a cephem.

### Claim 18 (depends on 17)

The method of claim 17, wherein the cephem is cefazolin, cephalexin, cephalosporin, cephalothin, cefapirin, cefaclor, cefamandole, cefuroxime, cefotetan, cefoxitin, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefdinir, cefepime, cefpirome, or ceftaroline.

### Claim 19 (depends on 18)

The method of claim 18, wherein the beta-lactam antibiotic is cefepime or ceftazidime.

### Claim 20 (depends on 1)

The method of claim 1, wherein the method comprises administering to the mammalian subject both: (a) an antibody that selectively binds PD-L1 or PD-1, and (b) a PARP inhibitor, a Chk1 inhibitor, or chlorambucil.

### Claim 21 (depends on 20)

The method of claim 20, wherein the antibody that selectively binds PD-L1 or PD-1 is cemiplimab, nivolumab, pembrolizumab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189.

### Claim 22 (depends on 20)

The method of claim 20, wherein the PARP inhibitor is rucaprib, olaparib, or niraparib.

### Claim 23 (depends on 22)

The method of claim 22, wherein the PARP inhibitor is olaparib.

### Claim 24 (depends on 20)

The method of claim 20, wherein the Chk1 inhibitor is MK8776 (SCH900776), LY2603618, CCT245737, or GDC-0575.

### Claim 25 (depends on 20)

The method of claim 20, wherein chlorambucil is administered to the mammalian subject.

### Claim 26 (depends on 1)

The method of claim 1, wherein the cancer is a gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, bladder cancer, lung cancer, colorectal cancer, melanoma, breast cancer, Merkel cell carcinoma, cervical cancer, hepatocellular cancer, head and neck cancer, sarcoma, lymphoma, leukemia, urothelial cancer, myelodysplasia, or sarcoma.

### Claim 27 (depends on 26)

The method of claim 26, wherein the cancer is an ovarian cancer, a bladder cancer, a breast cancer, or a melanoma.

### Claim 28 (depends on 27)

The method of claim 27, wherein the cancer is a breast cancer.

### Claim 29 (depends on 28)

The method of claim 28, wherein the breast cancer comprises a mutation in BRCA1.

### Claim 30 (depends on 28)

The method of claim 28, wherein the breast cancer does not comprise a mutation in BRCA2.

### Claim 31 (depends on 28)

The method of claim 28, wherein the breast cancer does not comprise a mutation in BRCA1 or BRCA2.

### Claim 32 (depends on 1)

The method of claim 1, wherein the cytoplasmic PD-L1 is located within the nucleus.

### Claim 33 (depends on 1)

The method of claim 1, wherein the measuring comprises immunohistochemistry, mass spectroscopy, immunoprecipitation, flow cytometry, or digital imaging.

### Claim 34 (depends on 1)

The method of claim 1, wherein the mammalian subject is a human.

### Claim 35 (depends on 1)

The method of claim 1, wherein the method further comprises detecting a mTORC1 signal or the one or more Lamtor proteins in the cancer.

### Claim 36 (depends on 35)

The method of claim 35, wherein the one or more LAMTOR protein is LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4, or LAMTOR5.

### Claim 37 (depends on 1)

The method of claim 1, wherein the anti-cancer therapy is an immune checkpoint blockade therapy.

### Claim 38 (depends on 37)

The method of claim 37, wherein the immune checkpoint blockade therapy is an antibody that selectively binds PD-1 or PD-L1.

### Claim 39 (depends on 1)

The method of claim 1, wherein the anti-cancer therapy is a chemotherapeutic, an immunotherapy, a gene therapy, a radiotherapy, a small molecule, a DNA therapy, an RNA therapy, a cryotherapy, a cellular therapy, a toll-like receptor agonist, a dual-targeting agent, a triple-targeting agent, or a surgery.

### Claim 40 (depends on 39)

The method of claim 39, wherein the anti-cancer therapy is cyclophosphamide or bevacizumab.

### Claim 41 (depends on 1)

The method of claim 1, wherein the cancer is a bladder cancer, a breast cancer, or a melanoma; and wherein the DDR inhibitor is a Chk1 inhibitor (Chk1i) or a PARP inhibitor (PARPi).

### Claim 42 (depends on 1)

The method of claim 1, wherein the cancer is a melanoma or an ovarian cancer; and wherein the anti-cancer therapy is pembrolizumab, bevacizumab, or cyclophosphamide.

### Claim 43 (depends on 1)

The method of claim 1, wherein the method does not comprise measuring surface PD-L1 expression by the cancer.

### Claim 44 (depends on 1)

The method of claim 1, wherein the method comprises measuring surface PD-L1 expression by the cancer.

### Claim 45 (depends on 1)

The method of claim 1, wherein the increased expression of cytoplasmic or intracellular PD-L1 indicates that greater than 50% of the total expressed PD-L1 in the cancer is cytoplasmic or intracellular PD-L1.

### Claim 46 (depends on 45)

The method of claim 45, wherein the increased expression has a ratio of cytoplasmic or intracellular PD-L1:surface PD-L1 of at least 1.5, or wherein the cancer expresses at least 1.5 times more cytoplasmic or intracellular PD-L1 than surface PD-L1.

### Claim at position 47

47-48. (canceled)

### Claim 49 (depends on 45)

The method of claim 45, wherein the increased expression has a ratio of cytoplasmic or intracellular PD-L1:surface PD-L1 of at least 3, or wherein the cancer expresses at least 3 times more cytoplasmic or intracellular PD-L1 than surface PD-L1.

### Claim 50

(canceled)

### Claim 51

A method for identifying an anti-cancer compound, comprising:
i) contacting a cancerous cell with a test compound; and subsequently
ii) measuring the level of expression in the cancerous cell of:
(a) cytoplasmic PD-L1 and/or
(b) one or more LAMTOR proteins;
wherein the cancerous cell expresses cytoplasmic or intracellular PD-L1 and/or one or more LAMTOR proteins; and wherein a decrease in cytoplasmic or intracellular PD-L1 or one or more LAMTOR proteins in the cancerous cell indicates that the test compound has anti-cancer properties.

### Claim at position 51

52-54. (canceled)

### Claim 55

An in vitro method for diagnosing a cancer, comprising:
i) obtaining a tissue sample comprising a cancer; and
ii) measuring the level of expression in the cancer of
(a) cytoplasmic or intracellular PD-L1 and/or
(b) one or more LAMTOR proteins;
wherein if the expression of cytoplasmic or intracellular PD-L1 or one or more LAMTOR proteins is decreased relative to a normal control, then the method comprises administering an anti-cancer therapy to the subject.

### Claim at position 53

56-89. (canceled)

### Claim 90

A method of treating a cancer in a mammalian subject, comprising administering to the subject a therapeutically relevant dose of:
(i) 9-(2-phosphonylmethoxyethyl)guanine (PMEG), chlorambucil, or a beta-lactam antibiotic, and
(ii) an antibody that selectively binds PD-L1 or PD-1
to the mammalian subject, and wherein the cancer is melanoma, ovarian cancer, gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, bladder cancer, lung cancer, colorectal cancer, melanoma, breast cancer, cervical cancer, hepatocellular cancer, head and neck cancer, sarcoma, lymphoma, leukemia, urothelial cancer, or myelodysplasia or sarcoma.

### Claim at position 55

91-103. (canceled)