# US 2024/0201203 A1 · Compositions and methods for treating individuals who have oncogene-negative cancer > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2024/0201203 A1 - Document ID: US20240201203A1 - Status: Published application - Kind: A1 - Application number: 18/288,372 - Filed: 2022-04-29 - Published: 2024-06-20 - Earliest claimed: 2021-04-30 - Applicants: The Board of Trustees of the Leland Stanford Junior University - Inventors: Dmitri A. Petrov; Monte M. Winslow; Gabor Boross; Maryam Yousefi - Web page: https://patentgrep.com/patent/US20240201203A1 ## CPC - A61K 31/497: containing further heterocyclic rings - G01N 33/6893: {related to diseases not provided for elsewhere} - A01K 67/0275: Genetically modified vertebrates, e.g. transgenic - A61K 31/501: not condensed and containing further heterocyclic rings - A61K 31/506: not condensed and containing further heterocyclic rings - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/00: Antineoplastic agents - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - G01N 33/5011: {for testing antineoplastic activity} - G01N 33/5044: {involving specific cell types} - A01K 2227/105: Murine - A01K 2267/0331: Animal model for proliferative diseases - G01N 2333/912: transferring phosphorus containing groups, e.g. kinases (2.7) - G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis - G01N 2800/7057: (Intracellular) signaling and trafficking pathways - 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) - 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) - A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - 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 Methods and compositions are provided for treating individuals who have an oncogene-negative cancer. In some cases, such individuals have an oncogene-negative tumor(s). In some cases, they have an oncogene-negative lung cancer. In some cases, they have an oncogene-negative lung adenocarcinoma. In some cases, treatment includes administering an inhibitor of the Ras/MAPK pathway. In some cases, treatment includes administering an inhibitor of the Ras/MAPK pathway and an inhibitor of the PI3K-AKT pathway. Methods and compositions are also provided for testing candidate cancer therapeutics. In some cases, such methods include contacting an oncogene-negative cell, in culture or in vivo, with a candidate agent, where the cell has increased Ras/MAPK pathway activity and/or increased PI3K-AKT pathway activity. ## Claims ### Claim 1 A method of treatment, comprising: administering a composition comprising an inhibitor of Ras/MAPK pathway activity to an individual who has a cancer previously determined to be oncogene-negative. ### Claim 2 (depends on 1) The method of claim 1, wherein the inhibitor of Ras/MAPK pathway activity comprises an inhibitor of SHP2. ### Claim 3 (depends on 2) The method of claim 2, wherein the inhibitor of SHP2 is RMC-4550 or RMC-4630. ### Claim 4 (depends on 1, 2, 3) The method of any one of claims 1-3, further comprising administering an inhibitor of PI3K-AKT pathway activity to the individual. ### Claim 5 (depends on 4) The method of claim 4, wherein said administering of the inhibitor of PI3K-AKT pathway activity comprises local administration to a tumor of the individual. ### Claim 6 (depends on 4, 5) The method of claim 4 or claim 5, wherein the inhibitor of PI3K-AKT pathway activity comprises an inhibitor of AKT1/2. ### Claim 7 (depends on 6) The method of claim 6, wherein the inhibitor of AKT1/2 is capivasertib. ### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7) The method of any one of claims 1-7, wherein the oncogene-negative cancer is a lung cancer. ### Claim 9 (depends on 8) The method of claim 8, wherein the lung cancer is lung adenocarcinoma. ### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9) The method of any one of claim 1-9, wherein said cancer was previously determined to be oncogene-negative by a method comprising genome sequencing. ### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9) The method of any one of claim 1-9, comprising a step of providing said previous oncogene-negative determination by assaying a biological sample of said cancer. ### Claim 12 (depends on 11) The method of claim 11, wherein said assaying comprises genome sequencing. ### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) The method of any one of claims 1-12, wherein, prior to said administering, said cancer of the individual was previously determined to exhibit increased: (i) Ras/MAPK pathway activity or (ii) Ras/MAPK pathway activity and PI3K-AKT pathway activity, compared to a control value. ### Claim 14 (depends on 13) The method of claim 13, wherein said method comprises a step of providing said previous determination of increased pathway activity by assaying a biological sample of said cancer. ### Claim 15 (depends on 14) The method of claim 14, wherein said assaying comprises genome sequencing and/or biomarker analysis. ### Claim 16 (depends on 15) The method of claim 15, wherein said biomarker analysis comprises measuring levels of: (i) phosphorylated ERK (pERK) or (ii) pERK and phosphorylated AKT (pAKT). ### Claim 17 (depends on 16) The method of claim 16, wherein said measuring comprises immunohistochemistry. ### Claim 18 A composition formulated for use in a method of treating an individual who has an oncogene-negative cancer, wherein the composition comprises an inhibitor of Ras/MAPK pathway activity. ### Claim 19 (depends on 18) The composition of claim 18, wherein the inhibitor of Ras/MAPK pathway activity comprises an inhibitor of SHP2. ### Claim 20 (depends on 19) The composition of claim 19, wherein the inhibitor of SHP2 is RMC-4550 or RMC-4630. ### Claim 21 (depends on 18, 19, 20) The composition of any one of claims 18-20, further comprising an inhibitor of PI3K-AKT pathway activity. ### Claim 22 (depends on 21) The composition of claim 21, wherein the inhibitor of PI3K-AKT pathway activity comprises an inhibitor of AKT1/2. ### Claim 23 (depends on 22) The composition of claim 22, wherein the inhibitor of AKT1/2 is capivasertib. ### Claim 24 (depends on 18, 19, 20, 21, 22, 23) The composition of any one of claims 18-23, wherein the oncogene-negative cancer is a lung cancer. ### Claim 25 (depends on 24) The composition of claim 24, wherein the lung cancer is lung adenocarcinoma. ### Claim 26 (depends on 18, 19, 20, 21, 22, 23, 24, 25) The composition of any one of claim 18-25, wherein the individual exhibits increased: (i) Ras/MAPK pathway activity or (ii) Ras/MAPK pathway activity and PI3K-AKT pathway activity, compared to a control value. ### Claim 27 A kit for use in a method of treating an individual who has an oncogene-negative cancer, the kit comprising: (a) an inhibitor of Ras/MAPK pathway activity; and (b) an inhibitor of PI3K-AKT pathway activity, wherein the components of the kit are separated from one another. ### Claim 28 (depends on 27) The kit of claim 27, wherein the inhibitor of Ras/MAPK pathway activity comprises an inhibitor of SHP2. ### Claim 29 (depends on 28) The kit of claim 28, wherein the inhibitor of SHP2 is RMC-4550 or RMC-4630. ### Claim 30 (depends on 27, 28, 29) The kit of any one of claims 27-29, wherein the inhibitor of PI3K-AKT pathway activity comprises an inhibitor of AKT1/2. ### Claim 31 (depends on 30) The kit of claim 30, wherein the inhibitor of AKT1/2 is capivasertib. ### Claim 32 (depends on 27, 28, 29, 30, 31) The kit of any one of claims 27-31, wherein the oncogene-negative cancer is a lung cancer. ### Claim 33 (depends on 32) The kit of claim 32, wherein the lung cancer is lung adenocarcinoma. ### Claim 34 (depends on 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33) The kit of any one of claim 17-33, wherein the individual exhibits increased: (i) Ras/MAPK pathway activity or (ii) Ras/MAPK pathway activity and PI3K-AKT pathway activity, compared to a control value. ### Claim 35 A method for testing candidate therapies, the method comprising: (a) administering a candidate therapeutic agent to a non-human genetically modified mammal that has an oncogene-negative genomic profile and comprises lung cells with one or more genomic alterations causing increased Ras/MAPK pathway activity and/or increased PI3K-AKT pathway activity; and (b) determining whether the candidate therapeutic agent prevented or reduced lung cancer in the individual relative to a control. ### Claim 36 (depends on 35) The method of claim 35, wherein said one or more genomic alterations cause increased Ras/MAPK pathway activity and increased PI3K-AKT pathway activity. ### Claim 37 (depends on 35, 36) The method of claim 35 or claim 36, wherein the increased Ras/MAPK pathway activity results from reduced expression of wild type Nf1 and/or wild type Rasa1. ### Claim 38 (depends on 35, 36, 37) The method of any one of claims 35-37, wherein the increased PI3K-AKT pathway activity results from reduced expression of wild type Pten. ### Claim 39 (depends on 35, 36, 37) The method of any one of claims 35-37, wherein the increased PI3K-AKT pathway activity results from a pathway-activating alteration of AKT. ### Claim 40 (depends on 35, 36, 37, 38, 39) The method of any one of claims 35-39, wherein the candidate therapeutic agent is administered locally to a tumor. ### Claim 41 (depends on 35, 36, 37, 38, 39) The method of any one of claims 35-39, wherein the candidate therapeutic agent is administered systemically to the individual. ### Claim 42 (depends on 35, 36, 37, 38, 39, 40, 41) The method of any one of claims 35-41, wherein said control is a predetermined threshold value. ### Claim 43 (depends on 35, 36, 37, 38, 39, 40, 41) The method of any one of claims 35-41, wherein said control is a control tumor in the same individual, wherein the control tumor is an untreated tumor or a tumor treated with a control agent. ### Claim 44 (depends on 35, 36, 37, 38, 39, 40, 41) The method of any one of claims 35-41, wherein said control is a cancer in a different individual, wherein said different individual is an untreated control animal or a control animal treated with a control agent. ### Claim 45 (depends on 35, 36, 37, 38, 39, 40, 41, 42, 43, 44) The method of any one of claims 35-44, wherein the non-human genetically modified mammal is a rodent. ### Claim 46 (depends on 35, 36, 37, 38, 39, 40, 41, 42, 43, 44) The method of any one of claims 35-44, wherein the non-human genetically modified mammal is a non-human primate. ### Claim 47 A method for testing candidate therapies, the method comprising: (a) contacting a population of cells with a candidate therapeutic agent, wherein said cells are mammalian cells that have an oncogene-negative genomic profile and comprise one or more genomic alterations causing increased Ras/MAPK pathway activity and/or increased PI3K-AKT pathway activity; and (b) determining whether the candidate therapeutic agent prevented or reduced proliferation of said population of cells relative to a control. ### Claim 48 (depends on 47) The method of claim 47, wherein said cells are from a non-human genetically modified mammal or are progeny of such cells, wherein said non-human genetically modified mammal has an oncogene-negative genomic profile and comprises one or more genomic alterations causing increased Ras/MAPK pathway activity and/or increased PI3K-AKT pathway activity. ### Claim 49 (depends on 47, 48) The method of claim 47 or claim 48, wherein said cells are rodent cells. ### Claim 50 (depends on 47, 48) The method of claim 47 or claim 48, wherein said cells are non-human primate cells. ### Claim 51 (depends on 47) The method of claim 47, wherein said cells are human cells. ### Claim 52 (depends on 47, 48, 49, 50, 51) The method of any one of claims 47-51, wherein said cells are lung cells. ### Claim 53 (depends on 47, 48, 49, 50, 51, 52) The method of any one of claims 47-52, wherein said one or more genomic alterations cause increased Ras/MAPK pathway activity and increased PI3K-AKT pathway activity. ### Claim 54 (depends on 47, 48, 49, 50, 51, 52, 53) The method of any one of claims 47-53, wherein the increased Ras/MAPK pathway activity results from reduced expression of wild type Nf1 and/or wild type Rasa1. ### Claim 55 (depends on 47, 48, 49, 50, 51, 52, 53, 54) The method of any one of claims 47-54, wherein the increased PI3K-AKT pathway activity results from reduced expression of wild type Pten and/or from a pathway-activating alteration of AKT. ### Claim 56 (depends on 47, 48, 49, 50, 51, 52, 53, 54, 55) The method of any one of claims 47-55, wherein said control is a predetermined threshold value. ### Claim 57 (depends on 47, 48, 49, 50, 51, 52, 53, 54, 55) The method of any one of claims 47-55, wherein said control is a control population of cells that are untreated or treated with a control agent. ### Claim 58 An oncogene-negative mouse for use as a lung cancer model, comprising: an oncogene-negative genomic profile and genomic alterations causing increased Ras/MAPK pathway activity and increased PI3K-AKT pathway activity. ### Claim 59 (depends on 58) The oncogene-negative mouse of claim 58, wherein the increased Ras/MAPK pathway activity is caused by reduced expression wild type Nf1 and/or wild type Rasa1. ### Claim 60 (depends on 58, 59) The oncogene-negative mouse of claim 58 or claim 59, wherein the increased PI3K-AKT pathway activity is caused by reduced expression wild type Pten. ### Claim 61 (depends on 58, 59) The oncogene-negative mouse of claim 58 or claim 59, wherein the increased PI3K-AKT pathway activity is caused by a pathway-activating alteration of AKT. ### Claim 62 (depends on 58, 59, 60, 61) The oncogene-negative mouse of any one of claims 58-61, wherein the increased Ras/MAPK pathway activity is caused by reduced expression wild type Nf1 and wild type Rasa1, and the increased PI3K-AKT pathway activity is caused by reduced expression wild type Pten. ### Claim 63 (depends on 62) The oncogene-negative mouse of claim 62, wherein the reduced expression of wild type Nf1, Rasa1, and Pten is caused by a genetic loss-of-function mutations in each of the Nf1, Rasa1, and Pten loci. ### Claim 64 (depends on 58) A cell, or progeny thereof, isolated from the oncogene-negative mouse of claim 58. ### Claim 65 (depends on 64) The cell, or progeny thereof, of claim 64, wherein the cell is a germ cell. ### Claim 66 (depends on 64) The cell, or progeny thereof, of claim 64, wherein the cell is a stem cell. ### Claim 67 (depends on 64) The cell, or progeny thereof, of claim 64, wherein the cell is a lung cell.