# US 2020/0399704 A1 · Use of sdha as a prognostic marker and therapeutic target in uveal melanoma

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- Number: US 2020/0399704 A1
- Document ID: US20200399704A1
- Status: Published application
- Kind: A1
- Application number: 16/759,265
- Filed: 2018-10-25
- Published: 2020-12-24
- Earliest claimed: 2017-10-27
- Assignees: Board of Regents, The University of Texas System
- Applicants: Board of Regents, The University of Texas System
- Inventors: Chandrani CHATTOPADHYAY; Janos ROSZIK
- Web page: https://patentgrep.com/patent/US20200399704A1

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- C12N 9/001: {acting on the CH-CH group of donors (1.3)}
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/158: Expression markers
- C12Y 103/05001: Succinate dehydrogenase (ubiquinone) (1.3.5.1)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

Provided herein are methods for identifying expression of SDHA, MIF, and or monosomy 3 or disomy 3 status in sample to identify the sample as high-risk melanoma and/or the sensitivity to oxidative phosphorylation inhibitors. Also provided herein are methods for treating monosomy 3 uveal melanoma by administering a SDHA inhibitor in combination with an oxidative phosphorylation inhibitor.

## Claims

### Claim 1

An in vitro method for detecting the expression of succinate dehydrogenase complex flavoprotein subunit A (SDHA) in a sample comprising:
(a) obtaining a sample from a subject diagnosed with or at risk for uveal melanoma;
(b) isolating RNA from the sample; and
(c) detecting an elevated expression of SDHA RNA.

### Claim 2 (depends on 1)

The method of claim 1, wherein detecting comprises performing RT-qPCR, RNA-sequencing or microarray analysis on the isolated RNA.

### Claim 3 (depends on 1)

The method of claim 1, wherein the uveal melanoma is further defined as BAP1 loss and/or monosomy 3 uveal melanoma.

### Claim 4 (depends on 1)

The method of claim 1, wherein the sample is a tissue biopsy, fine needle aspirate, saliva, urine, or plasma.

### Claim 5 (depends on 1)

The method of claim 1, wherein the sample is a tissue biopsy.

### Claim 6 (depends on 5)

The method of claim 5, wherein the tissue biopsy is further defined as formalin fixed paraffin embedded (FFPE) tissue.

### Claim 7 (depends on 5)

The method of claim 5, wherein the tissue biopsy is further defined as a tumor biopsy.

### Claim 8 (depends on 1)

The method of claim 1, further comprising detecting the expression of MIF.

### Claim 9 (depends on 1)

The method of claim 1, further comprising detecting the expression of one or more genes selected from the group consisting of BAP1_varA, BAP1_varB, MGP, SPP1, CXCL14, CLCA2, S100A8, BTG1, SAP130, ARG1, KRT6B, GJA, ID2, EIF1B, S100A9, CRABP2, KRT14, ROBOT, RBM23, TACSTD2, DSC1, SPRR1B, TRIM29, AQP3, TYRP1, PPL, LTA4H, and CST6.

### Claim 10 (depends on 1)

The method of claim 1, wherein elevated expression of SDHA as compared to a control identifies the sample as a high-risk uveal melanoma sample.

### Claim 11 (depends on 1)

The method of claim 1, further comprising detecting the sample as a monosomy 3 uveal melanoma sample or a disomy 3 uveal melanoma sample.

### Claim 12 (depends on 11)

The method of claim 11, wherein the elevated expression of SDHA in the monosomy 3 uveal melanoma sample as compared to a control identifies the subject as having a poor prognosis and/or low overall survival.

### Claim 13 (depends on 11)

The method of claim 11 wherein decreased expression of SDHA in the disomy 3 uveal melanoma sample identifies the subject as having a poor prognosis and/or low overall survival.

### Claim 14 (depends on 1)

The method of claim 1, wherein elevated expression of SDHA as compared to a control identifies the subject as resistant to an oxidative phosphorylation (OXPHOS) inhibitor and/or immune checkpoint inhibitor therapy.

### Claim 15 (depends on 1)

The method of claim 1, wherein the elevated expression of SDHA as compared to a control identifies the subject as at risk for decreased overall survival and/or metastasis.

### Claim 16 (depends on 1)

The method of claim 1, wherein the subject has previously been administered or is being administered an anti-cancer therapy.

### Claim 17 (depends on 16)

The method of claim 16, wherein the anti-cancer therapy is chemotherapy, immunotherapy, surgery, radiotherapy, or biotherapy.

### Claim 18 (depends on 16)

The method of claim 16, wherein the anti-cancer therapy is immunotherapy.

### Claim 19 (depends on 18)

The method of claim 18, wherein the immunotherapy is immune checkpoint inhibitor therapy.

### Claim 20 (depends on 1)

The method of claim 1, further comprising administering an OXPHOS inhibitor to the subject with elevated expression of SDHA.

### Claim 21 (depends on 20)

The method of claim 20, wherein the OXPHOS inhibitor is IACS-1131, IACS-10759, oligomycin, rotenone, or metformin.

### Claim 22 (depends on 1)

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

### Claim 23

An in vitro method for detecting expression of SDHA and MIF in a sample comprising:
(a) obtaining a sample;
(b) isolating RNA from the sample; and
(c) detecting gene expression of SDHA and MIF in the RNA.

### Claim 24 (depends on 23)

The method of claim 23, wherein detecting comprises performing RT-qPCR, RNA-sequencing or microarray analysis on the isolated RNA.

### Claim 25 (depends on 23)

The method of claim 23, wherein the uveal melanoma is further defined as BAP1 loss and/or monosomy 3 uveal melanoma.

### Claim 26 (depends on 23)

The method of claim 23, wherein the sample is a tissue biopsy, fine needle aspirate, saliva, urine, or plasma.

### Claim 27 (depends on 23)

The method of claim 23, wherein the sample is a tissue biopsy.

### Claim 28 (depends on 27)

The method of claim 27, wherein the tissue biopsy is further defined as FFPE tissue.

### Claim 29 (depends on 27)

The method of claim 27, wherein the tissue biopsy is further defined as a tumor biopsy.

### Claim 30 (depends on 23)

The method of claim 23, further comprising detecting the expression of one or more genes selected from the group consisting of BAP1_varA, BAP1_varB, MGP, SPP1, CXCL14, CLCA2, S100A8, BTG1, SAP130, ARG1, KRT6B, GJA, ID2, EIF1B, S100A9, CRABP2, KRT14, ROBOT, RBM23, TACSTD2, DSC1, SPRR1B, TRIM29, AQP3, TYRP1, PPL, LTA4H, and CST6.

### Claim 31 (depends on 23)

The method of claim 23, wherein elevated expression of SDHA and MIF as compared to a control identifies the sample as a high-risk uveal melanoma sample.

### Claim 32 (depends on 23)

The method of claim 23, wherein elevated expression of SDHA and MIF as compared to a control identifies the sample as a monosomy 3 uveal melanoma sample.

### Claim 33 (depends on 23)

The method of claim 23, wherein elevated expression of SDHA and MIF as compared to a control identifies the subject as resistant to an OXPHOS inhibitor and/or immune checkpoint inhibitor therapy.

### Claim 34 (depends on 1)

The method of claim 1, wherein the elevated expression of SDHA as compared to a control identifies the subject as at risk for decreased overall survival and/or metastasis.

### Claim 35 (depends on 1)

The method of claim 1, wherein the subject has previously been administered or is being administered an anti-cancer therapy.

### Claim 36 (depends on 35)

The method of claim 35, wherein the anti-cancer therapy is chemotherapy, immunotherapy, surgery, radiotherapy, or biotherapy.

### Claim 37 (depends on 35)

The method of claim 35, wherein the anti-cancer therapy is immunotherapy.

### Claim 38 (depends on 37)

The method of claim 37, wherein the immunotherapy is immune checkpoint inhibitor therapy.

### Claim 39 (depends on 23)

The method of claim 23, further comprising administering an OXPHOS inhibitor to the subject with elevated expression of SDHA.

### Claim 40 (depends on 39)

The method of claim 39, wherein the OXPHOS inhibitor is IACS-1131, IACS-10759, oligomycin, rotenone, or metformin.

### Claim 41 (depends on 1)

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

### Claim 42

A method of treating cancer in a subject comprising:
(a) determining an expression level of SDHA in a patient sample; and
(b) administering an effective amount of an SDHA inhibitor and an OXPHOS inhibitor to the patient identified to have an elevated expression of SDHA.

### Claim 43 (depends on 42)

The method of claim 42, wherein the cancer is uveal melanoma.

### Claim 44 (depends on 43)

The method of claim 43, wherein the uveal melanoma is metastatic melanoma.

### Claim 45 (depends on 42)

The method of claim 42, wherein the patient has monosomy 3 and/or BAP1 loss.

### Claim 46 (depends on 42)

The method of claim 42, wherein the SDHA inhibitor is an inhibitory nucleic acid.

### Claim 47 (depends on 46)

The method of claim 46, wherein the inhibitory nucleic acid is siRNA, shRNA, or miRNA.

### Claim 48 (depends on 42)

The method of claim 42, wherein the OXPHOS inhibitor is IACS-1131, IACS-10759, oligomycin, rotenone, or metformin.

### Claim 49 (depends on 42)

The method of claim 42, wherein the SDHA inhibitor and OXPHOS inhibitor are delivered simultaneously.

### Claim 50 (depends on 42)

The method of claim 42, wherein the SDHA inhibitor is delivered prior to the OXPHOS inhibitor.

### Claim 51 (depends on 50)

The method of claim 50, wherein the SDHA inhibitor restores sensitivity to the OXPHOS inhibitor.

### Claim 52 (depends on 42)

The method of claim 42, wherein the patient is human.

### Claim 53 (depends on 42)

The method of claim 42, further comprising administering at least one additional anti-cancer therapy.

### Claim 54 (depends on 53)

The method of claim 53, wherein the at least on additional anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, or biotherapy.

### Claim 55 (depends on 53)

The method of claim 53, wherein the at least one additional anti-cancer therapy is immunotherapy.

### Claim 56 (depends on 55)

The method of claim 55, wherein the immunotherapy is an immune checkpoint inhibitor.

### Claim 57 (depends on 56)

The method of claim 56, wherein the immune checkpoint inhibitor is selected from an inhibitor of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, BTLA, B7H3, B7H4, TIM3, KIR, or A2aR.

### Claim 58 (depends on 56)

The method of claim 56, wherein the immune checkpoint inhibitor is an anti-PD1 antibody and/or an anti-CTLA4 antibody.

### Claim 59 (depends on 58)

The method of claim 58, wherein the anti-PD1 antibody is nivolumab, pembrolizumab, pidillizumab, KEYTRUDA®, AMP-514, REGN2810, CT-011, BMS 936559, MPDL328OA or AMP-224.

### Claim 60 (depends on 58)

The method of claim 58, wherein the anti-CTLA-4 antibody is tremelimumab, YERVOY®, or ipilimumab.

### Claim 61

A composition comprising an effective amount of an SDHA inhibitor and an OXPHOS inhibitor for the treatment of cancer in a subject, wherein the subject is identified to have an elevated expression of SDHA.

### Claim 62 (depends on 61)

The composition of claim 61, wherein the cancer is uveal melanoma.

### Claim 63 (depends on 62)

The composition of claim 62, wherein the uveal melanoma is metastatic melanoma.

### Claim 64 (depends on 61)

The composition of claim 61, wherein the subject has monosomy 3 and/or BAP1 loss.

### Claim 65 (depends on 61)

The composition of claim 61, wherein the SDHA inhibitor is an inhibitory nucleic acid.

### Claim 66 (depends on 65)

The composition of claim 65, wherein the inhibitory nucleic acid is siRNA, shRNA, or miRNA.

### Claim 67 (depends on 61)

The composition of claim 61, wherein the OXPHOS inhibitor is IACS-1131, IACS-10759, oligomycin, rotenone, or metformin.

### Claim 68 (depends on 61)

The composition of claim 61, wherein the subject is human.

### Claim 69

A method for treating a cancer in a subject comprising administering an effective amount of an SDHA inhibitor to the subject.

### Claim 70 (depends on 69)

The method of claim 69, wherein administering the SDHA inhibitor overcomes resistance to an OXPHOS inhibitor.

### Claim 71 (depends on 69)

The method of claim 69, further comprising administering an OXPHOS inhibitor.

### Claim 72 (depends on 69)

The method of claim 69, wherein the SDHA inhibitor is an inhibitory nucleic acid.

### Claim 73 (depends on 69)

The method of claim 69, wherein the inhibitory nucleic acid is siRNA, shRNA, or miRNA.

### Claim 74 (depends on 69)

The method of claim 69, wherein the subject is identified to have increased expression of SDHA as compared to a control expression level.

### Claim 75 (depends on 69)

The method of claim 69, wherein the increased expression of SDHA is measured by RT-qPCR, RNA-sequencing, microarray analysis, western blot, ELISA, immunohistochemistry, or Nanostring nCounter assay.

### Claim 76 (depends on 69)

The method of claim 69, wherein the cancer is uveal melanoma.

### Claim 77 (depends on 69)

The method of claim 69, wherein the subject has monosomy 3 and/or BAP1 loss.

### Claim 78 (depends on 69)

The method of claim 69, wherein the OXPHOS inhibitor is IACS-1131, IACS-10759, oligomycin, rotenone, or metformin.

### Claim 79 (depends on 69)

The method of claim 69, further comprising administering at least a second anti-cancer therapy.

### Claim 80 (depends on 71)

The method of claim 71, wherein the anti-cancer therapy is chemotherapy, immunotherapy, surgery, radiotherapy, or biotherapy.

### Claim 81 (depends on 69)

The method of claim 69, wherein the SDHA inhibitor is administered orally, intravenously, intraperitoneally, intratracheally, intratumorally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, topically, regionally, or by direct injection or perfusion.

### Claim 82 (depends on 79)

The method of claim 79, wherein the SDHA inhibitor and/or at least one additional anti-cancer therapy are administered simultaneously.

### Claim 83 (depends on 79)

The method of claim 79, wherein the SDHA inhibitor is administered prior to the at least one additional anti-cancer therapy.

### Claim 84 (depends on 69)

The method of claim 69, wherein the subject is human.