An Achilles’ heel of ovarian cancer: targeting ARID1A mutant tumours

Project Member(s): Marsh, D., Faiz, A.

Funding or Partner Organisation: National Health & Medical Research Council (NHMRC - Ideas Grants)
National Health & Medical Research Council (NHMRC - Ideas Grants)

Start year: 2023

Summary: Ovarian cancer is the leading cause of death from gynaecological malignancies. There are a number of distinct subtypes, each with different molecular profiles and clinical behaviours. For e.g., most women with high-grade serous ovarian cancer initially respond to standard-of-care chemotherapy, however the majority relapse with treatment resistant disease. In contrast, most women with ovarian clear cell carcinoma (OCCC) do not respond to chemotherapy, with only 1-2% responding after relapse. In some Asian countries, OCCC constitute 25% of all ovarian cancers. To save lives, the lack of therapeutic options for chemotherapy resistant ovarian cancers must be urgently addressed. Few studies in ovarian cancer have focussed on what occurs “above the DNA” known as the epigenome. Our innovative approach to identifying new treatments for chemotherapy resistant ovarian cancers is to focus on components of a key chromatin remodelling complex known as SWI/SNF that remodels chromatin to direct transcription and DNA repair. Subunits of SWI/SNF are mutated in OCCC and disrupt its normal function. We hypothesise that mutation of the SWI/SNF subunit ARID1A represents an Achilles’ heel of ovarian cancer that can be targeted to make major breakthroughs in the development of new therapeutic opportunities for the difficult to treat subtype OCCC. Given the broader involvement of SWI/SNF complex members and specifically ARID1A in human cancer, our discoveries will have broad impact on human malignancy. AIMS: (1) Use unbiased whole-genome CRISPR KO and CRISPRa screens to identify new targets with the potential to treat ARID1A mutant ovarian cancer. (2) Use targeted screening approaches to inhibit SWI/SNF complex function in ARID1A mutated ovarian cancer.

Publications:

Field, NR, Dickson, K-A, Nassif, NT & Marsh, DJ 2024, 'SMARCA4 and SMARCA2 co-deficiency: An uncommon molecular signature defining a subset of rare, aggressive and undifferentiated malignancies associated with defective chromatin remodeling', Cancer Letters, vol. 605, pp. 217282-217282.
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Ma, Y, Dickson, KA, Field, N, Xie, T, Tran, N & Marsh, DJ 2024, 'Abstract A038: Epigenetic compound library screen of ovarian clear cell carcinoma cell line models identifies decreased cell viability following treatment with the Bruton tyrosine kinase inhibitor ibrutinib', American Association for Cancer Research (AACR), pp. A038-A038.
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Dickson, K-A, Field, N, Blackman, T, Ma, Y, Xie, T, Kurangil, E, Idrees, S, Rathnayake, SNH, Mahbub, RM, Faiz, A & Marsh, DJ 2023, 'CRISPR single base-editing: in silico predictions to variant clonal cell lines', Human Molecular Genetics, vol. 32, no. 17, pp. 2704-2716.
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Ma, Y, Field, NR, Xie, T, Briscas, S, Kokinogoulis, EG, Skipper, TS, Alghalayini, A, Sarker, FA, Tran, N, Bowden, NA, Dickson, K-A & Marsh, DJ, 'Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies—Therapeutic Vulnerabilities in Treatment-Resistant Subtypes', Cancers, vol. 16, no. 17, pp. 3068-3068.
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FOR Codes: Cancer cell biology, Expanding knowledge in the biomedical and clinical sciences