Lab research

Exploiting Vulnerabilities in Cancer Cells and TME for Therapeutic Benefit

Ferroptosis  is a vulnerability of mesenchymal cancer cells 

Ferroptosis is a recently characterized iron-dependent form of cell death driven by the oxidative modifications of membrane phospholipids. We and others have recently discovered an unrecognized role for peroxisomal ether-lipid synthesis genes in modulating ferroptosis susceptibility in high-grade serous ovarian cancer (HGSOC) (Zhou, Henry and Ricq et al., 2020). Importantly, although more mesenchymal cancer cells seem to be vulnerable to ferroptosis-inducing drugs, and elevated ether lipid levels have been associated with highly metastatic human breast carcinoma cells, whether ether lipid metabolism is mechanistically linked to EMT- dependent cancer progression is largely unknown. We are currently exploring the functional contribution of ether lipids in EMT, cancer progression and metastasis in order to identify vulnerabilities in cancer cells.

Enhancing the efficacy of immunotherapy in HGSOC

Immunotherapy, specifically immune checkpoint blockade (ICB) therapy, has revolutionized treatments of certain cancers, such as melanoma. However, the therapeutic benefits for most solid cancers have been limited, including notably, for ovarian cancer, partly due to an incomplete understanding of the biology underlying immunosuppression in ovarian cancer. Recently, our lab has generated a series of murine HGSOC cell lines bearing sets of mutant alleles that are found in corresponding human tumors and can grow in syngeneic, immunocompetent mouse hosts (Iyer et al., 2021). Provocatively, in mice bearing the line of HGSOC tumors that exhibit amplification of CCNE1, we achieved significant survival benefit by employing anti-PD-L1 + CTLA4 ICB together with inhibition of the CHK1 kinase by prexasertib (“triple therapy”). Importantly, we also uncovered non-genetic differences between sub-clonal tumors that responded differentially to such combination therapy. We are currently identifying the novel determinants of immunotherapy responses and developing therapeutic tools to target these factors in order to potentiate immunotherapy responses in ovarian cancer. Finally, we are determining the mechanisms that convert tumors that are initially responsive to ICB therapy to those that become refractory to treatment, leading to clinical relapses.