Browsing by Author "Sundaresan, Srividhya"

Epithelial Ovarian cancer remains to be one of the leading causes of cancer-related deaths in women, and 70-80% of EOC-related deaths are attributed to High-Grade Serous Ovarian Cancer (HGSC). The 5-year survival rate of HGSC remains concerning at 50%. Approximately 50% of HGSC patients exhibit impaired Homologous Recombination (HR) DNA repair, a high-fidelity double-stranded DNA damage repair mechanism. Patients with Homologous Recombination Deficient (HRD) tumors exhibit better responses to DNA-damaging platinum agents and Poly (ADP-ribose) polymerases (PARP) inhibitors. The success of these treatments is attributed to the inability of HRD tumors to repair DNA damage, ultimately leading to cell death. It is expected that Homologous Recombination Proficient (HRP) tumors have functional repair mechanisms to eliminate this damage. Therefore, they derive no durable benefit from DNA-damaging agents and PARP inhibitors, resulting in a poor prognosis. DNA damage can be identified by the presence of pHistoH2AX (phosphorylated H2AX protein). This protein is formed at an early stage in response to the presence of Double-Strand Breaks (DSBs), and its interaction with MDC1 is critical for the recruitment of subsequent DNA repair proteins. Interestingly, Immuno-Fluorescent Imaging has revealed the presence of pHistoH2AX in chemo naïve HRP tumors. This raises questions about the origin of this endogenous DNA damage in HRP tumors and whether it signifies underlying vulnerabilities that could be exploited for therapeutic purposes. To address these questions, my thesis aimed to identify the co-expression markers of pHistoH2AX. To achieve this objective, I analyzed existing data from Cytometry by Time of Flight and Cyclic Immunofluorescence experiments to identify interesting molecular candidates. These experiments gave rise to several interesting candidates including pSTAT3, PDL1, pAkt, pEGFR, Cyclin E1 and Vimentin as potential co-expressed markers in HRP tumors. I further validated the co-expression of pSTAT3 and pHistoH2AX in HGSC patient tissue sections by immunofluorescence staining. This study holds significant relevance for identifying alternative molecular targets that could potentially improve the survival outcomes of patients with HRP HGSC. Future studies, encompassing larger cohorts of HRP patients, may unveil suitable subpopulations that could benefit from targeting these identified proteins, paving the way for the development of more effective therapeutic strategies in the management of HRP HGSC.