Sunday, December 22, 2024
12/22/2024
Most ovarian cancer (OvCa) patients develop fatal chemotherapy-resistant disease. Elucidating mechanisms of chemoresistance in OvCa may identify therapeutic targets to prevent or treat relapsed OvCa. One understudied mechanism of chemotherapy resistance in OvCa is quiescence. Quiescent cells are transiently non-proliferating and thus refractory to standard therapies which target rapidly proliferating cells. The over- arching hypothesis of this project is that hypothesis is that understanding the biology of quiescent OvCa cancer cells will identify critical new therapeutic targets to improve patient outcomes. We have used multiple novel approaches to identify and characterize the transcriptional signature of quiescent OvCa cells. This work indicates that quiescent OvCa (qOvCa) cells have several unique characteristics including: (i) a unique Quiescence Associated Secretory Phenotype (QuASP) which drives chemotherapy resistance in non- quiescent cancer cells, and (ii) altered expression of select components of the ubiquitin-proteosome system (UPS) including induction of UBL7. Indeed, our preliminary data indicate that induction of UBL7 is sufficient to drive a quiescent cell phenotype, including the expression of the QuASP. Bio-informatic analysis of quiescent OvCa cell RNAseq data identified the SRF/MRTF transcription pathway as being inversely correlated with the OvCa quiescent signature. Consistent with this, a small molecule inhibitor of SRF/MRTF-mediated transcription, CCG081, (i) induces UBL7, (ii) drives cells into a dense quiescent state, and (iii), indicating a critical role for the UPS in quiescent cell viability, CCG081 sensitizes OvCa cells to proteasome inhibitors. Based on these discoveries, we propose: SA 1: To characterize the OvCa QuASP. We hypothesize that, characterizing the QuASP will identify critical biologic factors related to quiescence. We will identify QuASP factors, validate the expression of QuASP factors in ovarian cancer and other cancer types, and use knockdown and neutralizing antibodies to evaluate the function of these factors in quiescent OvCa cells.SA 2: To determine the role of the UPS and UBL7 in quiescent cancer cells. We hypothesize that UPS changes contribute to the quiescent cell state and are essential for quiescent cell viability. We will identify which components of the UPS contribute to the quiescent phenotype, including expression of the QuASP, and determine if the proteosome is essential to maintain quiescent OvCa cell viability. Finally, we will SA 3: Evaluate the impact of targeting the proteosome quiescent cells in vivo. We hypothesize that the ability to pharmacologically force these residual cells into a quiescent state and then eliminate these quiescent cells via proteosome inhibition will increase cure rates. We will evaluate the therapeutic potential of combined CCG081 and FDA-approved proteosome inhibitors as consolidative therapy after chemotherapy to eradicate residual quiescent cells. Impact: We will define the regulators of OvCa cell quiescence, providing therapeutic targets eradiate to improve patient outcomes.
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