Molecular Mechanisms of Therapeutic Resistance in Cancer.

[摘要] Development of therapeutic resistance limits the efficacy of current cancer treatment. Understanding the molecular basis for therapeutic resistance should facilitate the identification of actionable targets and development of new combination therapies for cancer patients. Yet the understanding of therapeutic resistance still remains incomplete. In this thesis, clinically relevant mouse models coupled with systematic genomic and imaging technologies are used to identify mechanisms driving resistance, which also formulate novel therapeutic paradigms for patients with drug-resistant tumors. In the first study, a genetically engineered mouse model of ovarian endometrioid adenocarcinoma (OEA) was utilized in combination with molecular imaging to understand mechanisms of chemoresistance in OEA. It was demonstrated that AKT signaling pathway was activated upon chemotherapy (cisplatin) administration, which protected cells from apoptosis and thereby leading to the development of resistance. In support of this observation, inhibition of AKT activity improved the efficacy of chemotherapy by enhanced induction of apoptosis.A second study was undertaken to develop a new understanding of the mechanistic basis for therapeutic resistance in glioblastoma using a patient derived xenograft model. An integrated transcriptome analysis revealed that chemoradioresistance was associated with an increased expression of genes involved in the mesenchymal and stem cell phenotype as well as a decreased expression of genes involved in cell death. TGF-β signaling was identified to be central to each of the mesenchymal/stem phenotype and therefore a critical player in modulating therapeutic resistance. In support, treatment with a TGF-β inhibitor partially restored the sensitivity to therapy in TMZ/IR resistant tumors. Overall, this thesis demonstrated the importance of the AKT and TGF-β signaling pathways in therapeutic resistance in a subset of ovarian cancer and glioblastoma patients, which provides clinical guidance for applying new combination therapies. It also demonstrates the concept that the combination of clinically relevant mouse models, molecular imaging and systematic genomic analysis can be used to derive novel insights into the dynamic signaling processes involved with gain of resistance. Future studies are needed to investigate if targeting these resistance mechanisms delays or prevents the development of resistance in treatment-naïve patients.

[发布机构] University of Michigan

[效力级别] gliobalstoma

[关键词] therapeutic resistance;gliobalstoma;ovarian cancer;signaling pathways;Molecular;Cellular and Developmental Biology;Science;Cellular and Molecular Biology