Adipose tissue immunometabolism in ovarian cancer progression and chemoresistance

点击翻译按钮获取中文摘要

Project Summary/Abstract Ovarian cancer (OvCa) has an overall poor prognosis due in part to high rates of metastasis at the time of diagnosis and few targeted therapeutic options. Microtubule targeted agents (MTAs), including the taxane paclitaxel (PTX), are some of the most effective agents used for the treatment of women’s cancers, including both breast and OvCas. Although PTX is often effective during the initial phase of treatment, the development of resistance is a significant limitation to long-term anticancer efficacy. MTAs are collectively classified as antimitotic agents; however, different drugs of this class have shown distinct effects on oncogenic signaling pathways with notable differences demonstrated particularly between microtubule stabilizers, like PTX, and microtubule destabilizers, such as the vinca alkaloids. Additionally, there is an opportunity to develop new classes of MTAs that can circumvent well-established mechanisms of taxane resistance, including the upregulation of drug efflux transporters. I hypothesize that the development of microtubule stabilizers that circumvent clinically relevant mechanisms of taxane resistance, as well as the identification of biomarkers that can be used to direct the more rational choice among different agents of this clinically validated and mechanistically diverse class of drugs, will provide improved options for patients with taxane-resistant OvCa. To complete my dissertation, I will use a combination of molecular and cellular biology, bioinformatics, and in vitro and in vivo cancer pharmacology to identify key determinants for the targeted use of distinct MTAs for the treatment of drug-resistant OvCa (F99 phase). I will test the hypothesis that the taccalonolide class of covalent microtubule stabilizers will retain efficacy in locally disseminated, taxane-resistant OvCa models. Additionally, I will follow up on findings that the Septin 9 isoform 1 (Sept9_i1) oncogene is differentially localized upon treatment with microtubule stabilizers and destabilizers to test the hypothesis that Sept9_i1 can serve as a biomarker for the differential response to these drugs, particularly in EGFR-driven breast and OvCas. In the K00 phase, I will expand my training into the area of metabolic disorders to elucidate the molecular mechanisms of adipocyte-mediated taxane resistance in OvCa. I will build on studies that demonstrate PTX promotes IL-8 production in adipocytes due to its ability to directly activate the inflammatory TLR4 signaling pathway and test the hypothesis that structurally distinct MTAs that do not activate TLR4 signaling will circumvent this resistance mechanism both in vitro and in vivo, which could be used to inform on more rational use of particular MTAs in subsets of women with OvCa. The proposed research will utilize an effective, but mechanistically underappreciated, class of drugs to determine mechanisms underlying taxane resistance that will guide future therapeutic choices. The research and career training provided by this F99/K00 mechanism will provide me an opportunity to smoothly transition from my predoctoral research to a postdoctoral fellowship and, ultimately, into an independent investigator with a focus on drug-resistance in women’s cancers.