Adipose tissue immunometabolism in ovarian cancer progression and chemoresistance

项目摘要/摘要 卵巢癌(OvCa)总体预后较差，部分原因是当时的高转移率 诊断和很少有针对性的治疗选择。微管靶向制剂(MTA)，包括紫杉烷 紫杉醇(PTX)是一些用于治疗女性癌症的最有效的药物，包括 包括乳房和卵子。尽管PTX在治疗的初始阶段往往有效，但其发展 耐药性的降低是长期抗癌疗效的一个重要限制。MTA统称为 抗有丝分裂药物；然而，这类药物在致癌信号转导方面显示出不同的作用。 有显著差异的通路尤其在微管稳定剂之间，如PTX和 微管失稳剂，如长春花碱。此外，还有机会开发新的 可以绕过紫杉烷耐药机制的一类MTA，包括 药物外排转运体的上调。我假设微管稳定剂的发展 规避紫杉烷耐药的临床相关机制，以及识别 可以用来指导不同药物之间更合理的选择，经过临床验证和 机制多样化的药物类别，将为紫杉烷耐药卵巢癌患者提供更好的选择。 为了完成我的论文，我将使用分子和细胞生物学、生物信息学和 体外和体内肿瘤药理学为靶向使用不同的MTA治疗肿瘤确定关键决定因素 耐药OvCa的治疗(F99期)。我将测试假设，塔卡洛内酯类的共价键 微管稳定剂将在局部播散的、紫杉烷耐药的OvCa模型中保持疗效。此外，我 将跟进Septin 9异构体1(SEPT9_I1)癌基因差异定位于 用微管稳定剂和去稳定剂治疗以验证SEPT9_i1可作为一种 对这些药物的不同反应的生物标记物，特别是在EGFR驱动的乳房和卵巢癌中。在 K00阶段，我将把我的培训扩展到代谢紊乱领域，以阐明分子 脂肪细胞介导的去卵巢紫杉烷耐药机制。我将在证明PTX的研究的基础上继续 通过直接激活炎症TLR4信号通路促进脂肪细胞产生IL-8 传递并测试假设，即结构上不同的不同的MTA不会激活TLR4信号将 在体外和体内都可以绕过这种抗性机制，这可以用来告知更合理的 在卵巢癌妇女亚群中使用特定的MTA。拟议的研究将利用一种有效的、但 机制上被低估的一类药物，用于确定紫杉烷耐药的潜在机制 将指导未来的治疗选择。F99/K00机制提供的研究和职业培训 将为我提供一个从博士后研究顺利过渡到博士后研究的机会 最终，成为一个独立的调查者，专注于女性癌症的耐药性。

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.