Adipose tissue immunometabolism in ovarian cancer progression and chemoresistance

卵巢癌进展和化疗耐药中的脂肪组织免疫代谢

• 批准号: 10640226
• 负责人: Samantha Yee
• 金额: $ 9.13万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640226
• 关键词: ABCB1 gene; Actins; Adipocytes; Adipose tissue; Agonist; Antimitotic Agents; Arachidonic Acids; Area; Binding; Bioinformatics; Biological Markers; Breast Cancer Model; Breast Cancer Treatment; Cancer Model; Cancer Prognosis; Chemoresistance; Chronic; Classification; Clinical; Cytoskeletal Proteins; Cytoskeleton; Development; Diagnosis; Disease; Disease Resistance; Drug Efflux; Drug resistance; Epidermal Growth Factor Receptor; Fellowship; Filament; Future; GTP-Binding Proteins; Growth Factor; High Fat Diet; IL8 gene; In Vitro; Inflammation; Inflammatory; Injections; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Metabolic Diseases; Microtubules; Modeling; Molecular; Molecular and Cellular Biology; Mus; N-terminal; Neoplasm Metastasis; Obesity; Omentum; Oncogenes; Oncogenic; Paclitaxel; Patients; Peritoneum; Pharmaceutical Preparations; Phase; Postdoctoral Fellow; Process; Production; Prognosis; Protein Isoforms; Research; Research Personnel; Resistance; Resistance development; Signal Pathway; Signal Transduction; Solid Neoplasm; Specificity; TLR4 gene; Tacca; Testing; Therapeutic; Time; Training; Up-Regulation; Vinca Alkaloids; Woman; anti-cancer; biomarker identification; cancer pharmacology; cancer therapy; career; clinically relevant; diet-induced obesity; disorder risk; docetaxel; effective therapy; efflux pump; follow-up; improved; in vivo; innovation; malignant breast neoplasm; novel; novel therapeutics; optimal treatments; pharmacophore; pre-doctoral; refractory cancer; relapse patients; resistance mechanism; response; targeted agent; targeted delivery; targeted treatment; taxane; tool; trafficking; tumor; tumor progression

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.

项目总结/摘要 卵巢癌（OvCa）具有总体不良预后，部分原因是在卵巢癌发生时的高转移率。 诊断和很少有针对性的治疗选择。微管靶向药物（MTA），包括紫杉烷 紫杉醇（PTX）是用于治疗女性癌症的一些最有效的药剂，包括 乳腺癌和卵巢癌虽然PTX在治疗的初始阶段通常是有效的，但发展中国家的治疗效果不佳。 耐药性是长期抗癌功效的重要限制。MTA被统称为 抗有丝分裂剂;然而，这类不同的药物对致癌信号传导表现出不同的作用。 具有显着差异的途径，特别是在微管稳定剂（如PTX）和 微管去稳定剂，如长春花生物碱。此外，还有机会开发新的 可以规避紫杉烷耐药机制的MTA类别，包括 药物外排转运蛋白的上调。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，以及鉴定 可用于指导临床验证的不同药物之间更合理的选择， 机制上多样化的药物类别，将为紫杉烷耐药OvCa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，生物信息学和生物信息学相结合的方法。 体外和体内癌症药理学，以确定不同MTA靶向使用的关键决定因素， 治疗耐药OvCa（F99期）。我将检验这样一个假设， 微管稳定剂将在局部播散的紫杉烷耐药OvCa模型中保持功效。而且我 Septin 9亚型1（Sept9_i1）癌基因在肿瘤细胞中的差异定位， 用微管稳定剂和去稳定剂处理，以检验Sept9_i1可以作为微管稳定剂的假设。 这些药物的差异反应的生物标志物，特别是在EGFR驱动的乳腺癌和OvCas。在 K 00阶段，我将把我的培训扩展到代谢紊乱领域，以阐明 OvCa中脂肪细胞介导的紫杉烷抗性的机制。我将建立在证明PTX的研究上 由于其直接激活炎性TLR 4信号传导的能力，促进脂肪细胞中IL-8的产生 并测试以下假设：不激活TLR 4信号传导的结构上不同的MTA将 在体外和体内规避这种耐药机制，这可以用来提供更合理的信息。 在患有OvCa的女性亚群中使用特定的MTA。这项研究将利用一种有效的，但 机制低估，一类药物，以确定机制的紫杉烷耐药性， 将指导未来的治疗选择。F99/K 00机制提供的研究和职业培训 我将有机会顺利地从博士前研究过渡到博士后研究 并最终成为一名独立的研究人员，专注于女性癌症的耐药性。