Improving targeted therapy for women's cancers

改善女性癌症的靶向治疗

• 批准号: 10305148
• 负责人: Samantha Yee
• 金额: $ 3.68万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305148
• 关键词: ABCB1 gene; Actins; Adipocytes; Agonist; Antimitotic Agents; Arachidonic Acids; Area; Binding; Bioinformatics; Biological Markers; Breast Cancer Model; Breast Cancer Treatment; Cancer Model; Cancer Prognosis; Chronic; 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; Microtubule Stabilization; Microtubules; Modeling; Molecular; Molecular and Cellular Biology; Mus; N-terminal; Neoplasm Metastasis; Obesity; Omentum; Oncogenes; Oncogenic; Paclitaxel; Patients; Peritoneum; Pharmaceutical Preparations; Phase; Process; Production; Prognosis; Protein Isoforms; Research; Research Personnel; Resistance; Resistance development; Signal Pathway; Signal Transduction; Solid Neoplasm; Specificity; Structure; 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

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.

项目摘要/摘要 卵巢癌（OVCA）的总体预后不良部分，部分原因是在 诊断和少数有针对性的治疗选择。微管靶向剂（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物，包括 乳房和卵子。尽管PTX通常在治疗的初始阶段有效，但发展 抵抗是长期抗癌效率的重要限制。 MTA共同归类为 抗魔法剂；但是，该类别的不同药物对致癌信号的影响有明显的影响 在微管稳定器（如PTX）和 微管稳定器，例如Vinca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 药物外输运蛋白的上调。我假设微管稳定剂的发展是 规避紫杉烷耐药性的临床相关机制，以及对生物标志物的识别 可以用来指导该临床验证的不同代理之间的更合理的选择， 机械上多样的药物将为抗紫杉烷耐药的OVCA患者提供改进的选择。 为了完成论文，我将结合分子和细胞生物学，生物信息学以及 体外和体内癌症药理学，以确定针对性使用不同MTA的关键决定剂 耐药OVCA的处理（F99期）。我将检验以下假设： 微管稳定器将保持局部耐紫外线抗紫外线的OVCA型号的易于放松。另外，我 将跟进Septin 9同工型1（sept9_i1）癌基因的发现。 用微管稳定剂和破坏稳定器来检验sept9_i1可以用作的假设 对这些药物的不同反应的生物标志物，特别是在EGFR驱动的乳房和卵子中。在 k00阶段，我将把训练扩展到代谢障碍区域，以阐明分子 OVCA中脂肪细胞介导的紫杉烷耐药的机理。我将基于证明PTX的研究 由于其能够直接激活炎症TLR4信号传导，因此促进脂肪细胞中的IL-8产生 途径并检验以下假设：未激活TLR4信号的结构上不同的MTA将会 在体外和体内规避这种抗性机制，可以用来告知更理性的 在OVCA女性子集中使用特定的MTA。拟议的研究将利用有效，但 从机械上讲，药物类别以确定基本抗紫杉烷耐药性的机制 将指导未来的治疗选择。该F99/K00机制提供的研究和职业培训 将为我提供一个机会，可以平稳地从我的研究前研究过渡到博士后奖学金 最终，进入独立调查员，专注于女性癌症的药物抗药性。