Targeting Vulnerabilities Exposed by Cancer Treatment-Induced Lineage Plasticity

针对癌症治疗引起的谱系可塑性暴露的脆弱性

• 批准号: 10343529
• 负责人: PETER S NELSON
• 金额: $ 40.26万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343529
• 关键词: Address; Adenocarcinoma; Aggressive Clinical Course; Androgen Receptor; Automobile Driving; BRAF gene; Biological Process; Carcinoma; Cell Lineage; Cell Survival; Cells; Characteristics; Clinical; Development; Drug Combinations; Environment; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelial; Exhibits; Gene Expression; Human; Lung; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mesenchymal Differentiation; Metastatic Prostate Cancer; Morphology; Neoplasm Metastasis; Oncogenes; Oncogenic; Pathway interactions; Patients; Pear; Phase; Phenotype; Process; Prostate; Receptor Signaling; Research Proposals; Resistance; Resistance development; Signal Pathway; Stress; Tars; Testing; Therapeutic; Tissues; Work; advanced prostate cancer; androgen deprivation therapy; cancer therapy; cell growth; design; epithelial to mesenchymal transition; inhibitor; melanoma; neoplastic cell; pressure; prevent; programs; receptor; response; stem cells; stem-like cell; therapeutic target; therapeutically effective; therapy development; therapy resistant; tissue repair; transdifferentiation; treatment strategy; tumor growth

SUMMARY/ABSTRACT The AR may be the earliest known example of a lineage oncogene: a master regulator of cell survival and growth to which neoplastic cells derived from prostate epithelium are addicted. Recognizing this unique feature, concerted efforts have focused on developing therapeutics capable of suppressing AR signaling. Androgen deprivation therapy (ADT) and AR pathway signaling inhibitors (ARSI) produce dramatic responses in the vast majority of patients with metastatic PC (mPC). Unfortunately, these responses are not accompanied by cures, with near universal development of treatment resistance. Studies from our group and others have determined that an increasing fraction of mPCs resisting AR pathway inhibition lose AR activity and gain a spectrum of new phenotypes, each of which exhibit an aggressive clinical course with limited treatment options. The processes by which tumor cells switch lineages under treatment pressure is not well understood. Determining the mechanisms that permit or drive this lineage plasticity may identify new treatment strategies. This proposal is designed to address a major clinical problem whereby AR pathway inhibition promotes tumor cell plasticity. We will test the hypothesis that targeting permissive epigenetic factors or lineage determinants together with AR pathway inhibition will prevent lineage-redirection, prolong response rates overall, and cure a subset of advanced prostate cancers. AIM 1. Identify the key determinants and permissive factors that promote a lineage switch from conventional AR- driven prostate cancer to new phenotypes following AR-directed treatment. AIM 2. Determine if modulating factors that drive or permit lineage specification can prevent, delay, or reverse resistance to AR pathway inhibition. AIM 3. Determine if co-targeting characteristics of re-directed lineages that emerge in the context of lineage switching will prolong responses to AR pathway inhibition. In order for effective therapeutics to be developed that can adequately address this new class of malignancy, the pathways permitting or driving lineage conversion must first be clearly defined; this project aims to elucidate those underlying mechanisms.

总结/摘要 AR可能是已知的最早的癌基因谱系的例子：细胞存活和生长的主要调节因子 来源于前列腺上皮的肿瘤细胞对其上瘾。认识到这一独特特征， 一致的努力集中于开发能够抑制AR信号传导的治疗剂。雄激素 剥夺疗法（ADT）和AR通路信号抑制剂（ARSI）在大量的 大多数转移性PC（mPC）患者。不幸的是，这些反应并没有伴随着治愈， 几乎普遍产生了治疗抗性。我们小组和其他人的研究已经确定 越来越多的抵抗AR通路抑制的mPCs失去了AR活性，并获得了一系列新的 表型，其中每一种表现出具有有限治疗选择的侵袭性临床过程。的过程 肿瘤细胞在治疗压力下如何转换谱系尚不清楚。确定 允许或驱动这种谱系可塑性的机制可以确定新的治疗策略。 该提议旨在解决一个主要的临床问题，即AR途径抑制促进肿瘤 细胞可塑性我们将检验这样一个假设，即靶向允许的表观遗传因素或谱系决定因素， 与AR通路抑制一起将防止谱系重定向，延长总体应答率，并治愈 晚期前列腺癌的亚组。 AIM 1.确定促进传统AR谱系转换的关键决定因素和许可因素- 在AR定向治疗后将前列腺癌驱动为新的表型。 AIM 2.确定驱动或允许世系规范的调节因素是否可以阻止、延迟或逆转 对AR途径抑制的抗性。 AIM 3.确定在谱系背景下出现的重定向谱系的共同靶向特征 转换将延长对AR途径抑制的反应。 为了开发能够充分解决这类新的恶性肿瘤的有效治疗方法， 允许或驱动血统转换的途径必须首先明确定义;该项目旨在阐明 这些潜在的机制。