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: 10650286
• 负责人: PETER S NELSON
• 金额: $ 39.45万
• 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/10650286
• 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; Drug Targeting; Environment; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelium; Exhibits; Gene Expression; Human; Invaded; Lung Adenocarcinoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mesenchymal Differentiation; Metastatic Prostate Cancer; Morphology; Neoplasm Metastasis; Oncogenes; Oncogenic; Pathway interactions; Patients; Phase; Phenotype; Process; Prostate; Receptor Signaling; Repression; Research Proposals; Resistance; Resistance development; Signal Pathway; Specific qualifier value; Stress; Testing; Therapeutic; Tissues; Tumor Promotion; Work; advanced prostate cancer; androgen deprivation therapy; cancer therapy; cell growth; design; epithelial to mesenchymal transition; inhibitor; melanoma; neoplastic cell; novel therapeutic intervention; permissiveness; pressure; prevent; programs; response; stem cell differentiation; stem-like cell; therapeutic target; therapeutically effective; therapy development; therapy resistant; tissue repair; transdifferentiation; 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.

摘要/文摘