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

基本信息

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
项目类别：
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

项目摘要

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/摘要 AR可能是已知最早的谱系癌基因的例子：细胞存活和生长的主要调节因子来自前列腺上皮的肿瘤细胞对其成瘾。认识到这一独特的功能，人们共同努力的重点是开发能够抑制 AR 信号传导的疗法。雄激素剥夺疗法 (ADT) 和 AR 通路信号抑制剂 (ARSI) 在广泛的人群中产生了显着的反应大多数患者患有转移性PC（mPC）。不幸的是，这些反应并没有伴随治疗，随着治疗耐药性的普遍发展。我们小组和其他人的研究已经确定越来越多的 mPCs 抵抗 AR 通路抑制，失去 AR 活性并获得一系列新的表型，每种表型都表现出侵袭性的临床病程，且治疗选择有限。流程肿瘤细胞在治疗压力下如何改变谱系尚不清楚。确定允许或驱动这种谱系可塑性的机制可能会确定新的治疗策略。该提案旨在解决 AR 通路抑制促进肿瘤的主要临床问题细胞的可塑性。我们将测试针对允许的表观遗传因素或谱系决定因素的假设与 AR 通路抑制一起将防止谱系重定向、延长总体反应率并治愈晚期前列腺癌的子集。目标 1. 确定促进传统 AR 谱系转换的关键决定因素和许可因素 AR 定向治疗后将前列腺癌推向新的表型。目标 2. 确定驱动或允许谱系规范的调节因素是否可以阻止、延迟或逆转对 AR 途径抑制的抵抗。目标 3. 确定在谱系背景中出现的重定向谱系是否具有共同目标特征转换将延长对 AR 通路抑制的反应。为了开发出能够充分解决这种新型恶性肿瘤的有效疗法，首先必须明确界定允许或推动血统转变的途径；该项目旨在阐明那些基本机制。