Targeting Vulnerabilities Exposed by Cancer Treatment-Induced Lineage Plasticity

摘要/摘要 AR可能是已知的最早的谱系癌基因：细胞生存和生长的主要调节因子 来自前列腺上皮的肿瘤细胞对其上瘾。认识到这一独特的特征， 共同努力的重点是开发能够抑制AR信号的疗法。雄激素 剥夺疗法(ADT)和AR通路信号抑制物(ARSI)在大范围内产生戏剧性反应 转移性前列腺癌(MPC)患者居多。不幸的是，这些反应并没有伴随着治疗， 治疗耐药性的发展几乎是普遍的。我们小组和其他人的研究已经确定 越来越多的抵抗AR途径抑制的MPC失去AR活性，并获得一系列新的 每种表型都表现出侵袭性的临床病程和有限的治疗选择。这些过程 肿瘤细胞在治疗压力下如何转换谱系还不是很清楚。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。 这项建议旨在解决AR途径抑制促进肿瘤的一个主要临床问题 细胞可塑性。我们将测试以允许的表观遗传因素或血统决定因素为目标的假设 再加上AR途径的抑制，将防止谱系重定向，延长总体应答率，并治愈A 晚期前列腺癌的子集。 目标1.确定关键决定因素和允许因素，促进从传统AR- 导致前列腺癌在AR导向治疗后出现新的表型。 目标2.确定驱动或允许血统规范的调节因素是否可以防止、延迟或逆转 对AR途径抑制的抗性。 目标3.确定在谱系背景下出现的重定向谱系的共同靶向特征 转换会延长对AR通路抑制的反应。 为了开发能够充分解决这种新类型的恶性肿瘤的有效疗法， 允许或驱动宗族转换的途径必须首先明确定义；本项目旨在阐明 这些潜在的机制。

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.