Investigation of luminal stem cells and castration resistance in prostate cancer

 描述(申请人提供)：晚期前列腺癌的主要治疗方法是雄激素剥夺疗法，但大多数最初对治疗有反应的前列腺癌最终变得去势抵抗和复发。这项K99/R00提案的重点是了解雄激素剥夺对前列腺干细胞/祖细胞和肿瘤增殖细胞的影响。沈实验室之前的研究已经在正常退化的成年小鼠前列腺中发现了Nkx3.1表达腔干细胞群(CANS)，可以作为前列腺癌的起源细胞。新的初步数据表明，在发育中的前列腺中也可以发现CANS，这是一个循环雄激素有限的环境，因此是研究去势抵抗和前列腺细胞分化潜力和可塑性的理想系统。这一应用是基于一个中心假设，即正常发育的前列腺腔内干细胞具有预先确定的在雄激素剥夺后存活的能力，前列腺癌也包含对雄激素剥夺具有预先存在抵抗的肿瘤增殖细胞。我建议使用遗传谱系追踪和体外培养方法研究干细胞和肿瘤增殖细胞的特性，具体目的如下：(1)分析无雄激素信号的前列腺癌前体细胞(K99期)；(2)分析前列腺癌中的肿瘤增殖细胞及其对雄激素剥夺的反应(K99和R00期)；(3)研究去势耐药前列腺癌(R00期)肿瘤生长的分子驱动因素。这些研究旨在扩大我们对去势抵抗干细胞在正常前列腺和肿瘤中的异同的理解，并为控制对雄激素剥夺的内在抵抗的分子机制提供见解。这些信息对于理解激素剥夺疗法失败的原因，以及开发更好的抗去势前列腺癌治疗方法将是重要的。如果成功，这些研究可能导致识别新的去势抵抗机制，这些机制可以转化为区分惰性和侵袭性前列腺癌和前列腺癌治疗的生物标记物。我的长期职业目标是在一家学术机构建立一个独立的实验室，并进行基础科学研究，以解决与干细胞和细胞分化在癌症起始和复发中的基本问题。目前的目标是开发一个有竞争力的独立研究项目，并获得更多的癌症研究和翻译研究经验。我提出的关于抗去势前列腺癌肿瘤传播的新基因和新途径的研究，应该能让我与我的导师区分开来。

 DESCRIPTION (provided by applicant): The mainstay of treatment for advanced prostate cancer is androgen deprivation therapy, but most prostate cancers that initially respond to treatment ultimately become castration resistant and recur. The focus of this K99/R00 proposal is on understanding how prostate stem/progenitor cells and tumor propagating cells are affected by androgen deprivation. Previous studies from the Shen lab have identified a Nkx3.1 expressing luminal stem cell population (CARNs) in the normal regressed adult mouse prostate that can act as a cell of origin for prostate cancer. New preliminary data suggests that CARNs can also be found in the developing prostate, which is an environment with limited circulating androgens, and thus an ideal system to study castration resistance and the differentiation potential and plasticity of prostate cells. This application is based on the central hypothesis tht luminal stem cells in normal developing prostates have a predetermined ability to survive androgen deprivation, and that prostate cancers also contain tumor propagating cells with preexisting resistance to androgen deprivation. I propose to investigate the properties of stem cells and tumor propagating cells using genetic lineage tracing and ex vivo culture approaches with the following specific aims: (1) Analysis of prostate progenitor cells in the absence of androgen signaling (K99 phase), (2) Analysis of tumor propagating cells in prostate tumors and their response to androgen deprivation (K99 and R00 phases), and (3) Investigation of molecular drivers of tumor propagation in castration resistant prostate cancer (R00 phase). These studies are designed to expand our understanding of the differences and similarities between castration resistant stem cells in normal prostates and in tumors, and provide insights into the molecular mechanisms controlling intrinsic resistance to androgen deprivation. Such information will be important for understanding why hormone deprivation therapies fail, and for developing better treatments for castration resistant prostate cancers. If successful, these studies could lead to the identification of new mechanisms for castration resistance that could be translated to biomarkers for distinguishing indolent and aggressive prostate cancers and prostate cancer treatments. My long-term career goal is to establish an independent laboratory at an academic institution and conduct basic scientific research to address fundamental questions related to stem cells and cellular differentiation in cancer initiation and recurrence. M immediate goal is to develop a competitive independent research program and gain additional cancer research and translational research experience. My proposed studies of novel genes and pathways involved in tumor propagation in castration resistant prostate cancer should allow me to distinguish myself from my mentor.