MDSC-tumor crosstalk in prostate cancer progression and castration resistance

 简介(申请人提供)：作为一名中国培训的临床医生，我对生物医学科学，特别是基础生物学和翻译生物学有着长期的兴趣，这源于我的个人经验。首先，我的母亲是肾癌的幸存者，我表弟的妻子死于胰腺癌。第二，我在陪同母亲去医院治疗她的静脉后综合征时，以及在中国医院的临床培训期间，看到了患者或家人的焦虑、失落、沮丧和悲伤。第三，我绝望地记得，在我的临床课程中，在照顾绝症患者时，“无论我们做什么，我们都永远无法帮助这样的家庭”。在Pier Paolo Pandolfi博士的实验室和Ronald DePinho博士的实验室接受了广泛的基础生物学培训后，我坚信我们不仅应该更好地了解癌症生物学背后的基础生物学，而且还应该努力使用翻译方法来弥合基础研究和临床医学之间的差距。本研究旨在通过探讨前列腺癌进展和去势抵抗的内在和外在机制，探索治疗前列腺癌的新途径，包括去势抵抗前列腺癌(CRPC)。我将特别关注MDSCs的生物学和肿瘤-MDSCs的串扰。前列腺癌(PCa)是美国男性最常见的非皮肤恶性肿瘤，目前对前列腺癌的主要治疗方法是去雄激素治疗，最终失败并导致慢性前列腺癌的发生。我未发表的结果表明，缺乏Pten和Smad4的小鼠前列腺癌不仅对手术去势和全面的AR信号阻断产生抵抗力，而且使用手术去势加上恩扎鲁胺，恩扎鲁胺是最近批准的一种治疗转移性CRPC的AR抑制剂。此外，MDSCs是肿瘤内浸润性免疫细胞中的主要亚群，在我们的小鼠模型中，抗Gr1中和抗体MDSCs的耗尽会导致肿瘤的急剧消退。因此，我建议在我们的小鼠模型中研究MDSCs在前列腺癌进展和去势抵抗中的作用。在Aim1中，我将描述MDSCs在肿瘤进展和对ADT的反应中的特征。我还将通过药物抑制和MDSCs的基因缺失来测试MDSCs是否对肿瘤进展是必要的和充分的。此外，我将测试MDSCs耗竭联合ADT是否提供了长期的治疗益处。在目标2中，我将进行分子图谱和生物信息学分析，以阐明MDSCs-肿瘤串扰的机制。因此，我将探索靶向MDSCs-肿瘤串扰以治疗前列腺癌和去势抵抗的可能性。因此，在目标3中，我将首先在多次分析中使用功能获得和功能损失方法对从目标2中识别的候选基因进行功能验证。此外，我将在人类前列腺癌样本中验证从我们的小鼠模型中识别的基因是否有可能用作生物标记物和潜在的治疗靶点。从这一目标获得的信息将帮助我们这项拟议的研究将帮助我形成一个强大的研究计划，在这个计划中，我将在学术/医学研究机构中担任一个独立的教员职位。为此，我的眼前目标是继续磨练我在小鼠遗传学、癌症免疫学、肿瘤微环境方面的技术技能，并扩大我在癌症免疫治疗、肿瘤基因组学、生物统计学和翻译生物学方面的技能。在我的职业发展方面，我将致力于提高我在实验室管理、指导博士后和学生、科学写作和演示以及寻求合作等方面的技能，因为这些技能都是我获得教员职位并作为PI成功的必备技能。安德森癌症中心(MDACC)和罗纳德·德皮尼奥实验室为我实现这些目标提供了一个极好的培训环境。即使DePinho博士现在是MDACC的总裁，他仍然承诺将2.5%的精力投入到我的培训和职业发展中。我还成立了一个由黄绵杰博士和朱利奥·德拉塔博士组成的特别咨询委员会。他们不仅将为我提议的研究提供技术支持，而且还将指导我寻找教员职位，并作为一名独立调查员取得成功。在K99/R00培训基金的帮助下，我将有一个良好的开端来实现我的长期目标，即作为学术/医学研究机构的实验室负责人，继续探索癌症生物学中的基本和翻译问题，包括前列腺癌进展和去势抵抗，并通过与其他科学家、医生和制药公司的合作，作为团队成员为开发新型癌症疗法做出贡献。

 DESCRIPTION (provided by applicant): As a clinician trained in China, I have a long stand interests in biomedical sciences, particularly basic and translational biology, which are stemmed from my personal experiences. First, my mother is a survival of renal carcinoma and my cousin's wife died from pancreatic cancer. Second, I had seen anxiety, sense of loss, frustration, and grief from patients or family when accompanying my mother to the hospital for treatment of her Postphlebitic syndrome and during my clinical training in hospitals in China. Third, I remembered despairingly that "whatever we do, we're never going to be able to help families like that" in the caring of terminally ill patients in my clinical curriculum. After receiing extensive training in basic biology, both in Dr. Pier Paolo Pandolfi's lab and Dr. Ronald DePinho's lab, I strongly believe that we should not only have a better understanding the basic biology underlying cancer biology, but also make an endeavor to bridge the gap between the basic research and clinical medicine using the translational approach. The proposed study is to explore novel therapeutic opportunities to cure prostate cancer, including castration resistant prostate cancer (CRPC) by explore the tumor-intrinsic and -extrinsic mechanism underlying prostate tumor progression and castration resistance. Particularly, I will focus on biology of MDSCs and the tumor- MDSCs crosstalk. Prostate cancer (PCa) is the most common noncutaneous malignancy in men in the United States and the mainstay therapy for PCa is androgen deprivation therapy, which ultimately failed and results in the development of CRPC. My unpublished results shows that mouse prostate tumors deficient for Pten and Smad4 not only became resistant to surgical castration and a comprehensive AR signaling blockage using surgical castration plus Enzalutamide, a recently approved AR inhibitor for metastatic CRPC. In addition, MDSCs are the predominant sub-population in the intratumoral infiltrated immune cells and anti-Gr1 neutralizing antibody MDSCs depletion in our mouse model lead to a dramatic regression of tumors. Thus I propose to study the role of MDSCs in prostate tumor progression and castration resistance in our mouse model. With Aim1, I will characterize the MDSCs during tumor progression and in the response to ADT. I will also test whether MDSCs are necessary and sufficient for tumor progression by using pharmacological inhibition and genetic depletion of MDSCs. Moreover, I will test whether MDSCs depletion in combination with ADT provides a prolonged therapeutic benefit. In Aim 2, I will perform molecular profiling and bioinformatic analysis to shed light on the mechanistic insight on the MDSCs-tumor crosstalk. Thus I will explore the possibility to target the MDSCs-tumor crosstalk in order to treat prostate caner and castration resistance. So in Aim 3, I will first perform functional validations of the candidate genes identified from Aim 2 using gain-of- function and loss-of-function approaches in multiple assays. Furthermore, I will validate the genes identified from our mouse model in human prostate cancer samples for their potential used as biomarkers as well as potential therapeutic targets. The information obtained from this aim will help us This proposed study would help me to form a strong research program, with which I will launch an independent faculty position in an academic/medical research institution. To that end, my immediate goals are to continue sharpening my technical skills in mouse genetics, cancer immunology, tumor microenvironment and expanding my skills in cancer immunotherapy, oncogenomics, biostatistics and translational biology. In terms of my career development, I will devote to improve my skills on managing lab, mentoring postdocs and students, scientific writing and presentation, and seeking for collaborations, among others, because these skills are all essential for me to land a faculty position and succeed as a PI. MD Anderson Cancer Center (MDACC) and the Ronald DePinho laboratory provide an excellent training environment for me to achieve these goals. Even though Dr. DePinho is President of MDACC now, he still promises to devote 2.5% effort to my training and career development. I have also formed an extraordinary advisory committee composed of Dr. Mien-Chie Huang, and Dr. Giulio Draetta. They will not only provide me technical support for my proposed study, but also guide me to look for a faculty position and succeed as an independent investigator. With the help of K99/R00 training grant, I will have a good start to achieve my long term goals, which are to continue exploring basic and translational problems in cancer biology, including prostate cancer progression and castration resistance, as a lab head in an academic/medical research institute and to contribute to developing novel cancer therapies as a team player by collaborating with other scientists, physicians and pharmaceutical companies.