MDSC-tumor crosstalk in prostate cancer progression and castration resistance

MDSC-肿瘤串扰在前列腺癌进展和去势抵抗中的作用

• 批准号: 9109989
• 负责人: Guocan Wang
• 金额: $ 10.44万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109989
• 关键词: Acute; Address; Advisory Committees; Androgens; Animals; Anxiety; Basic Science; Bioinformatics; Biological Assay; Biological Markers; Biology; Biometry; CTLA4 gene; Cancer Biology; Cancer Center; Cancer Immunology Science; Cancer Model; Cancer Patient; Candidate Disease Gene; Caring; Castration; Cell Communication; Cell physiology; Cells; China; Clinical; Clinical Medicine; Collaborations; Data; Development; Educational Curriculum; Environment; Event; Faculty; Family; Frustration; Genes; Genetic; Goals; Grant; Grief reaction; Head; Health; Hormones; Hospitals; Human; Immune; Immunity; Immunophenotyping; Immunosuppressive Agents; Immunotherapy; In Vitro; Infiltration; Institution; Laboratories; Lead; Light; Luciferases; Maintenance Therapy; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Medical Research; Membrane Proteins; Mentors; Modeling; Molecular; Molecular Profiling; Monitor; Mothers; Mus; Myelogenous; Myeloid Cells; Myeloproliferative disease; Neoplasm Metastasis; Pathway interactions; Patients; Pharmacologic Substance; Physicians; Play; Population; Population Heterogeneity; Positioning Attribute; Postdoctoral Fellow; Postphlebitic Syndrome; Predictive Factor; Prostate; Prostate Cancer therapy; Prostate carcinoma; Prostatic Neoplasms; Proteomics; Renal carcinoma; Reporter; Research; Research Institute; Research Personnel; Resistance; Role; Sampling; Science; Scientist; Signal Transduction; Staging; Students; Suppressor-Effector T-Lymphocytes; Technical Expertise; Terminally Ill; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Effect; Training; Translating; United States; Validation; Wife; Writing; angiogenesis; cancer genomics; cancer immunotherapy; cancer therapy; career development; castration resistant prostate cancer; cohort; deprivation; experience; gain of function; genetic signature; improved; in vivo; inhibitor/antagonist; insight; interest; loss of function; men; mouse model; neutralizing antibody; non-invasive imaging; novel; novel therapeutic intervention; novel therapeutics; preclinical trial; prognostic; programs; response; skills; standard of care; stem; therapeutic development; therapeutic target; therapy resistant; transcriptome sequencing; translational approach; tumor; tumor growth; tumor microenvironment; tumor progression

 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.

 描述（由申请人提供）：作为一名在中国接受培训的临床医生，我对生物医学科学有着长期的兴趣，特别是基础和转化生物学，这源于我的个人经历。首先，我的母亲是肾癌的幸存者，而我表妹的妻子死于胰腺癌。第二，在陪同母亲到医院治疗静脉炎后综合征和在中国医院进行临床培训期间，我看到了患者或家人的焦虑、失落感、沮丧和悲伤。第三，我绝望地记得，“无论我们做什么，我们永远无法帮助这样的家庭”在我的临床课程中照顾绝症患者。在Pier Paolo Pandolfi博士的实验室和罗纳德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理解癌症生物学的基础生物学，而且应该奋进使用转化方法弥合基础研究和临床医学之间的差距。拟定研究旨在通过探索前列腺肿瘤进展和去势抵抗的肿瘤内在和外在机制，探索治愈前列腺癌（包括去势抵抗性前列腺癌（CRPC））的新治疗机会。特别地，我将专注于MDSC的生物学和肿瘤-MDSC串扰。前列腺癌（PCa）是美国男性中最常见的非皮肤恶性肿瘤，PCa的主要治疗是雄激素剥夺治疗，最终失败并导致CRPC的发展。我未发表的结果表明，Pten和Smad 4缺陷的小鼠前列腺肿瘤不仅对手术去势和使用手术去势加Enzalutamide（一种最近批准用于转移性CRPC的AR抑制剂）的全面AR信号传导阻断具有抗性。此外，MDSC是肿瘤内浸润的免疫细胞中的主要亚群，并且在我们的小鼠模型中抗Gr 1中和抗体MDSC消耗导致肿瘤的显著消退。因此，我建议在我们的小鼠模型中研究MDSC在前列腺肿瘤进展和去势抵抗中的作用。利用Aim 1，我将描述肿瘤进展期间和ADT应答中的MDSC。我还将通过使用MDSC的药理学抑制和遗传耗竭来测试MDSC是否是肿瘤进展所必需和足够的。此外，我将测试MDSC消耗与ADT组合是否提供长期的治疗益处。在目标2中，我将进行分子分析和生物信息学分析，以阐明MDSC-肿瘤串扰的机制。因此，我将探索靶向MDSC-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，我将首先在多个测定中使用功能获得和功能丧失方法对目标2中鉴定的候选基因进行功能验证。此外，我将验证在人类前列腺癌样本中从我们的小鼠模型中鉴定的基因，以确定它们作为生物标志物和潜在治疗靶点的潜力。从这个目标获得的信息将帮助我们这个拟议的研究将帮助我形成一个强大的研究计划，我将推出一个独立的教师职位在学术/医学研究机构。为此，我的近期目标是继续提高我在小鼠遗传学，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，生物统计学和转化生物学方面的技能。在我的职业发展方面，我将致力于提高我在管理实验室，指导博士后和学生，科学写作和演讲以及寻求合作等方面的技能，因为这些技能对我获得教师职位并成功成为PI至关重要。MD安德森癌症中心（MDACC）和罗纳德德平霍实验室为我实现这些目标提供了极好的培训环境。尽管DePinho博士现在是MDACC的总裁，他仍然承诺将投入2.5%的精力用于我的培训和职业发展。我还成立了一个特别顾问委员会，由黄绵琦博士和朱利奥·德雷塔博士组成。他们不仅为我的研究提供技术支持，还指导我寻找教师职位，并成为一名成功的独立研究者。在K99/R 00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，即继续探索癌症生物学中的基本和转化问题，包括前列腺癌进展和去势抵抗，作为学术/医学研究机构的实验室负责人，并通过与其他科学家合作，作为团队成员开发新的癌症疗法，医生和制药公司。