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（由适用提供）：作为在中国接受过临床培训的临床培训，我对生物医学科学（尤其是基本和翻译的生物学）具有很长的兴趣，这是我的个人经历所造成的。首先，我的母亲是肾癌的生存，我堂兄的妻子死于胰腺癌。其次，当我的母亲去医院治疗她的后脑综合症以及我在中国的医院接受临床培训期间，我看到了患者或家人的焦虑，失去感，沮丧和害怕。第三，我绝望地记得：“无论我们做什么，我们将永远无法帮助像这样的家庭。”在接受了Pier Paolo Pandolfi博士的实验室和Ronald Depinho博士实验室的基本生物学方面进行了广泛的培训，我坚信，我们不仅应该更好地了解基本生物学生物学的基本生物学，而且还可以通过转化方法来弥合基本研究和临床医学之间的差距。拟议的研究是探索治疗前列腺癌的新型治疗机会，包括抗cast割前列腺癌（CRPC），通过探索前列腺肿瘤进展和抑制性抑制的肿瘤内部和 - 超支机制。特别是，我将专注于MDSC和肿瘤MDSCS串扰的生物学。前列腺癌（PCA）是美国男性中最常见的非外形恶性肿瘤，PCA的主要疗法是雄激素剥夺疗法，最终失败并导致CRPC的发展。我未发表的结果表明，缺乏PTEN和SMAD4的小鼠前列腺肿瘤不仅可以使用手术castration和enzalutamide抗药性，并具有综合的AR信号阻塞，这是最近经过批准的转移性CRPC的AR抑制剂。另外，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中和抗GR1中和抗体MDSC耗竭会导致肿瘤的显着回归。使用AIM1，我将在肿瘤进展过程中和对ADT的反应中表征MDSC。我还将通过使用MDSC的药理抑制和遗传耗竭来测试MDSC是否需要肿瘤进展。此外，我将测试MDSCS耗竭与ADT相结合提供长时间的治疗益处。在AIM 2中，我将进行分子分析和生物信息学分析，以阐明有关MDSCS-Tumor串扰的机械洞察力。我将探索针对MDSCS-tumor串扰的可能性，以治疗前列腺罐和cast割耐药性。因此，在AIM 3中，我将使用功能获得和功能丧失方法对从AIM 2确定的候选基因进行功能验证。此外，我将验证人类前列腺癌样品中从小鼠模型中鉴定出的基因，以用作生物标志物以及潜在的治疗靶标。从这个目标获得的信息将帮助我们这项拟议的研究将有助于我建立一项强大的研究计划，我将通过该计划在学术/医学研究机构中启动独立的教师职位。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，肿瘤微环境以及扩大我在癌症免疫疗法，致癌基因组学，生物统计学和转化生物学方面的技能方面的技术技能。就我的职业发展而言，我将致力于提高自己的技能，以管理实验室，心理的博士后和学生，科学写作和演讲，并寻求合作等，因为这些技能对我来说对于我担任教师职位并取得成功至关重要。 MD Anderson癌症中心（MDACC）和Ronald Depinho实验室为我提供了一个极好的培训环境，以实现这些目标。即使Depinho博士现在是MDACC的总裁，他仍然承诺为我的培训和职业发展投入2.5％的努力。我还成立了一个由Mien-Chie Huang博士和Giulio Draetta博士组成的非凡咨询委员会。他们不仅会为我的拟议研究提供技术支持，还可以指导我寻找教师职位，并成为独立研究者。在K99/R00培训补助金的帮助下，我将有一个良好的开端来实现我的长期目标，这将继续探索癌症生物学的基本和翻译问题，包括前列腺癌的进展和cast割抵抗，作为学术/医学研究所的实验室负责人，并通过与其他科学家公司合作发展新颖的癌症疗法。