11 Prostate Cancer

项目摘要/摘要 前列腺癌计划(PCAP)由50名成员组成(30名初级成员，18名助理成员，2名附属成员)，来自16个 各部门。该项目由国际公认的医生克里斯托弗·J·洛戈蒂斯博士领导 由实验室科学家蒂莫西·C·汤普森博士和菲利波·詹科蒂博士共同领导。 成就卓著的内科医生兼科学家。PCAP的主要科学目标是建立在我们对 开发更有效的前列腺癌治疗方法，提高护理水平。该计划是有组织的 围绕三个主题：1)进展和预测的生物标记物；2)针对免疫和非免疫 微环境的组成部分，包括免疫成分；以及3)靶向癌细胞信号。 每个主题都有一个特定的目标。目的1：开发血液、尿液和肿瘤组织的新检测方法 预测肿瘤复发、进展以及对现有和新的治疗方法的敏感性或抵抗力。目标2： 了解肿瘤细胞与宿主的相互作用，并将这一知识转化为新的 针对微环境的治疗方法。目标3：靶向前列腺癌细胞信号转导 新型单一药剂和顺序或同时使用的药剂组合。年度直接同行- 审查后的资助总额为3,693,347美元，其中包括前列腺癌孢子，2,204,086美元(60%)来自NCI 资助金。自上次提交以来，该计划已发表了350篇论文，其中183篇(52%)是内部- 方案方面，112个(32%)是方案间的，245个(70%)是外部协作。49% 20%的论文发表在IF&>5的期刊上，23%的文章出现在IF&>10的期刊上，包括癌症细胞， 柳叶刀，美国，自然，N Engl J医学，细胞，NAT Genet，J Natl癌症研究所，科学翻译 Med和J Clin Oncol.计划成员使用所有14个共享资源。在过去的6年里，PCAP有1) 已发现的预测对第二代病毒的反应性或初始/获得性耐药性的生物标志物 雄激素受体信号转导抑制剂；2)识别与“侵袭性变异”前列腺癌相关的生物标记物 临床和联合临床模型中预测铂类药物疗效的癌症表型；3) 前列腺癌已发现的免疫治疗靶点(如Vista)表达在T细胞和抗原上- 呈递细胞，包括巨噬细胞；4)带有免疫检查点的髓系来源的抑制细胞 前列腺癌的阻滞性；5)确定成纤维细胞生长因子是前列腺癌的靶点，提供了一种机制 对VEGFR和c-met抑制剂Cabozantinib的作用；6)阐明了 PI3K/AKT/mTOR信号通路在前列腺癌靶向治疗中的作用 癌症对雄激素抑制剂调节的PARP抑制剂的易感性；和8)确定 肿瘤诱导内皮细胞向具有成骨功能的细胞转化及其与骨的结合 转移瘤。

PROJECT SUMMARY/ABSTRACT The Prostate Cancer Program (PCaP) consists of 50 members (30 primary, 18 associate, 2 adjunct) from 16 departments. The program is led by Dr. Christopher J. Logothetis, an internationally recognized medical oncologist, and co-led by Drs. Timothy C. Thompson, a laboratory scientist, and Filippo Giancotti, an accomplished physician-scientist. The major scientific goal of the PCaP is to build on our understanding of prostate cancer to develop more effective treatment and improve standard of care. The program is organized around 3 themes: 1) Biomarkers for Progression and Prediction; 2) Targeting the Immune and Non-immune Components of the Microenvironment, including the immune component; and 3) Targeting Cancer Cell Signaling. Each theme is addressed by a specific aim. Aim 1: To develop new tests from blood, urine, and tumor tissues that predict tumor recurrence, progression, and sensitivity or resistance to existing and novel therapies. Aim 2: To understand tumor cell-host interactions and translate this knowledge into the development of novel therapeutic approaches targeting the microenvironment. Aim 3: To target prostate cancer cell signaling with novel single agents and with combinations of agents used sequentially or concurrently. The annual direct peer- reviewed funding totals $3,693,347, including a Prostate Cancer SPORE, and $2,204,086 (60%) is from NCI grants. Since the last submission, the program has authored 350 published papers, of which 183 (52%) are intra- programmatic, 112 (32%) are inter-programmatic, and 245 (70%) are external collaborations. Forty-nine percent of publications appeared in journals with IF >5 and 23% appeared in journals with IF >10, including Cancer Cell, Lancet Oncol, Proc Natl Acad Sci USA, Nature, N Engl J Med, Cell, Nat Genet, J Natl Cancer Inst, Sci Transl Med, and J Clin Oncol. Program members use all 14 shared resources. Over the past 6 years, the PCaP has 1) discovered biomarkers that predict responsiveness or initial/acquired resistance to the second-generation androgen receptor signaling inhibitors; 2) identified biomarkers associated with the “aggressive variant” prostate cancer phenotype that predict response to platinum-based combinations in clinical and co-clinical models; 3) discovered immunotherapy targets in prostate cancer (e.g., VISTA) that are expressed on T cells and antigen- presenting cells, including macrophages; 4) linked myeloid-derived suppressor cells with immune checkpoint blockade resistance in prostate cancer; 5) identified FGF as a target in prostate cancer, providing a mechanism of action for the VEGFR and c-met inhibitor cabozantinib; 6) elucidated the impact of cross-talk between PI3K/AKT/mTOR signaling in regulating efficacy of targeted therapy for prostate cancer; 7) identified prostate cancer vulnerability to PARP inhibitors regulated by androgen inhibitor-mediated BRCAness; and 8) identified cancer-induced transition of endothelial cells to cells with osteoblastic function and associated them with bone metastases.