15 Developmental Therapeutics

项目总结/摘要 发展治疗学项目（DTP）的中心主题是实践精确性原则 治疗，在恶性肿瘤的病理生理学中鉴定新靶点，以开发阻断肿瘤的新药物。 它们的功能，并将这些药物应用于恶性肿瘤显示生物标志物的患者的临床试验 表明靶蛋白或靶途径的存在或活性。该计划有47个成员（33个主要成员）， 和14名助理）来自13个部门，并由威廉普朗基特，谁开发了多个反， 白血病药物在实验室; Funda Meric-Bernard，一位领导第一阶段研究的物理学家， Giulio Draetta，一位在药物开发方面拥有丰富经验的医生科学家;以及 James Yao是一位临床试验者，他开发了多种靶向疗法。该计划是围绕 4大主题：1）新靶点的发现和验证，2）新疗法的开发，3）行为 原则性临床试验的证明，以及4）罕见癌症治疗的开发。每个主题都是 有具体的目标。目的1：鉴定和验证与肿瘤细胞分子生物学相关的新靶点。 目标2：开发单独和联合治疗中针对新靶点的药物;目标3： 用首次用于人类的药物或新的组合进行生物标志物驱动的试验;以及目标4： 治疗罕见肿瘤年度直接同行评审资金总额为10，284，482美元，其中2，839，686美元（28%） 来自NCI赠款，这是计划年度直接同行评审癌症相关资金的109% 自从上次竞争性续约以来。自上次提交以来，DTP成员已撰写了1048篇出版物： 454项（43%）为方案内合作，681项（65%）为方案间合作， 645项（62%）是机构间合作。59%的出版物出现在期刊上， IF >5的期刊占23%，IF >10的期刊包括Blood、Cancer Cell、Cancer Discov、Cell、JAMA、J Clin Invest、J Natl Cancer Inst、J Clin Oncol、Lancet、Lancet Oncol、Mol Cell和Nature。在上一次赠款期间 在此期间，发现了几个新的靶点，包括肺癌中的miR-155，S期激酶相关的 蛋白2泛素连接酶，以及依赖氧化磷酸化生存的肿瘤易感性。 重要的是，DTP成员已经发现了抑制这些靶点中的每一个的新型药物，并且正在开发中。 目前正在开发中。新的药物包括那些靶向miR-155，缺乏症，铂输出者， 卵巢癌、淋巴瘤中的BLy 3、c-Kit、JAK 2和STAT 3。DTP成员已经确定了需要 氧化磷酸化对它们的生长起重要作用，并且已经产生了一种候选抑制剂，目前正在进行临床试验。 与PI 3 K通路中激活突变相匹配的药物将1期缓解率从6%增加到27% 并延长了治疗失败前的时间。2011年首次化疗免疫治疗试验的15年分析 先前未治疗的CLL揭示了与该疾病的首次治愈相关的预后因素（37%）， 指导设计纳入新靶向药物的单机构药物启动试验。

PROJECT SUMMARY/ABSTRACT The central theme of the Developmental Therapeutics Program (DTP) is to practice the principles of precision therapy, identifying new targets within the pathophysiology of a malignancy to develop novel agents that block their functions and apply these agents to clinical trials in patients whose malignancies exhibit the biomarkers signifying the presence or activity of the target protein or pathway. The program has 47 members (33 primary and 14 associate) from 13 departments and is led by William Plunkett, who has developed multiple anti- leukemic agents in the laboratory; Funda Meric-Bernstam, a physician-scientist who leads the phase 1 department; Giulio Draetta, a physician-scientist who has extensive experience in drug development; and James Yao, a clinical trialist who has developed multiple targeted therapies. The program is organized around 4 major themes: 1) Discovery and Validation of Novel Targets, 2) Development of Novel Therapies, 3) Conduct of Proof-of-Principle Clinical Trials, and 4) Development of Therapies for Rare Cancers. Each theme is addressed by a specific aim. Aim 1: To identify and validate novel targets relevant to the molecular biology of tumors; Aim 2: To develop agents against new targets individually and in combination therapies; Aim 3: To conduct biomarker-driven trials with first-in-human agents or novel combinations; and Aim 4: To identify novel therapies for rare tumors. Annual direct peer-reviewed funding totals $10,284,482, of which $2,839,686 (28%) is from NCI grants, which is an increase of 109% in program annual direct peer-reviewed cancer-related funding since the last competitive renewal. Since the last submission, DTP members have authored 1048 publications: 454 (43%) represent intra-programmatic collaborations, 681 (65%) represent inter-programmatic collaborations, and 645 (62%) were inter-institutional collaborations. Fifty-nine percent of publications appeared in journals with IF >5, and 23% appeared in journals with IF >10, including Blood, Cancer Cell, Cancer Discov, Cell, JAMA, J Clin Invest, J Natl Cancer Inst, J Clin Oncol, Lancet, Lancet Oncol, Mol Cell, and Nature. During the last grant period, several novel targets were identified, including miR-155 in lung cancer, S-phase kinase-associated protein 2 ubiquitin ligase, and the susceptibility of tumors that depend on oxidative phosphorylation for survival. Importantly, novel agents to inhibit each of these targets have been discovered by DTP members and are currently in development. New agents include those that target miR-155, deficiency, the platinum exporter in ovarian cancer, BLy3 in lymphoma, c-Kit, JAK2, and STAT3. DTP members have identified tumors that require oxidative phosphorylation for their growth and have created a candidate inhibitor that is presently in clinical trials. Drugs matched with activating mutations in the PI3K pathway increased phase 1 response rates from 6% to 27% and increased the time before treatment failure. The 15-year analysis of the first chemoimmunotherapy trial in previously untreated CLL revealed prognostic factors associated with the first cures of this disease (37%), guiding the design of single-institution investigator-initiated trials that incorporate new targeted agents.