INTEGRATED ASSESSMENT OF NOVEL THERAPIES IN ONCOLOGY

该K-24补助金提案的目的是为主要研究者提供必要的支持，以指导学员开展以患者为导向的临床研究，将新型癌症疗法的早期临床试验与实验室相关研究联系起来。 受训者的临床研究将由首席研究员监督，实验室研究将由该领域的基础科学家监督。 在该补助金下进行的研究项目将涉及开发和使用实验室模型，以指导临床试验设计，并建立实验室测定，以测量临床试验过程中收集的组织和血浆样本的治疗干预的影响。 提供了两个例子。 其中一项涉及测量用新型基质金属蛋白酶抑制剂治疗的患者队列中肿瘤组织中基质金属蛋白酶水平和活性的变化。另一个涉及体外和体内模型的发展，导致细胞毒性化疗和环氧合酶-2抑制剂对已确定的癌症的组合的临床评价。 该假说基于3个主要观察结果：1）考克斯-2过表达对细胞凋亡具有抑制作用; 2）大多数细胞毒性剂通过细胞凋亡发挥其抗肿瘤作用;以及3）许多耐药肿瘤，包括超过70%的结肠和肺腺癌，过表达考克斯-2。 主要研究者13年来一直以各种身份参与以患者为导向的临床研究。 他的工作主要集中在肿瘤学的新药开发上，并广泛参与了临床试验的设计和实施，这些试验导致FDA批准了吉西他滨（用于胰腺癌）和伊立替康（CPT-11）（用于结直肠癌）。 他目前在范德比尔特癌症中心指导I期药物开发项目。 该补助金将允许候选人扩展他的经验，与基础研究人员和临床实习生更密切地合作，开发综合实验室/临床试验，以提供有关新型癌症治疗药物活性的最大信息量。

The purpose of this K-24 grant proposal is to provide the support necessary for the principal investigator to conduct and to mentor trainees in the conduct of patient-oriented clinical research that bridges early phase clinical trials of novel cancer therapies with laboratory correlative studies. Trainees will be supervised in their clinical research by the principal investigator and in their laboratory research by a basic scientist skilled in that area. Research projects pursued under this grant will involve the development and use of laboratory models to guide clinical trial design and the establishment of laboratory assays to measure the impact of the therapeutic intervention on tissue and plasma samples collected during the course of the clinical trial. Two examples are provided. One involves measurement of the change in matrix metalloproteinase level and activity in tumor tissue obtained from a cohort of patients treated with a novel matrix metalloproteinase inhibitor. The other involves the development of in vitro and in vivo models leading to the clinical evaluation of the combination of cytotoxic chemotherapy and cyclooxygenase-2 inhibitors on established cancers. This hypothesis is based on 3 main observations: 1) COX-2 overexpression has an inhibitory effect on apoptosis; 2) most cytoxic agents exert their antitumor effect through apoptosis; and 3) many drug-resistant tumors, including more than 70 percent of adenocarcinomas of the colon and lung,overexpress COX-2. The principal investigator has been continuously involved in patient-oriented clinical research in a variety of capacities for 13 years. His work has focused primarily on new drug development in oncology and he has been extensively involved in the design and conduct of the clinical trials that led to the FDA approval of gemcitabine (for pancreatic cancer) and irinotecan (CPT-11) (for colorectal cancer). He currently directs the Phase I Drug Development Program at the Vanderbilt Cancer Center. This grant will permit the candidate to extend his experience to work more closely with basic researchers and clinical trainees in the development of integrated laboratory/clinical trials that can provide the greatest amount of information regarding the activity of novel cancer therapeutic agents.