INTEGRATED ASSESSMENT OF NOVEL THERAPIES IN ONCOLOGY

这项K-24赠款建议的目的是为首席研究人员提供必要的支持，以指导受训人员进行以患者为导向的临床研究，将新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调查员监督，实验室研究将由一名精通该领域的基础科学家监督。根据这项拨款进行的研究项目将包括开发和使用实验室模型来指导临床试验设计，以及建立实验室分析来衡量治疗干预对临床试验过程中收集的组织和血浆样本的影响。这里提供了两个例子。其中一项涉及测量肿瘤组织中基质金属蛋白酶水平和活性的变化，这些变化来自一组接受新型基质金属蛋白酶抑制剂治疗的患者。另一项涉及体外和体内模型的开发，导致对细胞毒性化疗和环氧合酶-2抑制剂联合治疗已确定的癌症的临床评估。这一假说基于三个主要观察结果：1)COX-2过表达对细胞凋亡有抑制作用；2)大多数细胞毒药物通过细胞凋亡发挥抗肿瘤作用；3)许多耐药肿瘤，包括超过70%的结肠癌和肺腺癌，过表达COX-2。首席研究员13年来一直以各种身份持续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，他广泛参与了临床试验的设计和实施，这些试验导致FDA批准吉西他滨(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领导第一阶段药物开发计划。这笔赠款将允许候选人扩展他的经验，在开发综合实验室/临床试验方面与基础研究人员和临床实习生更密切地合作，这些试验可以提供关于新型癌症治疗药物活性的最大量信息。

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.