MODULATION OF CLINICAL SENSITIVITY TO CHEMOTHERAPY

调节临床对化疗的敏感性

• 批准号: 6514257
• 负责人: RAYMOND P PEREZ
• 金额: $ 12.99万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-16 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514257
• 关键词: antineoplastics; clinical research; clinical trials; drug resistance; gene expression; human subject; human therapy evaluation; melanoma; neoplasm /cancer chemotherapy; outcomes research; ovary neoplasms

The central hypothesis of the proposed research is that critical determinants of clinical sensitivity to anticancer drugs can be identified and modulated in patients. It is estimated that approximately 90 percent of cancer deaths are related to resistance to chemotherapy. Development of improved, novel treatments is therefore critical to the current and future practice of oncology. The proposed research program has the potential to identify clinically significant resistance mechanisms and promote rapid translation of novel treatments into early-phase clinical trials. The goal of these trials will be to establish feasibility of modulation-"proof-of-principle"-in human subjects, using biochemical and/or molecular intermediate endpoints. Mentoring of next-generation clinical investigators in the conduct of translational therapeutic investigations is also proposed, as progress against drug resistance will likely require the concerted efforts of current and future investigators. The proposed research includes three specific aims: (1) To quantitate relationships between expression of genes encoding survival factors and post-chemotherapy outcomes of patients with advanced ovarian carcinoma; (2) To perform initial clinical trials of novel treatment strategies designed to circumvent resistance to chemotherapy; and (3) To mentor beginning clinical investigators in the design and conduct of translational therapeutic trials. This Midcareer Investigator Award supports these patient-oriented research and mentoring activities of the candidate while promoting his immediate and long-term career development. The candidate's immediate career objectives are: (1) to continue current clinical correlative projects in ovarian carcinoma and melanoma, (2) to conduct mechanistic early-phase trials, (3) and to promote a clinical culture that values and supports such activities. His long-term career objectives are: (1) to develop and sustain an outstanding program in translational therapeutics and (2) within this program, to develop improved treatment strategies based on modulation of critical mechanisms that determine sensitivity to chemotherapy.

提出的研究的中心假设是临床对抗癌药物敏感性的关键决定因素可以在患者中确定和调节。据估计，大约90%的癌症死亡与化疗耐药性有关。因此，开发改进的、新颖的治疗方法对当前和未来的肿瘤学实践至关重要。拟议的研究项目有可能确定临床显著的耐药机制，并促进新疗法快速转化为早期临床试验。这些试验的目标将是利用生化和/或分子中间端点，在人类受试者中建立调节的可行性——“原理证明”。还建议指导下一代临床研究人员进行转化治疗研究，因为对抗耐药性的进展可能需要当前和未来研究人员的共同努力。本研究包括三个具体目的：(1)量化晚期卵巢癌患者生存因子基因表达与化疗后预后的关系；(2)开展旨在规避化疗耐药的新型治疗策略的初步临床试验；(3)指导初级临床研究人员设计和实施转化治疗试验。此职业中期研究者奖支持这些以患者为导向的研究和指导活动，同时促进候选人的近期和长期职业发展。候选人的近期职业目标是：(1)继续卵巢癌和黑色素瘤的临床相关项目，(2)进行机械的早期试验，(3)促进重视和支持这些活动的临床文化。他的长期职业目标是：(1)发展和维持一个杰出的转化治疗项目；(2)在这个项目中，基于决定化疗敏感性的关键机制的调节，开发改进的治疗策略。