MODULATION OF CLINICAL SENSITIVITY TO CHEMOTHERAPY

这项拟议研究的中心假设是，临床对抗癌药物敏感性的关键决定因素可以在患者身上识别和调节。据估计，大约90%的癌症死亡与化疗耐药有关。因此，开发改进的、新的治疗方法对目前和未来的肿瘤学实践至关重要。拟议的研究计划有可能确定临床上重要的耐药机制，并促进新疗法迅速转化为早期临床试验。这些试验的目标将是确定利用生化和/或分子中间终点在人体受试者中进行调制的可行性--“原则证明”。还建议在进行转化性治疗研究时指导下一代临床研究人员，因为对抗耐药性的进展可能需要现有和未来研究人员的共同努力。这项拟议的研究包括三个具体目标：(1)量化编码生存因素的基因表达与晚期卵巢癌患者化疗后结果之间的关系；(2)对旨在规避化疗耐药性的新治疗策略进行初步临床试验；以及(3)指导初步临床研究人员设计和实施转化性治疗试验。这一职业生涯中期研究人员奖支持候选人的这些以患者为导向的研究和指导活动，同时促进其当前和长期的职业发展。候选人的直接职业目标是：(1)继续目前卵巢癌和黑色素瘤的临床相关项目，(2)进行机械性的早期试验，(3)促进重视和支持此类活动的临床文化。他的长期职业目标是：(1)开发并维持一项杰出的转化治疗计划；(2)在该计划内，根据决定化疗敏感性的关键机制的调整，制定改进的治疗策略。

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.