Early Clinical Trials of New Anti-Cancer Agents with Phase 1 Emphasis

描述（由申请人提供）：我们在MSKCC的I期研究项目的目标是：1）确定有前途的新治疗药物; 2）对这些药物进行临床前研究，以更好地了解这些药物的作用机制; 3）通过剂量探索（I期）单药或联合试验，将临床前数据扩展到合理的以患者为导向的临床试验;和4）使用新的生物统计学、药代动力学和药效学方法确定1期研究实施的创新方法。为了实现这些目标，需要实验室和临床科学家之间的密切合作。我们将重点关注MSKCC实验室到临床转化研究的项目：（1）Hsp 90是一种丰富的细胞伴侣蛋白，它是未折叠蛋白质重折叠所必需的，我们已经证明，Hsp 90的抑制诱导HER 2的快速降解和其在膜上表达的丧失。我们利用Hsp 90抑制剂的这种独特性质，开发了一种新的非侵入性方法，用于成像肿瘤中HER 2表达的丧失。这种分子成像方法将为患者体内HspQO抑制剂的检测提供平台;（2）细胞毒性化疗仍然是许多癌症治疗的主要手段。由于大多数常规抗癌药物会对基因组造成损伤，因此也会激活细胞周期检查点，因此药理学上对侧支检查点通路的破坏可能会在肿瘤中选择性地产生“合成致死性”，并代表了一个重要的治疗机会;对靶点和治疗顺序的基本理解对于我们的临床研究设计是必要的;（3）表皮生长因子酪氨酸激酶抑制剂（EGFR TKIS）如吉非替尼和厄洛替尼改变了我们治疗非小细胞肺癌的方式。某些EGFR激酶结构域突变是EGFR TKIS显著敏感性的基础，但我们已经证明，EGFR TKIS获得性耐药总是发生，通常与EGFR的T790 M耐药突变相关，是肺癌患者的一个重要问题。进一步了解这一过程的机制将有助于克服和抑制获得性耐药性的发展。这些项目将我们的努力集中在建立强大的bench-to-bedside和back-to-bedside研究。这种开发新型靶向治疗的迭代研究方法对我们成功对抗癌症至关重要。

DESCRIPTION (provided by applicant): The goals of our Phase 1 research program at MSKCC are to: 1) identify promising new therapeutic agents; 2) preclinical study of these agents to better understand the mechanism of action of these agents; 3) extension of preclinical data into rational patient-oriented clinical trials through dose-finding (Phase I) single agent or combination trials; and 4) identification of innovative approaches to Phase 1 study conduct using novel biostatistical, pharmacokinetic, and pharmacodynamic approaches. A close collaboration between laboratory and clinical scientists are required to accomplish these goals. We will focus on projects as illustrative of the lab-to-clinic translational research at MSKCC: (1) Hsp90 is an abundant cellular chaperone that is required for refolding of unfolded proteins and we have demonstrated that inhibition of Hsp90 induces the rapid degradation of HER2 and loss of its expression on the membrane. We took advantage of this unique property of Hsp90 inhibitors and developed a novel non-invasive method for imaging loss of HER2 expression in the tumors. This molecular imaging approach will provide a platform for in vivo testing of HspQO inhibitors in patients; (2) Cytotoxic chemotherapy continues to be the mainstay of treatment for many cancers. Since most conventional anti-cancer agents impart damage to the genome and therefore also activate cell cycle checkpoints, pharmacological disruption of collateral checkpoint pathways might create 'synthetic lethality' selectively in tumors and represent a significant therapeutic opportunity; the basic understanding of the targets and sequence of treatment is necessary for our clinical study design; (3) Epidermal growth factor tyrosine kinase inhibitors (EGFR TKIS) such as gefitinib and erlotinib have changed how we treat non-small lung cancers. Certain EGFR kinase domain mutations underlie dramatic sensitivity to EGFR TKIS but we have shown that acquired resistance to EGFR TKIS invariably occurs and is often associated with the T790M resistance mutation of EGFR and represents a significant problem for patients with lung cancer. Further understanding of the mechanisms underlying this process will facilitate ways to both to both overcome and suppress the development of acquired resistance. These projects focus our effort on building strong bench-to-bedside and back-to-bench research. This iterative research approach to develop novel targeted therapy is critical to our success in the fight against cancer.