Clinical Investigation in Tumor Immunotherapy

描述（由申请人提供）：本提案是FOR （K24 CA97588）的K24，职业中期研究者奖的竞争性更新。该基金的题目为“肿瘤免疫治疗的临床研究”。一种不同的癌症治疗方法构成了这一建议的基础。替代肿瘤免疫治疗，应用的治疗是生物靶向，信号转导抑制剂给黑色素瘤患者。这些变化是由于这个机构（Vanderbilt）的优势和我的信念，这种癌症治疗方法在目前未观察到肿瘤免疫治疗的患者中有成功的潜力。在这个建议中，方向仍然是临床转化研究和开发一个最好的指导初级临床研究者的程序。黑色素瘤是美国增长最快的肿瘤类型之一。对于转移性疾病，免疫疗法一直是主要的治疗方法，但到目前为止还没有实现其巨大的希望。靶向（抑制）对肿瘤生长至关重要的组成激活的信号通路可以提供显着的临床益处（例如，伊马替尼治疗CML和GIST，曲妥珠单抗治疗乳腺癌，埃洛替尼和吉非替尼治疗非小细胞肺癌）。新疗法在这些恶性肿瘤中的成功为在其他癌症中寻找同样有效的药物提供了动力。2002年，在66%的黑色素瘤检测中发现了主要位于V600E的B-RAF“功能获得”突变。它与激酶抑制剂或RNAi的抑制作用导致动物异种移植物的肿瘤消退。其他与B-RAF相关的突变包括MITF过表达、CDK4或CCND1扩增、PTEN缺失以及Akt通路的激活。普遍突变的鉴定表明，针对“功能获得”突变、过度表达基因或激活途径的治疗可以提供主要的临床益处，而不会产生不可接受的毒性。针对黑色素瘤重要激活途径的新药物的可用性令人兴奋。这些药物需要训练有素的临床研究人员仔细评估，并特别注意对临床反应重要的因素。K24基金和黑色素瘤项目就是为了培训这些人。平移调查员。通过参加研讨会、会议、肿瘤委员会、肿瘤库以及临床和实验室培训的机会，初级临床研究者将获得极好的培训机会。K24活动将与T32、K12培训补助金和MSCI课程整合。

DESCRIPTION (provided by applicant): This proposal is the competitive renewal of a K24, Midcareer Investigator Award in FOR (K24 CA97588). The Grant had been titled "Clinical Investigation in Tumor Immunotherapy". A different approach to cancer therapy forms the basis of this proposal. Instead of tumor immunotherapy, the therapy applied is biologically targeted, signal transduction inhibitors administered to melanoma patients. These changes have been taken due to the strengths of this institution (Vanderbilt) and my belief that this approach to cancer therapy has potential for success in patients not presently observed with tumor immunotherapy. In this proposal, the orientation remains clinical translational research and the development of a program to best mentor junior clinical investigators. Melanoma is one of the fastest growing tumor types in the US. For metastatic disease, immunotherapy has been the primary approach to treatment, but has so far not fulfilled its great promise. Therapy targeting (inhibiting) a constitutively activated, signaling pathway critical to the cancer's growth can provide a remarkable clinical benefit, (i.e. imatinib in CML and GIST, traztuzumab in breast cancer, erlotinib and gefitinib in NSCLC). The success in these malignancies with new therapeutics provides an impetus to search for similarly effective agents in other cancers. In 2002, B-RAF "gain of function" mutations predominantly at V600E were identified in 66% of melanomas tested. Its inhibition with either a kinase inhibitor or RNAi led to tumor regression in animal xenografts . Other mutations cooperate with B-RAF including MITF overexpression, CDK4 or CCND1 amplification, PTEN loss, and activation of the Akt pathway. The identification of prevalent mutations suggest that therapy targeting "gain of function" mutations, overexpressed genes, or activated pathways could provide a major clinical benefit without unacceptable toxicity. The availability of new agents that can target activated pathways important to melanoma is exciting. These drugs will require careful evaluation by well-trained clinical investigators with special attention to what is important to a clinical response. This K24 grant and the melanoma program is vested in training these . translational investigators. Through access to seminars, conferences, tumor boards, a tumor repository, and opportunities in clinical and laboratory training, junior clinical investigators will get excellent training opportunities. The K24 activities will be integrated with the T32, K12 training grants, and the MSCI courses.