Clinical Investigation in Tumor Immunotherapy

描述（由申请人提供）：本提案是一个K24，中期职业生涯研究者奖在FOR（K24 CA 97588）的竞争性更新。该补助金的标题为“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。代替肿瘤免疫疗法，所应用的疗法是向黑色素瘤患者施用的生物靶向的信号转导抑制剂。这些变化是由于该机构（范德比尔特）的优势以及我的信念，即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具有成功的潜力。在这项提案中，方向仍然是临床转化研究和开发一个程序，以最好的导师初级临床研究者。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，免疫疗法一直是治疗的主要方法，但迄今为止尚未实现其巨大的希望。靶向（抑制）对癌症生长至关重要的组成性激活信号通路的治疗可提供显著的临床获益（即伊马替尼治疗CML和GIST，曲妥珠单抗治疗乳腺癌，厄洛替尼和吉非替尼治疗NSCLC）。新疗法在这些恶性肿瘤中的成功为在其他癌症中寻找类似有效的药物提供了动力。在2002年，B-RAF“功能获得”突变主要在V600 E被确定在66%的黑色素瘤测试。用激酶抑制剂或RNAi抑制其导致动物异种移植物中的肿瘤消退。其他突变与B-RAF协同作用，包括MITF过表达、CDK 4或CCND 1扩增、PTEN丢失和Akt途径激活。流行突变的鉴定表明，靶向“功能获得”突变、过表达基因或活化途径的治疗可以提供主要的临床益处，而没有不可接受的毒性。能够靶向对黑色素瘤重要的活化途径的新药物的可用性令人兴奋。这些药物需要经过良好培训的临床研究者进行仔细评估，特别注意对临床反应重要的因素。这个K24赠款和黑色素瘤计划是在培训这些归属。翻译研究者通过参加研讨会、会议、肿瘤委员会、肿瘤资料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培训赠款和MSCI课程相结合。

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.