SPORE in Skin Cancer

描述(由申请人提供)：宾夕法尼亚大学/维斯塔尔大学治疗皮肤癌的孢子的目的是通过开发有针对性的治疗方法来降低皮肤癌的发病率和死亡率。该孢子研究三种主要皮肤癌--黑色素瘤、皮肤T细胞淋巴瘤(CTCL)和鳞状细胞癌(SCC)。这些项目和核心关注的是皮肤癌死亡的主要原因--黑色素瘤。我们的主要假设是，通过干扰信号通路和/或刺激宿主免疫反应来获得最大的长期临床影响需要我们考虑肿瘤特异性和宿主特异性的遗传和表观遗传学特征。四个项目中的每一个都有明确的翻译目标和具体的假设，这些假设都建立在坚实的初步研究基础上。这三个核心支持项目以及发展研究和职业发展方案。第一个总体目标是开发治疗黑色素瘤的新疗法。在四个项目中的三个项目中，我们提出了晚期转移性黑色素瘤的临床试验，总体假设是黑色素瘤不是一种同质性疾病，因此应该采取不同的治疗策略。项目1和2利用了我们之前的发现，在BRAF突变的黑色素瘤中，对BRAF抑制的两个主要的可药物耐药机制是激活PI3K信号和自噬。项目1(Herlyn/Schuchter)建议进行广泛的基于组织的研究，以了解同时靶向突变的BRAF和P13K的影响。我们希望联合用药能更有效地杀灭肿瘤细胞，防止或延长大部分患者的复发。项目2(Amaravadi/Speicher)结合了BRAF突变黑色素瘤患者的自噬和BRAF抑制，并确定了其他具有BRAF野生型患者未来发展潜力的有效靶向治疗和自噬抑制剂组合策略。项目4(Vonderheide/Kalos/JUMP)涉及通过过继转移经改造可与肿瘤细胞结合的淋巴细胞进行黑色素瘤的免疫治疗。该项目建立在来自其他恶性肿瘤的高度鼓舞人心的数据基础上，这些数据表明激活的T细胞可以实现有效的肿瘤消退和持久的临床反应。第二个总体目标是在晚期黑色素瘤中建立新的生物标志物。我们假设，识别有意义的生物标志物不仅将增加我们对治疗前、治疗中和治疗后疾病消退和进展动态的了解，而且还将通过为患者量身定做的治疗选择、改善治疗期间的评估和增强结果预测来直接影响疾病的管理。在项目1和2中，我们将分析患者的黑色素瘤的遗传异常，目的是在开始治疗之前将他们分成至少五个不同的疾病组，这些疾病组将决定治疗决策。我们还将确定是否可以在患者的血清(项目2)、肿瘤(项目1和2)和/或血液(项目4)中检测到与治疗相关的变化。最后，项目3(Nathanson/Kanetsky)是一项全基因组关联研究，将调查遗传对急性毒性的遗传易感性和使用抗CTLA4药物Ipiimumab进行免疫刺激治疗的结果。在这里，我们希望发现新的基因特征，经过进一步的研究，可能有助于识别患者亚群，帮助制定治疗决策。我们期待这一高度互动的孢子项目将为黑色素瘤和其他皮肤癌的临床实践带来切实的结果。

DESCRIPTION (provided by applicant): The intent of the Penn/Wistar SPORE in Skin Cancer is to decrease the morbidity and mortality of skin cancers through the development of targeted therapies. This SPORE investigates three major skin cancers-melanoma, cutaneous T cell lymphoma (CTCL) and squamous cell carcinoma (SCC). The projects and cores focus on the leading cause of skin cancer deaths, melanoma. Our overarching hypothesis is that maximal long-lasting clinical impact achieved by interfering with signaling pathways and/or stimulating the host immune response requires that we take into account tumor-specific and host-specific genetic and epigenetic signatures. Each of the four projects has clear translational objectives and specific hypotheses that rest on a solid body of preliminary studies. The three cores support the projects and the developmental research and career developmental programs. The first overall objective is to develop novel therapies in melanoma. In three bf the four projects, we propose clinical trials of advanced metastatic melanoma with the overall hypothesis that melanoma is not a homogenous disease and, therefore, should be treated with different strategies. Projects 1 and 2 capitalize on our previous findings that two of the major druggable resistance mechanisms to BRAF inhibition in BRAF-mutant melanoma are activation of PI3K signaling and autophagy. Project 1 (Herlyn/Schuchter) proposes extensive tissue-based studies to understand the effects of concurrently targeting mutant BRAF and P13K. We expect the combination to be more effective in killing tumor cells and preventing or extending recurrence in a large subset of patients. Project 2 (Amaravadi/Speicher) combines autophagy and BRAF inhibition in patients with BRAF-mutant melanoma, and identifies other effective targeted therapy and autophagy inhibitor combination strategies that have future development potential for BRAF wild-type patients. Project 4 (Vonderheide/Kalos/June) deals with immunotherapy of melanoma by adoptive transfer of lymphocytes that are engineered to bind to tumor cells. The project is built on highly encouraging data from other malignancies that show activated T cells can achieve effective tumor regression and lasting clinical responses. The second overall objective is to establish new biomarkers in advanced melanoma. We hypothesize that identification of meaningful biomarkers not only will increase our knowledge of the dynamics of disease regression and progression before, during, and after therapy, but also will directly impact the management of the disease by tailored selection of therapy for patients, improved assessment during therapy, and enhanced outcome prediction. In projects 1 and 2, we will analyze patients' melanomas for genetic abnormalities with the intent of stratifying them prior to initiation of therapy into at least five different disease groups that will dictate therapeutic decision-making. We also will determine whether therapy-related changes can be detected in the sera (Project 2), tumors (Projects 1 and 2), and/or blood (Project 4) of patients. Finally, project 3 (Nathanson/Kanetsky) is a genome-wide association study that will investigate inherited genetic susceptibility to acute toxicities and outcomes of immunostimulatory therapy using the anti-CTLA4 drug, Ipilimumab. Here we expect to discover novel genetic signatures that may, after further study, facilitate identification of patient subgroups to help tailor therapeutic decision-making. We expect that this highly interactive SPORE program will yield tangible results for clinical practice in melanoma and other cancers of the skin.