SPORE in Skin Cancer

皮肤癌中的孢子

• 批准号: 7913471
• 负责人: Meenhard F Herlyn
• 金额: $ 17.58万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913471
• 关键词: SPORE; Skin; Cancer

DESCRIPTION (provided by applicant): The intent of the Wistar/Penn SPORE in Skin Cancer is to decrease the morbidity and mortality of skin cancers through improved understanding of the pathogenesis of these diseases using novel, validated molecular biomarkers of risk, progression and prognosis and the development of targeted therapies. This SPORE is focused on major skin cancers: melanoma, cutaneous T cell lymphoma (CTCL) and squamous cell carcinoma (SCC). The overall goals of this SPORE are to address five translationally important areas: 1) Risk assessment. We will test the hypothesis that susceptibility to melanoma stems from complex interactions of multiple factors, including inherited genotypes, environmental exposures, and endogenous pigmentation (Projects 1 and 2). 2) Risk prediction. Genotypes (Projects 1 and 2) will be integrated with existing risk factors to develop prediction models of individual melanoma risk. These models will be important in stratifying individuals for screening and prevention, and to enhance the efficacy of targeted prevention trials. 3) Prognosis. Using data from Projects 1 (alterations in DNA), and 2 and 3 (differences in protein levels) we will develop and externally validate comprehensive, biologically based prognostic models that will be used in clinical trials and in patient management. 4) Diagnosis. We will develop and validate biomarkers to distinguish melanoma in situ from invasive and/or tumorigenic melanoma (Project 3). 5) Therapy. We will investigate several novel therapies for advanced melanoma and CTCL (Projects 4, 5 and 6). These include: a) targeted therapy for melanoma: molecular targeting of MAP kinase signaling pathways capitalizing on the recent discovery that the majority of human melanomas have an activating mutation in BRAF (Project 6); b) cytokine therapy of CTCL: determination of the mechanisms whereby CTCL becomes refractory to recombinant human IL-12-based therapies and how therapeutic efficacy can be enhanced by cytokines, including IL-2 (Project 5); and c) active and passive immunotherapy of melanoma with lymphocytes and defined tumor antigens: an organotypic model of melanoma will define new cytotoxic T-cell specificities against human melanoma, leading to the identification of novel antigens for vaccine trials and "optimized" adoptive immunotherapy (Project 4). The Wistar/Penn SPORE addresses the most aggressive cancers of the skin. It is focused on melanoma because of its rising incidence and significant potential for lethality. It is the subject of five of the six Projects and three of the five Pilot Studies. CTCL is addressed in one Project and one Pilot Study, and SCC in one Pilot Study. This endeavor represents the synergistic integration of well-established individual research programs towards our collective goals.

描述（由申请人提供）： Wistar/Penn皮肤癌SPORE的目的是通过使用新的、经验证的风险、进展和预后分子生物标志物以及靶向治疗的开发来提高对这些疾病发病机制的理解，从而降低皮肤癌的发病率和死亡率。该SPORE专注于主要的皮肤癌：黑色素瘤，皮肤T细胞淋巴瘤（CTCL）和鳞状细胞癌（SCC）。本SPORE的总体目标是解决五个非常重要的领域：1）风险评估。我们将检验黑色素瘤易感性源于多种因素复杂相互作用的假设，包括遗传基因型、环境暴露和内源性色素沉着（项目1和2）。2)风险预测。基因型（项目1和2）将与现有的风险因素相结合，以开发个体黑色素瘤风险的预测模型。这些模型将在筛选和预防的个体分层中发挥重要作用，并提高靶向预防试验的有效性。3)预后利用项目1（DNA改变）、项目2和项目3（蛋白质水平差异）的数据，我们将开发和外部验证全面的、基于生物学的预后模型，这些模型将用于临床试验和患者管理。4)诊断.我们将开发和验证生物标志物，以区分原位黑色素瘤和侵袭性和/或致瘤性黑色素瘤（项目3）。5)疗法我们将研究几种治疗晚期黑色素瘤和CTCL的新疗法（项目4、5和6）。其中包括：a）黑色素瘤的靶向治疗：利用最近的发现，即大多数人黑色素瘤在BRAF中具有活化突变，（项目6）; B）CTCL的细胞因子疗法：确定CTCL对基于重组人IL-12的疗法变得难治的机制以及如何通过细胞因子（包括IL-2）增强治疗功效（项目5）;和c）用淋巴细胞和确定的肿瘤抗原对黑色素瘤的主动和被动免疫疗法：黑色素瘤的器官型模型将确定针对人黑色素瘤的新的细胞毒性T细胞特异性，导致鉴定用于疫苗试验和“优化的”过继免疫疗法的新抗原（项目4）。 Wistar/Penn SPORE解决了最具侵袭性的皮肤癌。它专注于黑色素瘤，因为它的发病率上升和潜在的致命性。这是六个项目中的五个项目和五个试点研究中的三个项目的主题。CTCL在一个项目和一个试点研究中解决，SCC在一个试点研究中解决。这一奋进代表了完善的个人研究计划对我们的集体目标的协同整合。