Defining a Role for c-KIT in Melanoma

描述（由申请人提供）：尽管黑色素瘤研究从预防、检测和诊断到治疗取得了重大进展，但黑色素瘤的发病率继续急剧上升，晚期疾病患者的5年生存率仍低于15%。随着我们进入靶向治疗时代，在亚组肿瘤的基础上 他们的驱动致癌突变，使适当的治疗药物可以开发。大多数黑色素瘤具有BRAF中的激活突变，其促进促分裂原活化蛋白激酶（MAPK）信号传导途径的激活。然而，有不同的黑色素瘤亚型，包括慢性日光损伤（CSD），肢端和粘膜，很少携带BRAF突变。c-KIT的扩增和/或功能获得性改变（例如，K642 E和L576 P）已被确定为这些黑色素瘤亚型中最常见的致癌事件。这导致在具有异常c-KIT的分层黑色素瘤患者中使用几种c-KIT抑制剂进行临床评价。尽管在接受c-KIT抑制剂治疗的患者中有四分之一的初始应答率，但即使剂量递增，最终也会出现耐药性。鉴于在这些肿瘤中经常发现高水平的基因组改变以及当前一代c-KIT抑制剂缺乏特异性，目前尚不清楚c-KIT是否是这些黑色素瘤亚群中可行的治疗靶点。向前推进c-KIT定向治疗需要开发忠实模拟人类疾病的临床前模型。为此，我们开发了一种新的黑色素瘤小鼠模型，使我们能够解决c-KIT在体内促进黑色素瘤发生、维持和进展中的作用。在Ink 4a/Arf缺失的情况下，突变型c-KIT（L576 P）在小鼠黑素细胞中的体内表达导致四分之一的小鼠中黑素瘤的发展，平均潜伏期为120天。拟议研究的目的是利用这种灵活的黑色素瘤小鼠模型来评估c-KIT在肿瘤发生、维持和进展中的作用，并确定协同遗传事件，以促进为肿瘤具有c-KIT改变的患者制定治疗干预策略。我们假设活性c-KIT可以引发黑色素瘤，并且通过加入协同遗传事件（例如，共表达HIF 1A或MITF）。我们将通过以下方式检验这一假设：（目的1）评估在黑色素瘤中经常观察到的其他c-KIT突变体和潜在协作基因在体内引发肿瘤的能力;（目的2）通过药理学和遗传学手段评价c-KIT在肿瘤维持中的作用;（目的3）研究c-KIT在体内促进黑色素瘤转移中的作用。.

DESCRIPTION (provided by applicant): Despite significant progress in melanoma research, from prevention, detection, and diagnosis to treatment, the incidence of melanoma continues to rise dramatically and 5-year survival for those with advanced disease remains static at less than 15 percent. As we enter the era of targeted therapy, it is critical to subgroup tumors on the basis of their driving oncogenic mutations so that appropriate therapeutic agents can be developed. The majority of melanomas possess activating mutations in BRAF, which promotes activation of the mitogen- activated protein kinase (MAPK) signaling pathway. However, there are distinct subtypes of melanoma including chronic sun damaged (CSD), acral, and mucosal that rarely harbor BRAF mutations. Amplification and/or gain-of-function alterations in c-KIT (e.g., K642E and L576P) have been identified as the most common oncogenic event in these melanoma subtypes. This has led to clinical evaluation with several c-KIT inhibitors in stratified melanoma patients possessing aberrant c-KIT. Despite an initial response rate in one-quarter of patients treated with c-KIT inhibitors, resistance eventually develops even with dose escalation. Given the high level of genomic alterations frequently identified in these tumors and the lack of specificity of current generation c-KIT inhibitors, it remains unclear if c-KIT is a viable therapeutic target in these melanoma subsets. Moving forward with c-KIT directed therapies requires the development of preclinical models that faithfully mimic the human disease. To this end we have developed a novel melanoma mouse model that enables us to address a role for c-KIT in promoting melanoma initiation, maintenance, and progression in vivo. Expression of mutant c- KIT (L576P) in mouse melanocytes in vivo in the context of Ink4a/Arf loss resulted in the development of melanoma in one-quarter of the mice with a mean latency of 120 days. The goal of the proposed studies is to utilize this flexible melanoma mouse model to evaluate the role of c-KIT in tumor initiation, maintenance and progression and to identify cooperating genetic events to facilitate the development of therapeutic intervention strategies for patients whose tumors possess alterations in c-KIT. We hypothesize that active c-KIT can initiate melanoma and that tumor growth and penetrance will be enhanced in vivo by the addition of cooperating genetic events (e.g., co-expression of HIF1A or MITF). We will test this hypothesis by (Aim 1) assessing the ability of additional c-KIT mutants and potential cooperating genes frequently observed in melanoma to initiate tumors in vivo; (Aim 2) evaluating a role for c-KIT in tumor maintenance through pharmacological and genetic means; and (Aim 3) investigating a role for c-KIT in promoting melanoma metastasis in vivo. .