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Rational approaches to melanoma therapy

黑色素瘤治疗的合理方法

基本信息

批准号：
10013137
负责人：
Michael Davies
金额：
$ 140.04万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013137
关键词：
Apoptosis Apoptotic Area BRAF gene Bioinformatics Biologic Characteristic Biological Markers Biological Response Modifier Therapy CTLA4 gene Cancer Therapy Evaluation Program Cell Line Characteristics Clinical Clinical Trials Collection Cutaneous Melanoma DNA DNA Damage Development Disease Drug resistance Enrollment Ensure FDA approved Fine needle aspiration biopsy Foundations Future Genes Genetic Genetic Heterogeneity Heterogeneity Histologic Human Immune checkpoint inhibitor Immunotherapeutic agent Institution Investigation Laboratories Lesion MAP Kinase Gene MEKs Malignant Neoplasms Melanoma Cell Metastatic Melanoma Modeling Molecular Mutation Neoplasm Metastasis Oncogenic PD-1 inhibitors Pathway interactions Patient Selection Patient-Focused Outcomes Patients Pharmacotherapy Phenotype Pilot Projects Pre-Clinical Model Property Proteins Proto-Oncogene Proteins c-akt RNA Receptor Protein-Tyrosine Kinases Regimen Relapse Resistance Resources Selection for Treatments Signal Transduction Solid Specimen Subgroup Testing Therapeutic Time Translating Tumor stage Xenograft Model Xenograft procedure cancer cell combinatorial disease heterogeneity established cell line improved in vivo inhibitor/antagonist kinase inhibitor melanoma multidisciplinary mutant novel drug combination novel marker novel therapeutic intervention patient subsets personalized medicine personalized therapeutic potential biomarker prevent programmed cell death ligand 1 programs research clinical testing resistance mechanism response success targeted treatment tool tumor tumor progression

项目摘要

Project Summary – Overall The outcomes of patients with metastatic melanoma have improved dramatically over the last decade due to an improved understanding of the molecular drivers of this disease. In particular, multiple targeted therapy regimens have been approved for patients with a BRAFV600E/K mutation, which are present in ~50% of cutaneous melanomas. These treatments achieve clinical responses in ~80% of patients with a BRAFV600E/K mutation, thus providing proof- of-concept of the therapeutic potential for personalized therapeutic strategies. However, most of the patients will progress within 2 years of starting those therapies. Further, currently there are no targeted therapies that have been shown to be effective in patients with a wild-type BRAF. Thus, there are unmet clinical needs to develop treatments that prevent or overcome resistance to existing therapies for patients with a BRAFV600E/K mutation, and that are effective in patients without a BRAF mutation. In order to facilitate the development of new therapeutic strategies, over the last 5 years we have led a major effort to develop a broad collection of PDX models to reflect the clinical, histological, and genetic heterogeneity of this disease. Our collection of >450 PDX models represents one of the largest collections for any human malignancy, and our initial testing demonstrates that the collection accurately recapituluates the oncogenic drivers and molecular heterogeneity that is observed in patients. This collection also includes a subset of PDX established from patients with acquired resistance to targeted therapies that have been maintained on those agents in vivo to sustain their resistant phenotype. Together these efforts have generated a robust resource to develop, refine, and prioritize new personalized combinatorial therapies for patients. Thus, we propose to establish a multi-disciplinary and multi-institutional PDTC Program focused on the use and continued expansion of our robutst melanoma PDX collection to identify new therapeutic approaches that fill important clinical gaps in this disease. Project 1 will characterize kinase inhibitors targeting receptor tyrosine kinases (RTKs) and the PI3K-AKT pathway in combination with approved targeted therapies in PDX models in treatment-naïve and drug- resistant BRAFV600E/K-mutant melanomas. Project 2 will characterize targeting the apoptotic machinery of cancer cells as a combinatorial approach with MAPK pathway inhibitors in PDX with and without BRAFV600E/K mutations, including in subsets with aberrancies in anti-apoptotic genes. Both Projects will utilize baseline characteristics of the PDX models to identify potential biomarkers of sensitivity and resistance to guide personalized patient selection for future clinical testing. In addition, tumors will be analyzed for treatment-induced effects that correlate with sensitivity to identified resistance mechanisms and potential new combinatorial strategies. Finally, markers identified in the preclinical models will be compared to parallel biomarker studies of metastatic melanoma patients enrolled in clinical trials utilizing the same agents. These studies will be supported by the PDX, Bioinformatics, and Administrative Cores to ensure their success, along with a Pilot Project program to open new areas of investigation. Together these studies will have high potential to translate into new personalized clinical trials for patients.

项目总结 – 总体由于转移性黑色素瘤患者的预后在过去十年中得到了显着改善提高了对该疾病的分子驱动因素的了解。尤其是多种靶向治疗方案已被批准用于具有 BRAFV600E/K 突变的患者，这种突变存在于约 50% 的皮肤黑色素瘤中。这些治疗在约 80% 的 BRAFV600E/K 突变患者中实现了临床缓解，从而提供了证据：个性化治疗策略的治疗潜力的概念。然而，大多数患者会开始这些疗法后 2 年内取得进展。此外，目前尚无靶向治疗药物经证明对野生型 BRAF 患者有效。因此，开发治疗方法尚有未满足的临床需求预防或克服对 BRAFV600E/K 突变患者现有疗法的耐药性，并且对没有 BRAF 突变的患者有效。为了促进新治疗策略的开发，在过去 5 年里，我们做出了重大努力，开发了广泛的 PDX 模型，以反映临床、这种疾病的组织学和遗传异质性。我们收集了超过 450 个 PDX 模型，代表了其中之一最大的人类恶性肿瘤集合，我们的初步测试表明该集合准确概括了在患者中观察到的致癌驱动因素和分子异质性。这个合集还有包括从对靶向治疗获得性耐药的患者中建立的 PDX 子集在体内维持这些药物以维持其耐药表型。这些努力共同产生了为患者开发、完善和优先考虑新的个性化组合疗法的强大资源。因此，我们建议建立一个多学科和多机构的 PDTC 计划，重点关注使用和持续扩展我们稳健的黑色素瘤 PDX 系列，以确定填补重要临床空白的新治疗方法这种疾病的空白。项目 1 将表征针对受体酪氨酸激酶 (RTK) 的激酶抑制剂以及 PI3K-AKT 通路与未经治疗和药物治疗的 PDX 模型中已批准的靶向治疗相结合耐药 BRAFV600E/K 突变黑色素瘤。项目 2 的特点是针对癌症的细胞凋亡机制细胞作为与 MAPK 通路抑制剂的组合方法治疗有或没有 BRAFV600E/K 突变的 PDX，包括抗凋亡基因存在异常的子集。这两个项目都将利用 PDX 模型可识别敏感性和耐药性的潜在生物标志物，以指导个性化患者选择未来的临床测试。此外，还将分析肿瘤与敏感性相关的治疗诱导效应确定耐药机制和潜在的新组合策略。最后，在临床前模型将与入组的转移性黑色素瘤患者的平行生物标志物研究进行比较使用相同药物的临床试验。这些研究将得到 PDX、生物信息学和确保其成功的行政核心，以及开辟新调查领域的试点项目计划。这些研究将有很大潜力转化为针对患者的新的个性化临床试验。