Progression, response, and resistance of RSPO fusion colorectal cancer

RSPO 融合结直肠癌的进展、反应和耐药

基本信息

批准号：
9751231
负责人：
LUKAS Edward DOW
金额：
$ 37.72万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751231
关键词：
Address Agonist Animal Model Automobile Driving Biological Models Biology CRISPR/Cas technology Cancer Etiology Cancer Model Cell membrane Cells Cessation of life Chimeric Proteins Chromosome abnormality Chromosomes Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Colorectal Cancer Complementary DNA Complex DNA Sequence Rearrangement Data Dependence Development Diagnosis Drug Targeting Drug resistance Event Family Gene Abnormality Gene Family Gene Fusion Genetic Genetic Determinism Genetic Engineering Genomics Goals Growth Human Hyperactive behavior Intestinal Mucosa Intestines Investigation Lead Lesion Ligands Link Malignant Neoplasms Maps Mediating Modality Modeling Molecular Mutate Mutation Oncogenic Organoids Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Polyps Porcupines Proteins Publishing Recurrence Recurrent Malignant Neoplasm Refractory Relapse Reporting Resistance Role Signal Pathway Signal Transduction TP53 gene Testing Therapeutic Therapeutic Intervention Treatment Failure Tumor Biology Tumor Initiators Tumor Suppressor Genes Tumor-Derived WNT Signaling Pathway Western World Work acquired drug resistance adenoma advanced disease base beta catenin cell transformation colorectal cancer treatment design effective therapy experimental study improved in vivo inhibitor/antagonist insight intestinal epithelium member molecular targeted therapies mutant novel overexpression patient population patient subsets prevent prospective receptor resistance mechanism response subcutaneous targeted treatment therapy resistant three dimensional cell culture treatment optimization treatment response tumor tumor progression tumor xenograft tumorigenesis

项目摘要

PROJECT SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer-related death in the Western world, and there are no effective therapies for patients with advanced disease. Large chromosome rearrangements involving two members of the RSPO family of WNT pathway co-agonists were recently described in 5-10% of human CRC, and offer a potential target to treat this subset of patients. However, we still do not fully understand how specific RSPO fusion proteins (e.g. PTPRK-RSPO3) contribute to tumorigenesis, and whether targeting this genomic change will provide meaningful therapeutic responses and improved patient outcomes. To begin to delineate the consequences of RSPO fusions, we developed genetically engineered animal models in which endogenous chromosome rearrangements can be generated in the intestine using an inducible CRISPR/Cas9 platform we pioneered. Using this approach, we provided the first evidence that Ptprk-Rspo3 chromosome rearrangements are sufficient to initiate tumor development in the gut. Moreover, tumors derived from endogenous chromosome alterations produce phenotypes distinct from published models that induce ectopic overexpression of an Rspo3 cDNA. Thus, defining the molecular consequences of specific fusion events is likely critical for understanding the true impact of such rearrangements on tumor biology. In addition, we showed that Ptprk-Rspo3 fusion lesions growing within the native intestinal mucosa are exquisitely sensitive to drugs that block WNT secretion, but that the accumulation of genetic alterations can influence drug response. Based on this work, we will test the hypothesis that Ptprk-Rspo3 fusion proteins provide a WNT-dependent cell intrinsic growth advantage due to the endogenous fusion event, but that the accumulation of cooperating oncogenic insults promotes WNT independence and drug resistance. Using ex vivo organoid model systems, Aim 1 will determine the molecular consequences of specific RSPO fusions and delineate how specific fusion events and loss of the fusion partner (PTPRK) promote cell transformation. In Aim 2, through sequential CRISPR-based editing in organoids and orthotopic tumor models, we will define genetic landscape and molecular mechanisms linked to therapy failure and acquired drug resistance. Together, this work will contribute significantly to a molecular understanding of how RSPO genomic rearrangements impact oncogenic WNT signaling, and has the potential to make an immediate and significant clinical contribution, by defining the mechanisms that influence tumor progression and therapy resistance. We expect our studies will reveal ways to more effectively identify patient populations that would respond to treatment and/or predict combination and second line therapies for treatment refractory tumors. Thus, results from this study will be a significant step toward the overall goal of safe and effective targeted therapies for CRC, and improved patient outcomes.

项目概要结直肠癌 (CRC) 是西方世界癌症相关死亡的第二大原因，并且对于晚期疾病患者没有有效的治疗方法。大规模染色体重排涉及 WNT 通路共激动剂 RSPO 家族的两个成员最近被描述在 5-10% 的人类中 CRC，并为治疗这部分患者提供了潜在的目标。然而，我们仍然不完全明白如何特定的 RSPO 融合蛋白（例如 PTPRK-RSPO3）有助于肿瘤发生，以及是否针对此基因组变化将提供有意义的治疗反应并改善患者的治疗结果。开始为了描述 RSPO 融合的后果，我们开发了基因工程动物模型，其中使用诱导型 CRISPR/Cas9 可以在肠道中产生内源染色体重排我们开创的平台。使用这种方法，我们提供了 Ptprk-Rspo3 染色体的第一个证据重排足以引发肠道肿瘤的发展。此外，肿瘤来源于内源性染色体改变产生的表型与已发表的诱导异位的模型不同 Rspo3 cDNA 的过度表达。因此，定义特定融合事件的分子后果是对于理解这种重排对肿瘤生物学的真正影响可能至关重要。此外，我们研究表明，在天然肠粘膜内生长的 Ptprk-Rspo3 融合病变对阻断 WNT 分泌的药物，但基因改变的积累会影响药物反应。基于这项工作，我们将检验 Ptprk-Rspo3 融合蛋白提供 WNT 依赖性细胞的假设由于内生融合事件而具有内在的增长优势，但合作的积累致癌损伤促进 WNT 独立性和耐药性。使用离体类器官模型系统，目标 1 将确定特定 RSPO 的分子后果融合并描述特定的融合事件和融合伴侣的丢失 (PTPRK) 如何促进细胞转变。在目标 2 中，通过在类器官和原位肿瘤模型中进行基于 CRISPR 的连续编辑，我们将定义与治疗失败和获得性药物相关的遗传景观和分子机制反抗。总之，这项工作将极大地有助于从分子角度理解 RSPO 基因组如何重排影响致癌 WNT 信号传导，并有可能立即产生重大影响通过定义影响肿瘤进展和治疗抵抗的机制来做出临床贡献。我们期望我们的研究将揭示更有效地识别对以下治疗有反应的患者群体的方法治疗和/或预测治疗难治性肿瘤的联合疗法和二线疗法。因此，结果这项研究将是朝着安全有效的靶向治疗总体目标迈出的重要一步 CRC，并改善患者的治疗结果。