Progression, response, and resistance of RSPO fusion colorectal cancer

RSPO 融合结直肠癌的进展、反应和耐药性

• 批准号: 10222596
• 负责人: LUKAS Edward DOW
• 金额: $ 38.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/10222596
• 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; Hyperactivity; 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 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

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.

项目总结 在西方世界，结直肠癌(CRC)是癌症相关死亡的第二大原因， 对晚期疾病的患者没有有效的治疗方法。大的染色体重排涉及 最近在5%-10%的人类中发现了WNT途径共激动剂RSPO家族的两个成员 CRC，并提供了治疗这一亚群患者的潜在靶点。然而，我们仍然不完全了解如何 特定的RSPO融合蛋白(例如，PTPRK-RSP03)有助于肿瘤的发生，以及是否靶向于此 基因组变化将提供有意义的治疗反应和改善患者预后。开始，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，在该模型中 使用可诱导的CRISPR/Cas9可以在肠道中产生内源性染色体重排 我们首创的平台。利用这种方法，我们首次提供了Ptprk-Rspo3染色体的证据 重排足以启动肠道肿瘤的发展。此外，肿瘤源于 内源性染色体改变产生的表型不同于已发表的导致异位的模型 Rspo3基因的过表达。因此，定义特定聚变事件的分子后果是 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 显示生长在天然肠粘膜内的Ptprk-Rspo3融合病变对 阻断WNT分泌的药物，但基因改变的积累可以影响药物反应。 在这项工作的基础上，我们将检验Ptprk-Rspo3融合蛋白提供WNT依赖细胞的假设 内在的增长优势源于内生的融合事件，而是合作的积累 致癌的侮辱促进了WNT的独立性和耐药性。 使用体外有机物模型系统，Aim 1将确定特定RSPO的分子后果 融合和描绘特定的融合事件和融合伙伴(PTPRK)的丢失如何促进细胞 转型。在目标2中，通过在器官和原位肿瘤模型中基于CRISPR的顺序编辑， 我们将定义与治疗失败和获得性药物相关的遗传格局和分子机制 抵抗。总之，这项工作将大大有助于从分子上理解RSPO基因组是如何 重排影响致癌的WNT信号，并有可能立即和显著地 临床贡献，通过定义影响肿瘤进展和治疗耐药性的机制。 我们预计我们的研究将揭示更有效地识别患者群体的方法，这些患者群体将对 治疗和/或预测联合疗法和二线疗法治疗难治性肿瘤。因此，结果 这项研究将是朝着安全有效的靶向治疗的总体目标迈出的重要一步 结直肠癌和改善患者预后。