Sensitizing Colorectal Cancer to Checkpoint Inhibitors by WNT Pathway Suppression

通过 WNT 通路抑制使结直肠癌对检查点抑制剂敏感

• 批准号: 9910324
• 负责人: Alyna Katti
• 金额: $ 4.55万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910324
• 关键词: Address; Adenomatous Polyposis Coli; Aftercare; Biological Models; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cessation of life; Clinic; Clinical; Clinical Data; Clinical Management; Clinical Research; Colonic Neoplasms; Colorectal Cancer; Combination immunotherapy; Combined Modality Therapy; Data; Diagnosis; Disease; Dose; Doxycycline; Engraftment; Exclusion; Exhibits; FOXP3 gene; Flow Cytometry; Genetic; ITGAM gene; Image; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immunosuppression; Immunotherapy; Individual; Intestines; Investigation; Liver; Luciferases; Modeling; Monitor; Morphology; Mus; Neoplasm Metastasis; Oncogenic; Organoids; Output; Pathway interactions; Patients; Pharmacology; Population; Pre-Clinical Model; Prognostic Marker; Regulation; Regulatory T-Lymphocyte; Resistance; Role; Stains; System; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Tissues; Transplant-Related Disorder; Transplantation; Treatment Failure; Tumor Burden; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; WNT Signaling Pathway; Withdrawal; Work; anti-CTLA4; anti-PD-1; anti-tumor immune response; beta catenin; checkpoint therapy; clinical predictors; clinically relevant; colon cancer patients; colorectal cancer treatment; draining lymph node; effective therapy; genetic approach; immune activation; immunoregulation; in vivo; inhibitor/antagonist; insight; melanoma; metastatic colorectal; mortality; neoplastic cell; novel therapeutics; pre-clinical; recruit; response; response biomarker; restoration; screening; small hairpin RNA; targeted treatment; transplant model; tumor; tumor growth

PROJECT SUMMARY More than 1.8 million people are diagnosed with colorectal cancer (CRC) each year, and while increased rates of endoscopic screening have led to a slight reduction in mortality, the disease still accounts for more than 800,000 deaths worldwide annually. Treatments for CRC have changed little over the past 10-15 years, though immune checkpoint inhibitors (ICIs) have recently become an exciting therapeutic option for the treatment of hypermutated metastatic CRC (15% of all CRCs) and various other tumor types. However, for the remaining majority of CRC patients, there exist no effective targeted therapies. Clinical studies have revealed a correlation between WNT pathway activation and T-cell exclusion, that may explain why ICIs do not generate anti-tumor immune responses in CRC. Hyperactivation of the WNT signaling pathway is a hallmark and major oncogenic driver of CRC, occurring in ~95% of tumors. Early work from our lab in mice supports the notion that WNT signaling promotes immune suppression and regulates immune cell recruitment and that WNT pathway inhibition can block immune suppression in established tumors. Using precision models in the lab, I will test the hypothesis that WNT signaling drives immune suppression in CRC and inhibiting WNT signaling in CRC will activate tumor immune responses to ICIs. To address this question, I will utilize a model system of metastatic CRC using tumor organoid transplants—the disease setting in which ICIs are used in the clinic. Three organoid lines will be generated to have three distinct levels of WNT activation, all of which can regulated to undergo complete WNT pathway suppression. In Aim 1, I will determine the effect of distinct levels of WNT signaling on effector immune populations within colon tumors. Further, I aim to test whether WNT signaling suppression within established, WNT-active colon tumors facilitates recruitment of anti-tumor immune populations and reverses immune suppression. The genetic approach I am employing allows for inducible and reversible control of WNT-signaling modulation. This system is uniquely powerful to address my hypothesis as it allows an assessment of potent WNT activation and suppression within tumor cells. In Aim 2, I aim to determine if WNT signaling suppression stimulates immune response to ICIs resulting in tumor regression. I will first evaluate immune responses in tumors with tumor intrinsic WNT suppression. I will then assess pharmacological WNT pathway inhibition, that targets non-specifically but is clinically relevant, in its ability to recapitulate the genetic findings. Identifying a safe and effective approach to stimulate anti-tumor immunity will have a profound impact on the clinical management of CRC. Thus, we believe our work will contribute significant pre-clinical data to develop combination therapies for the activation of immunotherapies in CRC and potentially other tumor types with activated WNT signaling.

项目概要 每年有超过 180 万人被诊断患有结直肠癌 (CRC)，并且发病率不断上升 内窥镜筛查使死亡率略有下降，但该疾病仍占超过 然而，过去 10 至 15 年间，全球 80 万人因 CRC 死亡而死亡。 免疫检查点抑制剂（ICIs）最近已成为治疗以下疾病的令人兴奋的治疗选择 然而，对于其余的肿瘤类型，高突变转移性 CRC（占所有 CRC 的 15%）和各种其他肿瘤类型。 对于大多数CRC患者来说，尚无有效的靶向治疗方法揭示了相关性。 WNT 通路激活和 T 细胞排斥之间的关系，这可能解释了为什么 ICI 不产生抗肿瘤作用 WNT 信号通路的过度激活是 CRC 的一个标志和主要致癌因素。 CRC 的驱动因素，发生在约 95% 的肿瘤中，我们实验室对小鼠的早期研究支持了 WNT 的观点。 信号传导促进免疫抑制并调节免疫细胞募集，并且 WNT 通路抑制 可以阻止已建立的肿瘤中的免疫抑制，我将在实验室中使用精密模型进行测试。 假设 WNT 信号传导驱动 CRC 中的免疫抑制并抑制 CRC 中的 WNT 信号传导 会激活对 ICI 的肿瘤免疫反应 为了解决这个问题，我将利用一个模型系统 使用肿瘤类器官移植治疗转移性结直肠癌——临床上使用 ICI 的疾病环境。 将生成具有三种不同水平的 WNT 激活的类器官系，所有这些都可以调节 在目标 1 中，我将确定不同水平的 WNT 的影响。 此外，我的目标是测试 WNT 信号传导是否有效。 在已建立的、具有 WNT 活性的结肠肿瘤内进行抑制有助于招募抗肿瘤免疫 我采用的遗传方法可以诱导和逆转免疫抑制。 WNT 信号调制的可逆控制该系统对于解决我的假设非常强大。 它可以评估肿瘤细胞内有效的 WNT 激活和抑制。在目标 2 中，我的目标是确定。 如果 WNT 信号抑制刺激对 ICI 的免疫反应，导致肿瘤消退，我会首先这样做。 通过肿瘤内在 WNT 抑制来评估肿瘤的免疫反应，然后我将评估药理学。 WNT 通路抑制，其目标是非特异性的，但具有临床相关性，能够重现 确定一种安全有效的方法来刺激抗肿瘤免疫力将具有深远的意义。 因此，我们相信我们的工作将贡献重要的临床前数据。 开发联合疗法以激活结直肠癌和其他潜在肿瘤类型的免疫疗法 具有激活的 WNT 信号传导。