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: 10321635
• 负责人: Alyna Katti
• 金额: $ 3.55万
• 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 2022-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321635
• 关键词: APC gene; Address; 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; Persons; 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; insight; melanoma; metastatic colorectal; mortality; neoplastic cell; novel therapeutics; organoid transplantation; 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.

项目总结 每年有超过180万人被诊断出患有结直肠癌(CRC)，尽管发病率不断上升 经内窥镜筛查后死亡率略有下降，该病仍占比超过 全球每年有80万人死亡。然而，在过去的10-15年里，结直肠癌的治疗方法几乎没有改变。 免疫检查点抑制剂(ICIS)最近已成为一种令人兴奋的治疗选择 高突变的转移性结直肠癌(占所有结直肠癌的15%)和各种其他肿瘤类型。然而，对于剩下的 对于大多数结直肠癌患者，尚无有效的靶向治疗方法。临床研究揭示了两者之间的相关性 在WNT途径激活和T细胞排斥之间，这可能解释了为什么ICIS不产生抗肿瘤 结直肠癌的免疫反应。WNT信号通路的过度激活是一个标志和主要的致癌因素 结直肠癌的驱动因素，发生在~95%的肿瘤中。我们实验室在小鼠身上的早期工作支持WNT的概念 信号促进免疫抑制并调节免疫细胞募集，而WNT途径抑制 可以阻断已建立的肿瘤中的免疫抑制。使用实验室中的精密模型，我将测试 WNT信号驱动结直肠癌免疫抑制和抑制结直肠癌WNT信号的假说 会激活肿瘤对ICIS的免疫反应。为了解决这个问题，我将使用一个模型系统 使用肿瘤器官移植的转移性结直肠癌--临床上使用ICIS的疾病环境。三 将产生具有三个不同水平的WNT激活的类器官线，所有这些都可以调节到 经历完全的WNT途径抑制。在目标1中，我将确定不同水平的WNT的影响 结肠肿瘤内效应免疫群体的信号转导。此外，我的目标是测试WNT信号 在已建立的、WNT活跃的结肠肿瘤中的抑制促进了抗肿瘤免疫的招募 并逆转免疫抑制。我正在使用的遗传方法允许诱导性和 WNT信号调制的可逆控制。这个系统是唯一强大的，可以解决我的假设为 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ICIS的免疫反应，导致肿瘤消退。我会先来 评估具有肿瘤固有WNT抑制的肿瘤的免疫反应。然后我会评估药理学 WNT途径抑制，它针对的是非特异性的但与临床相关的，因为它能够概括 基因方面的发现。寻找一种安全有效的方法来激发抗肿瘤免疫将具有深远的意义 对结直肠癌临床处理的影响。因此，我们相信我们的工作将有助于重要的临床前数据。 开发联合疗法以激活结直肠癌和潜在的其他肿瘤类型的免疫疗法 带有激活的WNT信号。

项目成果

An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants.

• DOI: 10.1158/2159-8290.cd-20-0442
• 发表时间: 2020-11
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Zafra MP;Parsons MJ;Kim J;Alonso-Curbelo D;Goswami S;Schatoff EM;Han T;Katti A;Fernandez MTC;Wilkinson JE;Piskounova E;Dow LE
• 通讯作者: Dow LE

Dietary fructose improves intestinal cell survival and nutrient absorption.

• DOI: 10.1038/s41586-021-03827-2
• 发表时间: 2021-09
• 期刊: Nature
• 影响因子: 64.8
• 作者: Taylor SR;Ramsamooj S;Liang RJ;Katti A;Pozovskiy R;Vasan N;Hwang SK;Nahiyaan N;Francoeur NJ;Schatoff EM;Johnson JL;Shah MA;Dannenberg AJ;Sebra RP;Dow LE;Cantley LC;Rhee KY;Goncalves MD
• 通讯作者: Goncalves MD