Tumor selective inhibition of the WNT pathway

WNT 通路的肿瘤选择性抑制

基本信息

批准号：
10708875
负责人：
LUKAS Edward DOW
金额：
$ 56.82万
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：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708875
关键词：
AXIN1 gene Active Immunotherapy Adult Advanced Malignant Neoplasm Animal Model Biological Models Breast Adenocarcinoma Breast Cancer cell line Cancer Cell Growth Cancer Model Cancer cell line Cell Proliferation Cells Chromosome 8 Chromosome Arm Chromosome Deletion Chromosomes Clinical Clinical Management Clustered Regularly Interspaced Short Palindromic Repeats Colon Colon Adenocarcinoma Colorectal Cancer Colorectal Neoplasms Complex Data Dependence Diploidy Disease Disease Progression Distal Drug resistance Engineering Enzymes Family member Gene Silencing Genes Genetic Models Genetic Transcription Genome Goals Growth Heterozygote Homeostasis Human Hyperactivity Immunocompetent Intestines Lead Link Lung Adenocarcinoma Maintenance Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Modeling Molecular Target Mus Mutation Normal Cell Normal tissue morphology Oncogenic Organ Organoids Pathway interactions Patients Pharmaceutical Preparations Pre-Clinical Model Process Proteins Proteomics Regulation Safety Series Signal Pathway Signal Transduction Solid Neoplasm System TNKS gene TP53 gene Tankyrase Testing Therapeutic Therapeutic Intervention Tissues Toxic effect Transgenic Organisms WNT Signaling Pathway Work beta catenin body system bone cancer cell cancer therapy cancer type cell type cellular engineering chromosome 8p loss colorectal cancer treatment efficacy evaluation genetic approach genome editing in vivo inhibitor injury and repair innovation malignant breast neoplasm molecular targeted therapies mouse model novel novel strategies novel therapeutic intervention pharmacologic pre-clinical precision oncology preclinical study resistance mechanism response small hairpin RNA small molecule small molecule inhibitor stem cells targeted treatment therapeutic target therapy resistant tissue regeneration treatment response tumor tumor progression

项目摘要

PROJECT SUMMARY WNT pathway hyperactivation is a dominant oncogenic driver in colorectal cancer (CRC), and directly linked to disease progression and drug resistance in many other cancer types, including lung (LUAD), breast and prostate cancer. Indeed, there is strong evidence from pre-clinical model systems that targeting hyperactive WNT signaling can provide significant therapeutic benefit in multiple cancer models. We and others have shown that blocking the function of redundant Tankyrase enzymes (TNKS and TNKS2) can suppress hyperactive WNT signaling, impede cancer cell proliferation and drive differentiation, particularly in CRC. However, WNT signaling is also critical for the homeostatic maintenance of multiple organ systems. Consequently, drugs that effectively block WNT, like TNKS inhibitors, have shown a range of on-target toxicities in essential tissues such as the intestine and bone. Defining a strategy for tumor-restricted WNT pathway suppression is a major goal in precision oncology. Advanced cancers often contain significant disruptions to their genomes, including gains and losses of large chromosome segments. These large-scale alterations encompassing many genes are presumed to support cancer cell growth. However, they also lead to loss of ‘passenger’ genes that do not drive cancer progression, but may unintentionally ‘rewire’ the signaling networks. Such cancer-specific collateral damage may provide opportunities for therapeutic intervention. We will test the hypothesis that a large chromosomal deletion on chromosome 8p, which induce loss of TNKS, create a tumor-specific dependency on TNKS2 that can be exploited to block WNT only in cancer cells. Because normal cells express both redundant family members, they should remain unaffected by selective targeting. In Aim 1, using a panel of CRC, LUAD and breast cancer cell lines and patient-derived organoids, in combination with CRISPR-based genome editing, we will determine how heterozygous and homozygous chromosome deletions impact the response to TNKS2 inhibition. Further, we will define downstream protein targets that are most sensitive to TNKS disruption and TNKS2 suppression. In Aim 2 we will exploit a unique transgenic shRNA system we developed, to define the safety of systemic and selective TNKS2 inhibition in vivo and determine the efficacy of selective TNKS2 inhibition in immunocompetent animal models of aggressive CRC and LUAD. Aim 3 will determine the efficacy of novel TNKS2-selective small molecules in cancer cell lines and organoid models and evaluate potential mechanisms of therapy resistance to TNKS2 inhibition. Identifying a safe and effective approach to block hyperactive WNT signaling in multiple tumor types could have a profound impact on the clinical management of advanced cancers. Thus, we believe our work will contribute substantially to the overall goal of developing safe and effective targeted therapies for WNT-driven cancers.

项目概要 WNT 通路过度激活是结直肠癌 (CRC) 的主要致癌驱动因素，并与许多其他癌症类型的疾病进展和耐药性，包括肺癌 (LUAD)、乳腺癌和前列腺癌事实上，针对过度活跃的 WNT 的临床前模型系统有强有力的证据。我们和其他人已经证明，信号传导可以在多种癌症模型中提供显着的治疗益处。阻断多余的端锚聚合酶（TNKS 和 TNKS2）的功能可以抑制过度活跃的 WNT 信号传导，阻碍癌细胞增殖并促进分化，特别是在 CRC 中。然而，WNT 信号传导。对于经测试的多个器官系统的稳态维持也至关重要，有效的药物。与 TNKS 抑制剂一样，阻断 WNT 已在重要组织中表现出一系列靶向毒性，例如确定肿瘤限制性 WNT 通路抑制策略是精确度的一个主要目标。肿瘤学。晚期癌症的基因组通常受到严重破坏，包括大量基因的增加和损失。据推测，这些包含许多基因的大规模改变支持了染色体片段。然而，它们也会导致不驱动癌症进展的“过客”基因的丢失，但可能会无意中“重新连接”信号网络。我们将检验大规模染色体缺失的假设。 8p 染色体会诱导 TNKS 丢失，从而产生对 TNKS2 的肿瘤特异性依赖性，这可以通过仅在癌细胞中用于阻断 WNT，因为正常细胞表达两种冗余的家族成员。在目标 1 中，使用一组 CRC、LUAD 和乳腺癌细胞，应该不会受到选择性靶向的影响。细胞系和源自患者的类器官，结合基于 CRISPR 的基因组编辑，我们将确定如何杂合和纯合染色体缺失会影响对 TNKS2 抑制的反应。 In Aim 定义对 TNKS 破坏和 TNKS2 抑制最敏感的下游蛋白质靶标。 2 我们将利用我们开发的独特转基因 shRNA 系统来定义系统性和选择性的安全性体内 TNKS2 抑制并确定免疫活性动物中选择性 TNKS2 抑制的功效侵袭性 CRC 和 LUAD 模型将确定新型 TNKS2 选择性小药物的功效。癌细胞系和类器官模型中的分子，并评估治疗耐药的潜在机制 TNKS2 抑制。确定一种安全有效的方法来阻断多种肿瘤类型中过度活跃的 WNT 信号传导可能会产生以下效果：对晚期癌症的临床管理产生深远的影响因此，我们相信我们的工作将做出贡献。基本上实现了针对 WNT 驱动的癌症的安全开发和有效靶向治疗的总体目标。