Tumor selective inhibition of the WNT pathway

WNT 通路的肿瘤选择性抑制

• 批准号: 10503200
• 负责人: LUKAS Edward DOW
• 金额: $ 59.72万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/10503200
• 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; Homeostasis; Human; Hyperactivity; Hypersensitivity; 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; Pharmacology; 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; base; beta catenin; body system; bone; cancer cell; cancer therapy; cancer type; cellular engineering; chromosome 8p loss; colorectal cancer treatment; genetic approach; genome editing; in vivo; inhibitor; injury and repair; innovation; malignant breast neoplasm; molecular targeted therapies; mouse model; novel; novel strategies; 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; treatment strategy; tumor; tumor progression

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 癌症。事实上，来自临床前模型系统的有力证据表明，针对过度活跃的 WNT 信号传导可以在多种癌症模型中提供显着的治疗益处。我们和其他人已经证明 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，特别是在结直肠癌中。然而，WNT 信号传导 对于多个器官系统的稳态维持也至关重要。因此，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 肠和骨。定义肿瘤限制性 WNT 通路抑制策略是精准度的主要目标 肿瘤学。 晚期癌症的基因组通常受到严重破坏，包括大量基因的获得和损失。 染色体片段。这些涵盖许多基因的大规模改变被认为支持 癌细胞生长。然而，它们也会导致不会驱动癌症进展的“过客”基因的丢失， 但可能会无意中“重新连接”信号网络。这种癌症特异性的附带损害可能会提供 治疗干预的机会。我们将检验以下假设： 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 仅用于阻断癌细胞中的 WNT。由于正常细胞同时表达冗余的家族成员，因此它们 应不受选择性目标的影响。在目标 1 中，使用 CRC、LUAD 和乳腺癌细胞组 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。此外，我们将 定义对 TNKS 破坏和 TNKS2 抑制最敏感的下游蛋白质靶标。瞄准 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。目标 3 将确定新型 TNKS2 选择性小分子药物的功效 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： 对晚期癌症的临床治疗产生深远影响。因此，我们相信我们的工作将做出贡献 基本上实现了为 WNT 驱动的癌症开发安全有效的靶向疗法的总体目标。