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.

项目摘要 WNT通路过度活化是结直肠癌（CRC）中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 癌事实上，有来自临床前模型系统的有力证据表明，靶向过度活跃的WNT 信号传导可以在多种癌症模型中提供显著的治疗益处。我们和其他人已经证明， 阻断多余的端锚聚合酶（TNKS和TNKS 2）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驱动分化，特别是在CRC中。然而，WNT信令 对于多器官系统的稳态维持也是至关重要的。因此，有效的药物 阻断WNT，像TNKS抑制剂一样，已经显示出在必需组织中的一系列靶向毒性，例如 肠和骨头。确定肿瘤限制性WNT通路抑制策略是精确性的主要目标 肿瘤学 晚期癌症通常包含对其基因组的显著破坏，包括大细胞的获得和损失。 染色体片段这些包含许多基因的大规模改变被认为支持了 癌细胞生长然而，它们也会导致不会推动癌症进展的“乘客”基因的丢失， 但可能无意地“重新布线”信令网络。这种癌症特有的附带损害可能会提供 治疗干预的机会。我们将测试一个假设，即一个大的染色体缺失， 染色体8p诱导TNKS的丢失，产生对TNKS 2的肿瘤特异性依赖性， 仅在癌细胞中阻断WNT。因为正常细胞表达两种冗余家族成员， 不应受到选择性目标的影响。在目标1中，使用一组CRC、LUAD和乳腺癌细胞， 线和患者来源的类器官，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影响对TNKS 2抑制的应答。此外，我们将 定义了对TNKS破坏和TNKS 2抑制最敏感的下游蛋白质靶标。在aim中 2.我们将利用我们开发的独特的转基因shRNA系统，来确定系统性和选择性的安全性。 体内TNKS 2抑制和确定选择性TNKS 2抑制在免疫活性动物中的功效 侵袭性CRC和LUAD的模型。目的3将确定新的TNKS 2选择性小靶向治疗的功效。 分子在癌细胞系和类器官模型中的作用，并评估对 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， 对晚期癌症的临床管理产生深远影响。因此，我们相信我们的工作将有助于 这基本上符合为WNT驱动的癌症开发安全有效的靶向疗法的总体目标。