Tumor selective inhibition of the WNT pathway

WNT 通路的肿瘤选择性抑制

• 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
• 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

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.

项目总结 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，从临床前模型系统中有强有力的证据表明，针对过度活跃的WNT 信号转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了 阻断多余的Tankyrase酶(TNKS和TNKS2)的功能可以抑制WNT的过度活性 信号，阻碍癌细胞的增殖和驱动分化，特别是在结直肠癌中。然而，WNT信令 对维持多器官系统的动态平衡也是至关重要的。因此，有效的药物 与TNKS抑制剂一样，阻断WNT在必要的组织中显示出一系列靶标毒性，如 肠子和骨头。确定肿瘤限制性WNT途径抑制的策略是精确度的主要目标 肿瘤学。 晚期癌症通常包含对其基因组的重大破坏，包括大量的得失 染色体片段。这些包含许多基因的大规模改变被认为支持 癌细胞生长。然而，它们也会导致不会导致癌症进展的“乘客”基因的丢失， 但可能会无意中重新布线信令网络。这种癌症特异性的附带损害可能会提供 治疗干预的机会。我们将检验这样一种假设，即大量的染色体缺失 染色体8p会导致TNKS的丢失，从而产生对TNKS2的肿瘤特异性依赖，这种依赖可以是 仅在癌细胞中用于阻断WNT。因为正常细胞表达两个多余的家庭成员，所以他们 应该保持不受选择性目标的影响。在目标1中，使用一组CRC、LUAD和乳腺癌细胞 与基于CRISPR的基因组编辑相结合，我们将确定如何 杂合性和纯合性染色体缺失影响对TNKS2抑制的反应。此外，我们还将 确定对TNKS干扰和TNKS2抑制最敏感的下游蛋白质靶点。在AIM 2我们将开发一种独特的转基因shrna系统，以确定系统性和选择性的安全性。 免疫活性动物体内对TNKS2的抑制作用及选择性抑制效果的测定 积极进取的CRC和LUAD模型。目标3将确定新型TNKS2选择性Small的疗效 肿瘤细胞系和有机模型中的分子，并评估治疗耐药的潜在机制 TNKS2抑制作用。 找出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信号可能会 对晚期癌症的临床治疗产生了深远的影响。因此，我们相信，我们的工作将为 这大大有助于为WNT驱动的癌症开发安全有效的靶向治疗的总体目标。