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.

项目摘要 Wnt途径过度激活是结直肠癌（CRC）的主要致癌驱动力，直接与许多其他癌症类型的疾病进展和耐药性，包括肺（LUAD），乳房和前列腺癌症。实际上，临床前模型系统有强有力的证据，这些系统针对多活跃Wnt 信号传导可以在多个癌症模型中提供显着的热益处。我们和其他人表明阻止冗余坦克酶酶的功能（TNK和TNK2）可以抑制过度活跃的Wnt 信号传导，阻碍癌细胞增殖和驱动分化，尤其是在CRC中。但是，Wnt信号传导对于多器官系统的稳态维护也至关重要。因此，有效的药物像TNK的抑制剂一样，块Wnt在基本时机（例如肠道和骨头。定义抑制肿瘤限制WNT途径的策略是精确的主要目标肿瘤学。高级癌症通常包含对其基因组的严重破坏，包括大的收益和损失染色体段。这些大规模的变化包括许多基因以支持癌细胞生长。但是，它们还导致损失不会驱动癌症进展的“乘客”基因，但是可能无意中的是信号网络。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：诱导TNK损失的8p染色体，会产生对TNK2的肿瘤特异性依赖性利用仅在癌细胞中阻止Wnt。因为正常细胞表达两个多余的家庭成员，所以应该不受选择性定位的影响。在AIM 1中，使用一组CRC，LUAD和乳腺癌细胞线条和患者衍生的类器官，结合基于CRISPR的基因组编辑，我们将确定如何确定杂合和纯合染色体缺失会影响对TNKS2抑制的反应。此外，我们会的定义对TNK中断和TNK2抑制最敏感的下游蛋白靶标。目标 2我们将利用我们开发的独特的转基因shRNA系统，以定义系统性和选择性的安全性 TNKS2在体内抑制，并确定免疫能力动物中选择性TNKS2抑制的效率积极的CRC和LUAD模型。 AIM 3将确定新型TNK2选择性小的效率癌细胞系和类器官模型中的分子，并评估治疗耐药性的潜在机制 TNKS2抑制。确定一种安全有效的方法来阻止多种肿瘤类型中的多动Wnt信号传导对高级癌症的临床管理有深远的影响。那我们相信我们的工作会做出贡献基本上是为WNT驱动的癌症开发安全有效的靶向疗法的总体目标。