Targeting stem cell populations in lung cancer by modulating the Wnt and p53 path

通过调节 Wnt 和 p53 路径靶向肺癌干细胞群

• 批准号: 8394835
• 负责人: Darren Orton
• 金额: $ 25.95万
• 依托单位: STEMSYNERGY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394835
• 关键词: Accounting; Biological Assay; Biological Products; Breast; Cancer Etiology; Cancer Model; Cancer Patient; Cell Line; Cell-Cell Adhesion; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Colon; Development; Diagnosis; Disease; Down-Regulation; Drops; Drug Delivery Systems; Drug Industry; Drug resistance; E-Cadherin; Epidermal Growth Factor Receptor; Event; FDA approved; Future; Gene Targeting; Genetic; Goals; Image; In Vitro; KRAS2 gene; Laboratories; Lead; Literature; Loss of E-cadherin Expression; Malignant Neoplasms; Malignant neoplasm of lung; Marketing; Methodology; Modern Medicine; Molecular; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphorylation; Population; Probability; Procedures; Process; Progression-Free Survivals; Proteins; Radiation therapy; Recurrence; Resistance; Side; Signal Transduction; Small Business Innovation Research Grant; Staging; Staining method; Stains; Stem cells; Survival Rate; TCF Transcription Factor; Testing; Therapeutic; Tumor-Derived; cancer cell; cancer stem cell; cancer therapy; casein kinase; casein kinase I; cell type; chemotherapy; commercialization; design; improved; in vivo; in vivo Model; inhibitor/antagonist; mortality; mutant; response; small molecule; standard of care; stem cell differentiation; stem cell population; synovial sarcoma; tumor

DESCRIPTION (provided by applicant): Despite significant advancements in modern medicine with regards to surgery, radiation therapy and imaging of tumors, the survival rate for patients with non-small-cell lung carcinoma (NSCLC) remain almost identical to 20 years ago. Current therapies targeting the proliferative mechanisms of NSCLC cancers such as K-RAS and EGFR have been the focus of a large effort in the pharmaceutical industry and academic laboratories. Such therapies have benefits over classical chemotherapy agents in prolonging median progression-free survival but have almost no effect on overall survival. In recent years, it has become clear that cancers are highly heterogeneous and the initial sensitivity to chemotherapy is the effect on the more differentiated (highly proliferative) cell types. The cancer stem cell population distributed within the initial tumor mass is resistant to chemotherapy and displays a highly invasive/metastatic phenotype. StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development, and commercialization of drugs that target pathways fundamental to stem cells and cancer stem cells. Recent high profile literature studies have shown that cancer stem cell populations in NSCLC demonstrate aberrant Wnt pathway activity are sensitive to secreted Wnt inhibitors. There is an urgent need for inhibitors of the Wnt pathway because currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target this pathway. This application describes the discovery and development of a new class of Wnt pathway inhibitors that activate Casein Kinase 1a (CK1a). Additional to the highly potent Wnt inhibitory activity, these small molecules activate p53. StemSynergy aims to develop a treatment for NSCLC that synergizes with current FDA approved drugs for NSCLC by targeting the drug resistant cells/cancer stem cells to eliminate ALL cancer cells and therefore increase survival for lung cancer patients. PUBLIC HEALTH RELEVANCE: Lung cancer is the largest cause of mortality and morbidity with 1.4 million deaths per year worldwide. StemStynergy is developing Wnt inhibitors to target the drug resistant cancer stem cell population to decrease metastasis and increase overall survival.

描述（由申请人提供）：尽管现代医学在手术，放射治疗和肿瘤成像方面取得了重大进步，但非小细胞肺癌（NSCLC）患者的存活率仍与20年前几乎相同。当前针对NSCLC癌症（例如K-RAS和EGFR）增殖机制的疗法一直是制药行业和学术实验室中大量努力的重点。这种疗法比经典化学疗法剂具有益处，可以延长中位无进展生存期，但几乎对总体生存没有影响。近年来， 已经很清楚的是，癌症是高度异质性的，对化学疗法的初始敏感性是对更分化（高度增殖）细胞类型的影响。癌症 在初始肿瘤质量内分布的干细胞种群对化学疗法有抵抗力，并且表现出高度侵入性/转移性表型。 Stemsynergy Therapeutics Inc.（SSTI）是一家生物制药公司，致力于发现针对干细胞和癌症干细胞基础的药物的发现，开发和商业化。最近的知名文献研究表明，NSCLC中的癌症干细胞群体表明异常的Wnt途径活性对分泌的Wnt抑制剂敏感。迫切需要对WNT途径的抑制剂，因为目前，在针对该途径的后期临床试验中，没有FDA批准的药物或药物。该应用描述了激活酪蛋白激酶1a（CK1A）的新类Wnt途径抑制剂的发现和开发。除了高度有效的Wnt抑制活性外，这些小分子激活了p53。 STEMSYNERGY旨在开发NSCLC的治疗方法，该治疗方法通过靶向抗药性细胞/癌症干细胞来消除所有癌细胞，从而与当前FDA批准的NSCLC批准的药物协同作用，从而增加肺癌患者的存活率。 公共卫生相关性：肺癌是死亡率和发病率的最大原因，全球每年140万人死亡。 Stemstynergy正在开发WNT抑制剂，以靶向抗药性癌症干细胞群，以减少转移并增加总体生存率。