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

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展，但非小细胞肺癌（NSCLC）患者的生存率与20年前几乎相同。目前靶向NSCLC癌症增殖机制（如K-RAS和EGFR）的治疗一直是制药行业和学术实验室的重点。这种疗法在延长中位无进展生存期方面优于经典化疗药物，但对总生存期几乎没有影响。近年来 癌症是高度异质性的，并且对化疗的初始敏感性是对更分化（高度增殖）的细胞类型的影响。癌症 分布在初始肿瘤块内的干细胞群对化疗具有抗性，并显示出高度侵袭性/转移性表型。StemSynergy Therapeutics Inc.（SSTI）是一家生物制药公司，专注于发现，开发和商业化的药物，目标是干细胞和癌症干细胞的基本途径。最近的高知名度文献研究表明，NSCLC中的癌症干细胞群体表现出异常的Wnt途径活性，对分泌的Wnt抑制剂敏感。迫切需要Wnt通路的抑制剂，因为目前还没有FDA批准的药物或处于后期临床试验阶段的药物靶向该通路。本申请描述了一类新的激活酪蛋白激酶1a（CK 1a）的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，这些小分子还激活p53。StemSynergy旨在开发一种NSCLC治疗方法，通过靶向耐药细胞/癌症干细胞来消除ALL癌细胞，从而与目前FDA批准的NSCLC药物协同作用，从而提高肺癌患者的生存率。 公共卫生相关性：肺癌是死亡和发病的最大原因，全球每年有140万人死亡。StemStynergy正在开发Wnt抑制剂，以靶向耐药癌症干细胞群体，以减少转移并提高总生存率。

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.