Development of a WNT Inhibitor for Advanced Stage Lung Cancer

描述（由申请人提供）：非小细胞肺癌（NSCLC）是最常见的肺癌。一半的NSCLC显示WNT激活，这标志着较差的生存率。StemSynergy Therapeutics公司（SSTI）发现了一个基于新型化学支架的WNT抑制剂家族，我们的先导分子（SST-215）显示出对WNT驱动的结直肠癌的疗效。在I期SBIR研究中，许多NSCLC细胞系对SSTI化合物也非常敏感。值得注意的是，SST-215对来自肺转移的治疗耐药细胞系、KRAS突变肺癌细胞系和患者来源的非小细胞肺癌异种移植模型都有疗效——这是一个很高的疗效标准。尽管有这样的前景，SST-215在肺和脑（NSCLC转移部位）被代谢和积累到低水平。我们建议测试我们的先导分子支架的衍生物，其中许多已经合成，以确定具有生物利用度和分布特征的化合物，优化肺癌，包括常见的转移部位。有效化合物将根据吸收、分布、代谢、排泄和毒性（ADMET）特征进一步分层。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the most common lung cancer. Half of NSCLC shows WNT activation, marking poor survival. StemSynergy Therapeutics Inc (SSTI) has identified a family of WNT inhibitors based on a novel chemical scaffold, with our lead molecule (SST-215) demonstrating efficacy against WNT-driven colorectal cancer. In Phase I SBIR studies, many NSCLC cell lines were also exquisitely sensitive to SSTI compounds. Remarkably, SST-215 showed efficacy against both therapy-resistant cell lines derived from lung metastases, in KRAS mutant lung cancer lines, and in a patient-derived NSCLC xenograft model--a high bar for efficacy. Despite this promise, SST-215 is metabolized and accumulates to low levels in lung and brain (sites of NSCLC metastases). We propose to test derivatives of our lead molecule scaffold, many of which are already synthesized, to identify compounds with bioavailability and distribution characteristics optimized for the lung cancer, including the common sites of metastases. Potent compounds will be further stratified by absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Efficacy will be assessed in a spectrum of lung cancer mouse models, with a goal of advancing a lead molecule into clinical development for the treatment of metastatic lung cancer.