Development of a WNT Inhibitor for Advanced Stage Lung Cancer

开发用于晚期肺癌的 WNT 抑制剂

• 批准号: 8928059
• 负责人: Darren Orton
• 金额: $ 90.73万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928059
• 关键词: Academia; Accounting; Animal Model; Animals; Bioavailable; Biodistribution; Biological Assay; Biological Availability; Biological Markers; Brain; Cancer Patient; Cancer cell line; Cell Line; Cessation of life; Characteristics; Chemicals; Chemistry; Clinical; Clinical Treatment; Clinical Trials; Colorectal Cancer; Common Neoplasm; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Excretory function; Family; Goals; Growth; Health; In Vitro; KRAS2 gene; Lead; Legal patent; Libraries; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Marketing; Maximum Tolerated Dose; Metabolic; Metabolism; Metastatic malignant neoplasm to brain; Modeling; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Property; Protocols documentation; Resistance; Signal Transduction; Site; Small Business Innovation Research Grant; Staging; Testing; Therapeutic; Toxic effect; WNT Signaling Pathway; Work; Xenograft Model; Xenograft procedure; absorption; analog; base; cancer therapy; cancer type; experience; good laboratory practice; improved; in vitro Model; in vivo; inhibitor/antagonist; mortality; mouse model; mutant; novel; novel therapeutics; patient population; pre-clinical; preclinical safety; scaffold; small molecule; standard of care; targeted treatment; therapy development; therapy resistant; toxicity characteristics; tumor

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.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是最常见的肺癌。 NSCLC的一半显示了Wnt激活，标志着存活率差。 Stemsynergy Therapeutics Inc（SSTI）基于新的化学支架确定了Wnt抑制剂家族，我们的铅分子（SST-215）表现出对WNT驱动的结直肠癌的有效性。在I期SBIR研究中，许多NSCLC细胞系也对SSTI化合物非常敏感。值得注意的是，SST-215对源自肺转移酶，KRAS突变肺癌系和患者来源的NSCLC异种移植模型的抗治疗耐药细胞系显示了功效。尽管有这样的承诺，SST-215仍被代谢，并在肺和大脑（NSCLC转移的位点）中积累到低水平。我们建议测试我们的铅分子支架的衍生物，其中许多已经合成，以鉴定具有针对肺癌优化的生物利用度和分布特征的化合物，包括转移的常见部位。有效化合物将通过吸收，分布，代谢，排泄和毒性（ADMET）特征进一步分层。 功效将在肺癌小鼠模型范围内进行评估，其目的是将铅分子推进到临床发育中，以治疗转移性肺癌。