Mechanisms of Biguanide Sensitivity in GBM

项目总结/摘要 广泛用于治疗2型糖尿病的双胍类药物二甲双胍正在被评估为一种抗糖尿病药物。 肿瘤药物，包括GBM（NCT 02780024，NCT 03243851）。的各种作用机制 二甲双胍作为一种抗肿瘤药物仍在研究中，但最近的研究明确表明， 其在肿瘤细胞生长、细胞死亡、基因表达和信号传导中的治疗作用依赖于抑制肿瘤细胞生长、细胞死亡、基因表达和信号传导。 线粒体复合体I基于二甲双胍在某些癌症联合治疗中的成功， 目前正在研究线粒体复合物I抑制剂（MCI-i）。二甲双胍的血浆扩散 膜发生缓慢。它的进入是由两个转运蛋白OCT 1和OCT 2促进的，这两个转运蛋白在细胞外没有很好地表达。 肝脏和肾脏。由于其在治疗浓度下缺乏在其他组织中的积累，这提出了一个问题。 因此，可以利用对低浓度二甲双胍反应更好的肿瘤亚型的鉴定 用于靶向二甲双胍治疗。Metabolic GBM试验可能不令人满意，因为没有分子标记物 区分二甲双胍应答者和非应答者。分子标记的鉴定可以大大改善 二甲双胍和其他基于MCI-i的治疗GBM。我们发现丙酮酸脱氢酶亚基（PDHA 1）是一种 GBM中MCI-1治疗的可能分子信标。我们将在体外和体内进行测试。我们还发现， 能量传感器AMPK在GBM的子集中提供对MCI-1疗法的抗性。我们将测试一种穿透大脑的AMPK 抑制剂恢复体内MCI-1敏感性。最后，我们的分子分析表明，ErbB激活是一个可能的机制， 对AMPK抑制的抗性。在小鼠模型中，我们将测试脑穿透ErbB抑制剂是否能克服AMPK 体内抑制剂抗性。

Project Summary/Abstract The biguanide drug metformin that is widely used for the management of Type 2 diabetes is being evaluated as an anti- neoplastic agent in cancer trials including GBM (NCT02780024, NCT03243851). The various mechanisms of action of metformin as an anti-neoplastic agent is still being investigated, but recent studies have unequivocally demonstrated that its therapeutic effects in tumor cell growth, cell death, gene expression, and signaling are dependent on inhibition of mitochondrial complex I. Based on the success of metformin in combination therapy in some cancers, new generation of mitochondrial complex I inhibitors (MCI-i) are currently under investigation. Diffusion of metformin across the plasma membrane occurs slowly. Its entry is facilitated by two transporters OCT1 and OCT2 that are not well expressed outside the liver and kidney. This presents a problem due its lack of accumulation in other tissues at therapeutic concentrations. Therefore, identification of tumor subtypes that respond better to lower concentrations of metformin may be leveraged for targeted metformin therapy. Metformin GBM trials may be unsatisfactory since there are no molecular markers to distinguish metformin responders from non-responders. Identification of molecular markers may greatly improve metformin and other MCI-i-based therapy in GBM. We identified that a pyruvate dehydrogenase subunit (PDHA1) is a possible molecular beacon for MCI-i therapy in GBM. We will test this in vitro and in vivo. We also found that the cellular energy sensor AMPK provides resistance to MCI-i therapy in a subset of GBM. We will test if a brain-penetrating AMPK inhibitor restores MCI-i sensitivity in vivo. Lastly, our molecular analysis showed that ErbB activation is a likely mechanism of resistance to AMPK inhibition. In mouse models we will test if a brain-penetrating ErbB inhibitor overcomes AMPK inhibitor resistance in vivo.