Pemetrexed and sildenafil for lung cancer

培美曲塞和西地那非治疗肺癌

• 批准号: 9229539
• 负责人: PAUL DENT
• 金额: $ 31.4万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-11 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229539
• 关键词: 5' -AMP-activated protein kinase; Aminoimidazole Carboxamide; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Autophagocytosis; BAX gene; BCL1 Oncogene; Biological Models; Biology; Blood flow; CASP8 and FADD-like apoptosis regulating protein; Cancer Patient; Cancer cell line; Carboplatin; Cells; Cellular Structures; Cessation of life; Cialis; Cisplatin; Clinic; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Diagnosis; Dose; Doxorubicin; Drug Combinations; Drug Interactions; Enzymes; Erectile dysfunction; Etoposide; FDA approved; FRAP1 gene; Folic Acid; Folic Acid Antagonists; Genetic Models; Human; Hydroxymethyltransferases; In Vitro; Ischemia; Lead; Ligands; Lung; Maintenance Therapy; Malignant Epithelial Cell; Malignant neoplasm of lung; Molecular; Mus; Myocardium; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Pathway interactions; Patients; Pemetrexed; Pharmaceutical Preparations; Phosphorylation; Platinum; Protein Tyrosine Phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Pulmonary Hypertension; Reaction; Receptor Activation; Recruitment Activity; Regulation; Relaxation; Reperfusion Therapy; Research; Resistance; Ribonucleotides; Site; Stimulus; Synthase I; System; TNFRSF6 gene; Therapeutic Agents; Thymidylate Synthase; Thymidylate Synthase Inhibitor; Toxic effect; Toxicity due to chemotherapy; Transgenic Organisms; Translating; Treatment Efficacy; Tyrosine Phosphorylation; Vascular Smooth Muscle; Viagra; Vincristine; base; cancer cell; cancer therapy; cell killing; cell type; clinically relevant; experience; gemcitabine; glycine amide; in vivo; inhibitor/antagonist; innovation; killings; mTOR inhibition; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; phase I trial; phosphodiesterase V; public health relevance; receptor; sildenafil; standard of care; tadalafil; thymidylate synthase-dihydrofolate reductase; tumor; tumor growth; vardenafil

DESCRIPTION (provided by applicant): In the this application we propose to build on our experience with Pemetrexed (NCT01450384) and develop a novel drug therapy for non-small cell lung carcinoma (NSCLC) combining the standard of care drug Pemetrexed with approved phosphodiesterase-5 (PDE5) inhibitors. Pemetrexed synergizes with approved PDE5 inhibitors to kill NSCLC cells in vitro and in vivo. Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are inhibitors of PDE5, which regulate cGMP levels and induce expression of nitric oxide synthase (NOS), increasing NO and ONOO- levels in tumor cells. Pemetrexed was developed as an inhibitor of thymidylate synthase but which was subsequently shown to inhibit the enzyme AICART. Aim 1. Determine in detail the molecular mechanisms by which PDE5 inhibitors and Pemetrexed interact to kill NSCLC cells. We hypothesize that PDE5 inhibitor and Pemetrexed treatment interact to abolish AKT, mTOR and p70 S6K activities leading to elevated levels of toxic autophagy and reduced expression of c-FLIP-s, BCL-XL and MCL-1. We hypothesize that PDE5 inhibitor and Pemetrexed treatment increases PERK/eIF2α phosphorylation also leading to suppression of c-FLIP-s, MCL-1 and BCL-XL expression. This results in higher free BAX and BAK (activity) and elevated levels of untethered Beclin1 which also facilitates the induction of toxic autophagy. We will determine the mechanisms by which sildenafil overcomes Pemetrexed resistance in NSCLC cells. We also hypothesize that PDE5 inhibitors: (a) increase iNOS levels which inactivates mTOR and p70 S6K and; (b) inhibit PTPase activity promoting death receptor CD95 tyrosine phosphorylation, ligand independent receptor activation and DISC formation. Aim 2. Determine using animal models whether PDE5 inhibitors enhance the therapeutic efficacy of Pemetrexed in NSCLC tumors. We will make use of transgenic and athymic animal models of NSCLC. Aim 2 will validate our in vitro data with NSCLCs using animal models with human lung cancer cell lines and mouse genetic models of lung cancer. We will determine whether sildenafil/Pemetrexed treatment chemo-sensitizes lung cancer tumors in vivo (to cisplatin).

描述（由申请人提供）：在本申请中，我们建议以培美曲塞（NCT01450384）的经验为基础，结合标准护理药物培美曲塞和已批准的磷酸二酯酶 5 (PDE5) 抑制剂，开发一种针对非小细胞肺癌 (NSCLC) 的新型药物疗法。培美曲塞与已批准的 PDE5 抑制剂协同作用，可在体外和体内杀死 NSCLC 细胞。西地那非 (Viagra)、伐地那非 (Levitra) 和他达拉非 (Cialis) 是 PDE5 抑制剂，可调节 cGMP 水平并诱导一氧化氮合酶 (NOS) 的表达，从而增加肿瘤细胞中 NO 和 ONOO- 的水平。培美曲塞被开发为胸苷酸合酶抑制剂，但随后被证明可以抑制 AICART 酶。目标 1. 详细确定 PDE5 抑制剂和培美曲塞相互作用杀死 NSCLC 细胞的分子机制。我们假设 PDE5 抑制剂和培美曲塞治疗相互作用，消除 AKT、mTOR 和 p70 S6K 活性，导致毒性自噬水平升高，并减少 c-FLIP-s、BCL-XL 和 MCL-1 的表达。我们假设 PDE5 抑制剂和培美曲塞治疗会增加 PERK/eIF2α 磷酸化，也导致 c-FLIP-s、MCL-1 和 BCL-XL 表达受到抑制。这导致更高的游离 BAX 和 BAK（活性）以及不受束缚的 Beclin1 水平升高，这也有助于诱导毒性自噬。我们将确定西地那非克服 NSCLC 细胞中培美曲塞耐药性的机制。我们还假设 PDE5 抑制剂： (a) 增加 iNOS 水平，从而使 mTOR 和 p70 S6K 失活； (b) 抑制 PTPase 活性，促进死亡受体 CD95 酪氨酸磷酸化、配体非依赖性受体激活和 DISC 形成。目标 2. 使用动物模型确定 PDE5 抑制剂是否增强培美曲塞在 NSCLC 肿瘤中的治疗效果。我们将利用非小细胞肺癌的转基因和无胸腺动物模型。目标 2 将使用人类肺癌细胞系动物模型和肺癌小鼠遗传模型来验证我们的 NSCLC 体外数据。我们将确定西地那非/培美曲塞治疗是否使体内肺癌肿瘤化疗敏感（对顺铂）。