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（由应用程序提供）：在本应用程序中，我们建议以Pemetrexed（NCT01450384）的经验来建立我们的经验，并开发了一种新型的药物治疗，以结合了与批准的磷酸二二酶-5（PDE5）的护理药物标准的非小细胞肺癌（NSCLC）相结合的护理药物标准。 Pemetrexed与认可的PDE5抑制剂协同杀死NSCLC细胞在体外和体内杀死NSCLC细胞。西地那非（伟哥），瓦丁纳非（Levitra）和他达拉非（cialis）是PDE5的抑制剂，它们调节CGMP水平并影响一氧化氮合酶（NOS）的表达，肿瘤细胞中不增加和on-On-On-On-On-On-On-On-On-On-On-On-On-On-On-On-On-On-On-On-On-nos。 Pemetrexed作为胸苷酸合酶的抑制剂开发，但随后被证明可以抑制酶AICART。 AIM 1。详细确定PDE5抑制剂和Pemetrexed相互作用以杀死NSCLC细胞的分子机制。我们假设PDE5抑制剂和Pemetrexed治疗相互作用，以取消AKT，MTOR和P70 S6K活性，从而导致有毒自噬水平升高，并且C-FLIP-S，BCL-XL和MCL-1的表达降低。我们假设PDE5抑制剂和Pemetrexed治疗增加了PERK/EIF2α磷酸化也导致C-Flip-S，Mcl-1和Bcl-XL表达抑制。这会导致更高的自由bax和bak（活动）和不受束缚的beclin1水平升高，这也促进了有毒自噬的诱导。我们将确定硅酸盐克服NSCLC细胞中刺激性抗性的机制。我们还假设PDE5抑制剂：（a）增加使MTOR和p70 S6K失活的iNOS水平和； （b）抑制促进死亡受体CD95酪氨酸磷酸化，配体独立受体激活和椎间盘形成的PTPase活性。 AIM 2。确定使用动物模型PDE5抑制剂是否提高了NSCLC肿瘤中垂体的治疗效率。我们将利用NSCLC的转基因和无腹动物模型。 AIM 2将使用具有人类肺癌细胞系和肺癌小鼠遗传模型的动物模型来验证我们的体外数据。我们将确定Sildenafil/Pemetrexed治疗化学敏感性肺癌肿瘤是否体内（到顺铂）。