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/eIF2? 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).

Public Health Relevance

Non-small cell lung carcinoma (NSCLC) is diagnosed in > 200,000 patients per annum with ~160,000 deaths, so there is a desperate need for new approaches to treat NSCLC. Our research will define the mechanisms by which clinically relevant PDE5 inhibitors synergize with Pemetrexed to kill NSCLC cells and determine whether these combinations translate into animal model systems of NSCLC to suppress tumor growth, prolong survival, and to have negligible normal tissue toxicities. Based on our track record to translating drug combinations to the clinic, e.g. NCT01075113, NCT01450384, NCT01817751; NCT01375699, our data has the potential to lead to a Phase I trial in NSCLC patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Arya, Suresh
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Virginia Commonwealth University
Schools of Medicine
United States
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Booth, Laurence; Roberts, Jane L; Kirkwood, John et al. (2018) Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells. Adv Cancer Res 137:1-15
Booth, Laurence; Roberts, Jane L; Rais, Rumeesa et al. (2018) [Neratinib + Valproate] exposure permanently reduces ERBB1 and RAS expression in 4T1 mammary tumors and enhances M1 macrophage infiltration. Oncotarget 9:6062-6074
Booth, Laurence; Roberts, Jane L; Rais, Rumeesa et al. (2018) Palbociclib augments Neratinib killing of tumor cells that is further enhanced by HDAC inhibition. Cancer Biol Ther :1-12
Booth, Laurence; Roberts, Jane L; Samuel, Peter et al. (2018) The irreversible ERBB1/2/4 inhibitor neratinib interacts with the PARP1 inhibitor niraparib to kill ovarian cancer cells. Cancer Biol Ther 19:525-533
Booth, Laurence; Roberts, Jane; Poklepovic, Andrew et al. (2018) The CHK1 inhibitor SRA737 synergizes with PARP1 inhibitors to kill carcinoma cells. Cancer Biol Ther 19:786-796
Booth, Laurence; Roberts, Jane Lisa; Poklepovic, Andrew et al. (2018) Prior exposure of pancreatic tumors to [sorafenib + vorinostat] enhances the efficacy of an anti-PD-1 antibody. Cancer Biol Ther :1-13
Booth, Laurence; Roberts, Jane L; Avogadri-Connors, Francesca et al. (2018) The irreversible ERBB1/2/4 inhibitor neratinib interacts with the BCL-2 inhibitor venetoclax to kill mammary cancer cells. Cancer Biol Ther 19:239-247
Booth, Laurence; Roberts, Jane L; Rais, Rumeesa et al. (2018) Valproate augments Niraparib killing of tumor cells. Cancer Biol Ther 19:797-808
Booth, Laurence; Roberts, Jane L; Poklepovic, Andrew et al. (2018) The levels of mutant K-RAS and mutant N-RAS are rapidly reduced in a Beclin1 / ATG5 -dependent fashion by the irreversible ERBB1/2/4 inhibitor neratinib. Cancer Biol Ther 19:132-137
Booth, Laurence; Roberts, Jane L; Spiegel, Sarah et al. (2018) Fingolimod augments Pemetrexed killing of non-small cell lung cancer and overcomes resistance to ERBB inhibition. Cancer Biol Ther :1-11

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