The Akt/mTOR pathway is an emerging target in cancer, because Akt and mTOR are constitutively active in many types of cancer, which often confers a poor prognosis. Our studies have identified an important role for this pathway in the formation, maintenance, and therapeutic resistance of lung cancer. We have a series of therapeutic and non-therapeutic protocols that are currently open, as well as protocols that are in the planning stage. Our therapeutic protocols utilize pathway inhibitors as single agents or in combination with other standard chemotherapies, and our protocols are open at the Clinical Research Center. This past year we completed enrollment in a Phase I trial of nelfinavir in subjects with relapsed for refractory solid tumors. This protocol is based on our preclinical studies that showed that nelfinavir is an effective anti-cancer agent in vitro and in vivo that works through multiple mechanisms including Akt inhibition and the induction of apoptosis, ER stress and autophagy. We established the MTD, DLT, and observed clinical activity in patients with neuroendocrine tumors. We plan on continuing clinical evaluation of nelfinavir in combination with other drugs, and as a single agent. A second protocol that is open is a Phase I/II protocol of combining sirolimus (an inhibitor of mTOR) with pemetrexed in patients with refractory or resistant NSCLC. This protocol is based on work from our laboratory that shows that this combination was highly effective in vitro and in vivo. We have completed the Phase I portion and have defined the MTD and DLT. We have observed a RR of 37%, which exceeds the 9% RR of pemetrexed as a single agent in the second line setting. The Phase II portion continues. A third protocol that is open is a pilot trial of sirolimus in patients with PTEN hamartoma tumor syndromes (PHTS). The most common syndrome in PHTS is Cowden Syndrome, and all of these syndromes are characterized by benign tumors in many tissues and an increased predisposition to many types of cancer. Because most of these patients have germline mutations in the tumor suppressor PTEN, which negatively controls the Akt/mTOR pathway, we are testing whether sirolimus will inhibit mTOR in various tissues, and whether it will affect tumor growth or metabolism. We have completed enrollment in this trial, and have observed clinical benefit in all patients as defined by regression of benign tumors in skin or GI tract and/or improvement in neuropsychological testing. We plan on continued testing of sirolimus in this population, with extension of the treatment time and dose adjustment based on trough level. We also plan on testing other pathway inhibitors in this patient population. The last trial that is open is a tissue procurement study at NCI/Navy Medical Oncology. This protocol allows to procure tissues from cancer patients when it does not involve significant morbidity. Such tissues are anonymized and are quite valuable in studies designed to assess new predictive or prognostic biomarkers. Finally, we have other trials that are in the approval process but are not yet open. These include a pilot prevention study of sirolimus in heavy smokers or those at high risk to develop lung cancer. A similar study is also in development with metformin. These studies are consistent with our mission and will further our understanding of the utility of inhibiting the Akt/mTOR pathway for the treatment or prevention of lung cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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West, Lisandra; Vidwans, Smruti J; Campbell, Nicholas P et al. (2012) A novel classification of lung cancer into molecular subtypes. PLoS One 7:e31906
Zhang, Chunyu; Elkahloun, Abdel G; Robertson, Matthew et al. (2011) Loss of cytoplasmic CDK1 predicts poor survival in human lung cancer and confers chemotherapeutic resistance. PLoS One 6:e23849
West, Kip A; Dennis, Phillip A (2011) Starting with the ABCs: Akt in breast cancer. Mol Cancer Ther 10:2031
Hollander, M Christine; Blumenthal, Gideon M; Dennis, Phillip A (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11:289-301
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Hollander, M C; Maier, C R; Hobbs, E A et al. (2011) Akt1 deletion prevents lung tumorigenesis by mutant K-ras. Oncogene 30:1812-21
Zhang, Chunyu; Elkahloun, Abdel G; Liao, Hongling et al. (2011) Expression signatures of the lipid-based Akt inhibitors phosphatidylinositol ether lipid analogues in NSCLC cells. Mol Cancer Ther 10:1137-48
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Han, Wei; Gills, Joell J; Memmott, Regan M et al. (2009) The chemopreventive agent myoinositol inhibits Akt and extracellular signal-regulated kinase in bronchial lesions from heavy smokers. Cancer Prev Res (Phila) 2:370-6

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