Lung cancer kills more Americans than any other cancer, and ~90,000,000 Americans are at permanent increased risk to develop lung cancer. To address this health problem, our group studies the role of signal transduction pathways that promote the formation, maintenance, and therapeutic resistance of lung cancer. We have focused on one pathway, the Akt/mTOR pathway. Our research can broadly divided into two areas, to understand the mechanisms of activation and consequences of activation of the Akt/mTOR pathway in lung cancer, and to develop approaches to inhibit the pathway. Several studies from our group have validated the Akt/mTOR pathway as a target for prevention of lung cancer. We showed that two tobacco components, nicotine and the tobacco-specific carcinogen, NNK, rapidly activate the pathway in normal human lung epithelial cells. Activation occurred within minutes at concentrations that are achievable in smokers, and could be inhibited with pathway inhibitors or nicotinic antagonists. Because activation of Akt caused a partially transformed phenotype through inhibition of apoptosis and decreased reliance on extracellular growth factors, we have hypothesized that Akt activation serves as a biochemical gatekeeper for tobacco-related carcinogenesis. In support of this hypothesis, we showed that activation of Akt and mTOR increased with phenotypic progression of tobacco-induced lung lesions in a mouse model of lung cancer. Most recently, we showed that rapamycin, an mTOR inhibitor that is FDA-approved for other indications, inhibited the number of tobacco carcinogen-induced lung lesions by 90%, as well as tumor size. Together, these studies have expanded the concept of how tobacco causes lung cancer, and have raised awareness of pathway activation as a biomarker for prevention studies. Importantly, they provide a strong rationale to use mTOR inhibitors in human lung cancer prevention trials.
Other studies from our group have validated inhibition of the Akt pathway as a target for treatment of lung cancer. We first identified constitutive activation of Akt in 16/17 NSCLC cell lines, and showed that pathway activation promoted cellular survival under conditions of serum deprivation or administration of chemotherapy or radiation therapy. Using a set of 252 lung cancer specimens with surrounding normal tissues and clinical outcomes, we have shown that Akt activation is specific for lung cancers and not surrounding lung tissue, and confers a poor prognosis especially for those with early stage disease. This is potentially important because most patients diagnosed with lung cancer through screening will have early stage disease. Determining which subset of patients will benefit most from more intensive observation and/or therapy could be of great clinical benefit. Our studies suggest that Akt activation could be one factor to distinguish patients that are at increased risk to relapse or recur.
Despite the strong rationale to target Akt, no Akt inhibitors are clinically approved. We have led a large collaborative effort in academia, industry and the Developmental Therapeutics Program at NCI, to develop lipid-based inhibitors of Akt called phosphatidylinositol ether lipid analogues (or PIAs). PIAs were synthesized using molecular modeling of Akt, and members of our group and our colleagues at Georgetown University are co-inventors of PIAs. Unlike most pharmaceutical efforts to develop Akt inhibitors that have focused on the ATP binding domain, the PIAs that we are developing target the pleckstrin homology (PH) domain. We identified 5 active PIAs that inhibit Akt within minutes and selectively kill cancer cells with high levels of Akt activation. More recently, we have identified molecular correlates of response to PIAs, as well as other biological effects of PIAs that contribute to their toxicity, and could be used as biomarkers for administration of PIAs. We are continuing to investigate mechanisms of action of PIAs and other lipid-based Akt inhibitors, and we are comparing the biologic activities of lipid-based inhibitors to small molecule inhibitors that target the ATP binding region of Akt. Other efforts to develop pathway inhibitors include the use of bioinformatics to perform virtual screening of large chemical libraries, and the screening of drugs that are FDA-approved for other indications for inhibition of Akt and induction of apoptosis in Akt-dependent cancer cells.
To complement our preclinical efforts to develop Akt inhibitors, we are implementing clinical trials that are testing inhibitors of the Akt/mTOR pathway in lung cancer patients. Examples of proposed trials include first-in-human (so called ''Phase 0'') trials with PIAs, trials combining mTOR inhibitors with standard chemotherapies, and trials that will test ''off the shelf'' drugs for their ability to inhibit Akt in lung cancer patients. Together, these studies could increase therapeutic options for lung cancer patients and could shed insight into the clinical benefit achieved by inhibiting the Akt/mTOR pathway.
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