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Exploring Mechanisms and Predictors of Treatment Response to Improve Outcome of Standard Chemotherapy in Non-Small Cell Lung Cancer


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Non-small cell lung cancer (NSCLC) constitutes 85 percent of all lung cancers with systemic chemotherapy as the major treatment option. This cancer affects all major cross sections of the population in the US including military service members, veterans, their families, and other military beneficiaries. The standard frontline and maintenance therapies for non-squamous NSCLC rely heavily on pemetrexed (PEM) but the response to PEM is highly variable. Our preliminary data indicate that the dexamethasone (Dex), given to prevent PEM toxicity, may interfere with such treatment, mediated by the glucocorticoid receptor (GR) present in many tumors. Furthermore, work in our laboratories has shown that extended Dex treatment induces irreversible cell cycle blockade and senescence, which itself my therapeutic. Also, induction of cellular senescence may contribute to tumor sensitivity to the treatments, by mobilizing immune response against the tumors. We have assessed if this is a significant clinical issue using the experimental tracer, 3'-fluoro-3'-deoxy-thymidine ( FLT) (IND #105034), for positron emission tomography (PET), which we developed. FLT-PET will be used to determine if Dex, by interfering with proliferation in GR-positive tumors could make them resistant to PEM and help induce senescence. PEM targets thymidylate synthase (TS) and other synthetic enzymes in folate metabolism, thus inhibiting DNA synthesis. Dex, which acts through the GR, is typically administered on the days prior to, during and following PEM chemotherapy mainly to alleviate PEM-induced severe skin rash. Our studies of a panel of NSCLC cell line models have shown that Dex frequently arrests cells in the early G1 phase of the cell cycle. We have found in cell lines the effect of Dex leads to decreased FLT retention. This was confirmed by PET imaging in our first pilot patient, who demonstrated a marked decline of FLT retention after Dex treatment.



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