At the molecular level, anticancer chemotherapeutic agents such as Taxol and Taxotere bind directly totubulin or microtubules and block cells at mitosis, eventually leading to cell death. These microtubuletarqetinqdrugs, have also emerged within the past ten years as an integral part of the treatment of non-smallcell lung cancer (NSCLC). How-ever, despite their significant clinical efficacy, the development of drugresistance and the toxicity to normal tissues hamper the clinical applicability of taxanes in NSCLC. There isan increasing need for novel anticancer agents that would more specifically target NSCLC cells, sparingnormal tissues. One such example of targeted agents is the family of farnesyl-transferase inhibitors(FTIs). FTIs, originally developed as specific inhibitors of Ras farnesylation and activity, were recently shownto synergize with the taxanes in numerous preclinical models and early-phase clinical trials. Notwithstandingthese promising results, the molecular mechanism responsible for this clinically relevant synergy betweenthe FTIs and taxanes is largely unknown. In an effort to dissect this molecular mechanism, we have recentlydiscovered that FTIs affect microtubule acetylation and stability, partly due to inhibition of the tubulindeacetylase HDAC6. Thus, we hypothesize that inhibition of HDAC6 by the FTI lonafarnib leads to increasedtubulin acetylation and that this is the molecular basis for the synergy of FTIs with Taxol. The mainobjective of this project is to further investigate the molecular mechanism under-lying the synergy betweenFTIs and taxanes, as outlined in four Specific Aims: (1) Aim 1: Determine whether FTIs bind directly tomicrotubules (2) Aim 2:Elucidate the molecular mechanism underpinning the FTI/taxane synergy bydetermining the role of the tubulin deacetylase HDAC6 as well as the requirement for FTase inhibition (3)Aim 3: Conduct a molecular endpoint-driven Phase Ib clinical trial with the FTI lonafarnib and docetaxel (4)Aim 4: Evaluate NSCLC patients' surgical tissue obtained from another randomized clinical trial (NATCHtrial; PI: Rafael Resell) for levels of HDAC6, acetylated tubulin and the presence of tubulin mutations, in aneffort to identify molecular markers predictive of Taxane clinical activity in NSCLC. We are con-fident ourstudy will provide important insights into the mechanism of FTI and taxane function and synergy at themolecular level, and that this information will aid in the development of more effective targeted therapeuticcombinations against NSCLC in the future.
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