At the molecular level, anticancer chemotherapeutic agents such as Taxol and Taxotere bind directly to tubulin or microtubules and block cells at mitosis, eventually leading to cell death. These microtubuletarqetinq drugs, have also emerged within the past ten years as an integral part of the treatment of non-small cell lung cancer (NSCLC). How-ever, despite their significant clinical efficacy, the development of drug resistance and the toxicity to normal tissues hamper the clinical applicability of taxanes in NSCLC. There is an increasing need for novel anticancer agents that would more specifically target NSCLC cells, sparing normal 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 shown to synergize with the taxanes in numerous preclinical models and early-phase clinical trials. Notwithstanding these promising results, the molecular mechanism responsible for this clinically relevant synergy between the FTIs and taxanes is largely unknown. In an effort to dissect this molecular mechanism, we have recently discovered that FTIs affect microtubule acetylation and stability, partly due to inhibition of the tubulin deacetylase HDAC6. Thus, we hypothesize that inhibition of HDAC6 by the FTI lonafarnib leads to increased tubulin acetylation and that this is the molecular basis for the synergy of FTIs with Taxol. The main objective of this project is to further investigate the molecular mechanism under-lying the synergy between FTIs and taxanes, as outlined in four Specific Aims: (1) Aim 1: Determine whether FTIs bind directly to microtubules (2) Aim 2:Elucidate the molecular mechanism underpinning the FTI/taxane synergy by determining 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 (NATCH trial;PI: Rafael Resell) for levels of HDAC6, acetylated tubulin and the presence of tubulin mutations, in an effort to identify molecular markers predictive of Taxane clinical activity in NSCLC. We are con-fident our study will provide important insights into the mechanism of FTI and taxane function and synergy at the molecular level, and that this information will aid in the development of more effective targeted therapeutic combinations against NSCLC in the future.
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