Targeting Microtubules and HDAC6 in NSCLC

Emory University, Atlanta GA

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Abstract

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