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Project details

ENU Team Leader: Guido Cavaletti (Principal Investigator)

Other ENU members involved: Angelica Squarzoni, Olga Tarasiuk, Luca Crippa, Paola Marmiroli, Mariarosaria Miloso, Gabriella Nicolini, Annalisa Canta, Alessia Chiorazzi, Alessio Malacrida, Virginia Rodriguez-Menendez

Total Contribution: 294K €
Project Duration: 5 years
Start Date: April 2021
End Date: April 2026

Abstract 
Background
  • Vorinostat, the first Histone Deacetylase HDAC inhibitor (HDACi) was approved by the FDA in 2006, and since then others have been approved and several phase 2/3 trials have been performed HDACi.

  • Available efficacy and safety data strongly suggest that HDACi are likely candidates for combined chemotherapy, particularly when used against solid cancers.

  • Chemotherapy-related neurotoxicity is frequent, can be dose-limiting, severe, and even permanent.

  • Apart from their anticancer activity, HDACi have been tested with positive results in several experimental models of nervous system damage, also when induced by chemotherapy.

  • No studies reporting simultaneously the effect of combined HDACi administration on efficacy and neurotoxicity have been performed using xenografted immunodeficient mice.

Hypothesis
  • HDACi are suitable candidates for combination chemotherapy since they could enhance the efficacy of conventional anticancer drugs.

  • They also have central and peripheral neuroprotective potential, demonstrated by animal studies.

  • HDACi chemical structure with a simple and flexible pharmacophore allows medicinal chemists to operate and optimize independent lead series, with different affinity for the 11 human HDAC isoforms: this might allow modeling/optimizing new molecules.

  • In order to allow this optimization and test new drugs, reliable preclinical evidence must be provided, and this can be preliminarily achieved using approved or other well-characterized HDACi with remarkably different specificity for the most relevant cancer-related human HDAC, i.e. HDAC 1-3 and HDAC6.

Aims

This project is aimed at testing with a sequential preclinical approach if it is possible to enhance anticancer treatment efficacy and simultaneously reduce neurotoxicity through the administration of approved HDACi in combination with paclitaxel or oxaliplatin, both severely neurotoxic anticancer drugs

Experimental Design

The project will initially test and optimize the efficacy of selective and non-selective HDACi against a panel of breast and colorectal cancer cells in order to select the most active compound(s) to be combined with paclitaxel or oxaliplatin, respectively.

The selected combinations will be administered to ad hoc-designed animal models of central and peripheral neurotoxicity induced by paclitaxel/oxaliplatin administration: to test simultaneously the increased efficacy and the neuroprotection due to the co-administration of the selected HDACi, these studies will be performed using breast/colorectal xenografts in immunodeficient mice.

Expected Results

It is expected that the co-administration of HDACi plus paclitaxel/oxaliplatin will provide evidence of the correctness of the working hypothesis, although it is likely that the results will require further optimization.

This second step might be achieved as a follow-up of the project in collaboration with medicinal chemists able to synthesize more potent HDACi with selective action on specific human HDAC isoforms.

Impact On Cancer

In case of successful completion of the project, a major contribution to cancer treatment would be provided, since preclinical evidence for a simultaneous increase in efficacy and reduction in neurotoxicity (one of the major toxicities in most chemotherapy regimens) would allow to develop very rapidly clinical trials using already approved drugs. Moreover, these results might allow exploiting the large libraries of investigational HDACi developed by several Pharmaceutical Companies to discover new, more potent and specific drugs. Finally, additional HDACi/drug combinations might be tested using a similar preclinical approach.

HDACi: the Columbus’s egg in improving cancer treatment and reducing neurotoxicity?