Understanding and targeting CHEMOtherapy-related neuroTOXicity (CHEMOTOX)

Abstract

Cancer patients’ life expectancy is substantially increased, which translates into millions of persons with a history of cancer and long-term side effects of chemotherapy to be managed. Most of the commonest chemotherapy-induced toxicities are now effectively treated, while the impact of side effects involving the central (CNS) and/or the peripheral nervous system (PNS) is still relevant in the treatment of the tumor “big killers” because of the severe, long-term/permanent consequences on patients’ quality of life. Moreover, these side effects not only add more burden of disease to already severely challenged persons but also have still largely underestimated social and economic costs (e.g. loss of working capacity, impaired social activities, increased healthcare social and security costs).

CNS neurotoxicity, defined as chemotherapy-induced cognitive impairment (CICI) is frequent in breast, lung, prostate, and ovarian cancers patients, impairing memory, learning, concentration, reasoning, executive functions, attention, and visuospatial skills during and after discontinuation of chemotherapy. Chemotherapy-induced PNS toxicity (CIPN), leading to pain, paresthesias, and motor impairment, ranks among the commonest dose-limiting toxicities of several widely used anticancer drugs. A great number of cancer survivors suffer from CIPN even years after termination of the therapy and perceive it as one of the most severe side effects of treatment. Despite the evident and urgent need to reduce the toxic effects of chemotherapy on the nervous system led to a great number of studies, the cellular and molecular events underlying CICI and CIPN pathogenesis still remain elusive.

Histone deacetylase inhibitors (HDACi) have been tested in several experimental models of CNS disorders, such as stroke and Alzheimer’s disease, and it has been demonstrated that they can remarkably improve neuronal plasticity and memory. The key target for HDACi in neuroprotection is HDAC6. Experimental use of HDAC6 inhibitors (HDAC6i) 260-has proven to be effective in animal models of CICI and CIPN, but the models used to demonstrate efficacy are questionable. This project is based on 4 main pillars:

1. CICI and CIPN can be reliably modeled in new preclinical models based on schedules that are more close to the clinical use (i.e. repeated, intermittent iv administration)
2. CICI and CIPN may have detectable morphological and functional correlates
3. CICI and CIPN can be simultaneously modulated by the administration of HDAC6i
4. Mitochondrial dysfunction and neuroinflammation may play a role in the neurotoxicity of anticancer drugs.

The completion of the project will overcome several current limitations in knowledge and in modeling that are still preventing effective investigation of CIPN and CICI pathogenesis and, potentially, the identification of new druggable targets.

Publications