Pre-clinical validation of Phase II peptide LRP-1 agonist to treat and prevent chemotherapy induced peripheral neuropathy.

PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a common, toxic side effect of chemotherapy agents. CIPN can be described as mainly sensory nerve impairment accompanied by chronic pain that will decrease the quality of life of the individual. Symptoms and the severity vary between those affected and they can include tingling, temperature- or touch-induced paresthesias and dysesthesias, and painful sensations such as mechanical or thermal allodynia or hyperalgesia. In severe cases, it can lead to irreversible and permanent damage to the peripheral nerves and severe disability. It effects over half of the 28 million cancer survivors. Pain associated with CIPN developed during the chemotherapy treatment can commonly cause the reduction of dose administered and decrease treatment adherence, which could affect the outcome of the treatment. Although the etiological mechanism for the peripheral nerves damage slightly differ from one antitumoral drug to another: Inflammation always plays a key role in CIPN, as it has been confirmed by several studies showing an increase of pro-inflammatory cytokine levels during CIPN episodeThere are no curative treatments for CIPN, current the therapeutic options involved steroids, local anesthetics, antidepressants, anti-seizures drugs, and opioid and narcotic which are reserved for severe pain. All these non-specific treatments aim at temporarily reducing the pain to a manageable level but won’t cure the underlying nerve damage, additionally all these molecules can cause severe side effect and addiction. Herein, we propose to establish a preclinical proof-of-concept for the use of the therapeutic peptide SP16 drug and second-generation reduced size cyclic analogs (RSA), as an effective and safe treatment against peripheral neuropathy. These analogs won’t only address CIPN’s symptoms by reducing inflammation and pain, but they will also heal patient by promoting nerve healing and regeneration. This proposal is articulated around 3 main tasks, first we will determine the basic PK constant for our lead analogs. Secondly, we will evaluate their activity in an in vivo CIPN mice model and finally examine in vitro their effect, or lack of, on a panel of breast cancer cell lines and on their response to antitumoral treatment.