Project description
A new drug to potentially reduce chemotherapy side effects
Chemotherapy-induced cardiotoxicity is a major issue associated with cancer treatments, causing serious side effects such as arrhythmia and heart failure. The current approach of reducing doses for a longer period to mitigate these effects negatively impacts quality of life. There is evidence implicating the p38 signalling pathway in cardiotoxicity, but despite the development of many inhibitors, the results in clinical trials have been disappointing so far. Funded by the European Research Council, the p38_InTh project aims to improve the potency of a new class of p38 inhibitors and validate their potential therapeutic use to ameliorate the cardiotoxicity induced by chemotherapy drugs. The project will offer hope for a new drug that could overcome the side effects of chemotherapy.
Objective
p38_InTh aims at improving the potency of a new class of highly specific p38 pathway inhibitors and validate their potential therapeutic use to ameliorate chemotherapy-induced cardiotoxicity without affecting the cancer cell toxicity of the chemotherapeutic. Chemotherapeutics used for cancer treatments have serious side effects, both the most broad-spectrum ones (such as anthracyclines) and the directed ones (such as trastuzumab). In particular, the cardiotoxicity is a major issue associated to chemotherapy. Cardiooncology research has recently emerged to tackle this serious unmet medical need. The cardiotoxicity induced by chemotherapeutics includes from arrhythmia to heart failure. To mitigate it, cardiooncologists usually adjust the treatment with reduced doses for a longer period, but this makes the anticancer treatments less efficient and consequently reduces the quality of life of the patients. There is evidence that cardiomyocyte death induced by anthracyclines involves activation of a specific p38 pathway, suggesting that inhibition of this pathway may reduce the cardiotoxicity associated with chemotherapeutics. Over the last two decades, many p38 pathway inhibitors have been developed by industry. However, these are mostly ATP competitors and have shown disappointing results in clinical trials. In contrast, we have recently identified novel compounds that inhibit only one of the target isoforms and through a novel MoA, selectively antagonizing the activation of this isoform by one of its protein partners. We propose to improve the potency of these hits and validate their potential therapeutic use to ameliorate chemotherapy-induced cardiotoxicity without affecting the cancer cell toxicity. Importantly, our new drug would inhibit only a subset of the p38 pathway regulated functions, which is expected to result in increased specificity, thereby overcoming the undesired side-effects found in clinical trials for the classical ATP competitive p38 pathway inhibitors.
Fields of science
Programme(s)
Funding Scheme
ERC-POC - Proof of Concept GrantHost institution
08028 Barcelona
Spain