A new class of BRAF inhibitor drugs aims to outpace the current standard treatment for melanoma, which stops working in all patients within months. The problem is stark: the leading BRAF inhibitor, PLX4032, shrinks tumours in more than 80% of patients whose melanomas carry a BRAF mutation, but every single patient eventually becomes resistant. Worse, 30% of patients develop secondary skin cancers called squamous cell carcinomas. The researchers have designed three new inhibitors that they believe will avoid both pitfalls—working in tumours driven by a different mutation (NRAS) and causing fewer secondary cancers. If successful, this project could deliver a Phase I clinical trial of one of these inhibitors in melanoma patients. The team will first run dog and rat toxicity studies, then move to a human trial testing the drug in three groups: patients who have never been treated, those who have stopped responding to PLX4032, and those with NRAS-mutant cancers. The goal is to show longer progression-free survival and fewer squamous cell carcinomas than the current drug. For the 30% of melanoma patients who develop resistance or secondary cancers, this could mean a genuinely better treatment option.
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mutated in ~50% malignant melanomas, where it is a validated oncogene driver and therapeutic target. Inhibitors to target mutant BRAF have been developed and the most advanced of these, PLX4032, is in Phase III clinical trials with responses in >80% of patients with BRAF mutations. However, the responses are limited with all patients eventually developing resistance. Furthermore, 30% of patients on this drug develop keratoacanthomas/squamous cell carcinomas (SCC). With Trust funding, we have designed, synthesised and selected 3 preclinical BRAF inhibitors with properties and selectivity profiles different from PLX4032. We believe any of our 3 inhibitors will be effective in mutant BRAF driven melanomas and, unlike PLX4032, our inhibitors will also be effective in mutant NRAS driven cancers and elicit lower incidences of SCC. We propose to conduct a Phase I clinical trial with one of our inhibitors to test its performance, The project involves the preclinical development of our BRAF inhibitors, which will include: (1) CRO dog pharmacokinetics on three of our inhibitors, (2) CRO non-GLP dog and rat toxicity studies on two inhibitors selected from (1) (3) CRO GLP toxicity studies of one inhibitor selected from (2) (4) A clinical trial on the inhibitor from (3) in melanoma patients. 8 Our aim is to develop one of our inhibitors, with the objective of showing improved progression-free-survival and/or reduced SCC rates relative to PLX4032 and also to investigate the selected inhibitor in treatment naive mutant BRAF patients, PLX4032 refractory patients and in NRAS mutant patients.
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