A team of investigators from the and the was awarded a $3.2 million grant from the National Institutes of Health to identify new ways to prevent and overcome treatment resistance to targeted therapy in patients with all sub-types of cutaneous melanoma, an aggressive form of skin cancer.
Virtually all cutaneous melanomas display genetic alterations that activate a cancer-driving pathway called MAPK. In about half of advanced cutaneous melanomas, specific mutations in a protein called BRAF provide targets for a currently approved MAPK-targeted therapy. While some patients with BRAF mutated melanomas respond to existing MAPK-targeted therapy, many develop resistance over time, leading to clinical relapses and more aggressive cancers. For the other half of patients with melanomas lacking the specific BRAF mutations, there is currently no FDA-approved options for treatment with MAPK-targeted drugs. In order to improve existing and develop new treatments, it is critical to understand how all melanomas evolve resistance in response to one or two drugs aimed at turning off the MAPK pathway.
The new grant, led by , professor of medicine and molecular and medical pharmacology at the , and Alan Tackett, professor of biochemistry and molecular biology at UAMS, supports their work in creating the Melanoma Resistance Evolution Atlas (MREA). This atlas, which uses fragments of tumors from patient biopsies and implanted to grow in specialized mice, will allow the team to test different combination therapies. A technical core facility creating these specialized mice is directed by Gatien Moriceau, assistant adjunct professor of medicine at the David Geffen School of Medicine at UCLA.
The team will then examine the unique characteristics and behaviors of each patient’s tumor, before and after it is treated with MAPK-targeted drugs as well as when it stops responding all together. They will use proteogenomic and single-cell analyses to identify new drug targets to design future experimental combination therapies. The MREA will comprise rich data matched to individual patients represented by the mouse models, serving as a unique resource for the broader cancer research field.
“It is really important for the field to use a comprehensive set of in vivo models that reflect the full-spectrum of patient-specific disease sub-types to generate rich multi-omic data on how melanomas respond to and then evolve resistance to evade this important type of therapy,” said Tackett.
“We will use current and newer MAPK-targeting agents as foundations to add other types of drugs,” said Lo. “Better MAPK inhibitor-based combination treatments will benefit not only patients with melanoma but also a large fraction of patients with other types of common and aggressive tumors such as lung and colorectal cancers.”
