Dermatology Researchers Awarded Grants to Study Melanoma and Drug Development

Barbara Bedogni, Ph.D., a member of the tumor biology program at Sylvester Comprehensive Cancer Center and associate professor of the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, and Naiem T. Issa, M.D., Ph.D., third-year resident in the department, have been awarded more than $700,000 in grants for their research efforts.

Dr. Bedogni received a pilot grant of $100,000 from the Melanoma Research Alliance and a two-year grant of $600,000 from the Ivy Foundation.

“I was very excited,” Dr. Bedogni said. “I did not expect it at all. I’ve been submitting to the Melanoma Research Alliance several times in the past with no success, except during my early years when they awarded me a junior grant. I guess they like the story this time. And I really did not expect to get the Ivy Foundation grant, which made the surprise even sweeter.”

The award from the MRA will examine the potential of combining a novel compound with immunotherapy. Dr. Bedogni’s team discovered that Notch1, a protein that is highly expressed in melanoma, is associated with lower response of patients to immunotherapy. The team devised a novel antibody to counteract its function and plan to determine its efficacy in combination with immunotherapy in preclinical models of melanoma by using mice. This will be the first step toward a potential new therapy that may help patients acquire a response that is resistant to immunotherapy.

Treatment Combo Shows Promise

For the second grant with the Ivy Foundation, Dr. Bedogni continues the work in her first melanoma publications where she found the MT1-MMP enzyme. This particular protein plays a critical role in metastases and also resistance to targeted therapy, while later discovering it is associated with response to radiation and chemotherapy.

By acquiring a novel small molecule inhibitor for MT1-MMP, the team tested in breast cancer and glioblastoma multiforme, as these two malignancies are typically treated with radio-chemotherapy. They found an improvement in survival when they combined the inhibitor with radiation in GBM mouse models. Mice lived twice the time than with radiation alone.

“The success obtained in GBM has encouraged us to apply these findings to melanoma brain metastases,” Dr. Bedogni said. “These metastases are still treated with radiation and mortality is still quite high. We plan to combine this new inhibitor with radiation in melanoma brain metastasis models to determine if we can extend survival; and will determine what mechanism underlies the role of MT1-MMP in radio-sensitization.”

Computational Approaches to Drug Development

Dr. Issa’s $20,000 award from the Dermatology Foundation was awarded to further his study on silico (or computational) approaches to drug development. This new era of drug development has scientists now able to model biological targets with sophisticated software to study structure, physics, chemistry, and biochemical reactions.

It works by first identifying a protein whose pharmacological modulation could be therapeutic. This target is then modeled using computational resources to understand where a drug could bind, what conformation that target should be in so that it is either inhibited or activated, etc.

By understanding the structure, scientists are then able to use tools such as docking and molecular dynamics to simulate how a drug may bind, make important contacts with the target, and alter the conformation of the target. These simulations can be done on large scales to screen hundreds of millions to billions of chemical structures to efficiently prioritize drugs for testing in the lab and clinic,  shortening the overall time of drug development and reduce incurred costs.

Focus on Sturge-Weber Syndrome

With the grant, Dr. Issa plans to develop discoveries in his interest on a rare pediatric disease known as Sturge-Weber Syndrome. The disease, caused by an activating mutation in GNAQ (Gq) protein, which causes capillary malformations in the skin, eyes, and brain leading to skin vascular staining and deformities, glaucoma, seizures, and intellectual impairment among other co-morbidities.

“No small molecule drug has been identified for this target to date,” Dr. Issa said. “Through in silico modeling, I have identified the potential first small molecule inhibitor. With the Dermatology Foundation grant, I will be able to truly determine if this drug acts as a Gq inhibitor and to further identify new drugs with different chemical structures with the potential to inhibit Gq using in silico modeling and medicinal chemistry.”

Finding a Gq small molecule inhibitor is a momentous milestone as it opens a world of research for finding new pharmaceuticals and repurposing old ones for Gq-mediated diseases such as Sturge-Weber Syndrome.

Though there are still many steps and questions to address, such as the safety of the new drugs, length of use, and measure of therapeutic endpoint, the major foundation of Gq protein inhibition will help enable all subsequent endeavors.

Tags: Dermatology Foundation, Dr. Barbara Bedogni, Ivy Foundation, Melanoma Research Alliance, Naiem T. Issa, Sylvester Comprehensive Cancer Center