April 23, 2020

Study explores melanoma drug’s effectiveness

A study by Vanderbilt research-ers supports the clinical development of a new second-line treatment for metastatic melanoma.

A study by Vanderbilt researchers supports the clinical development of a new second-line treatment for metastatic melanoma.

The potential treatment, KRT-232, inhibits a gene that promotes tumor formation.

The researchers demonstrated that KRT-232 significantly slowed the growth of tumors in mice resulting from patient-derived xenografts.

The drug inhibits the protein MDM2 from degrading the cancer-fighting protein P53. The findings from the study were published in Clinical Cancer Research.

While 60% of melanoma patients initially respond to immunotherapies, many patients end up in need of a second-line treatment. Second-line targeted therapies are currently based on BRAF mutation status, leaving patients without a BRAF mutation with little therapeutic options.

Ann Richmond, PhD

KRT-232 was found to be effective as a monotherapy for tumors with typical BRAF status and was effective as a combination therapy with BRAF mutant tumors when paired with the targeted therapies dabrafenib and trametinib.

“This very exciting finding provides a new therapeutic option for melanoma patients who do not have BRAF mutation,” said Ann Richmond, PhD, Ingram Professor of Cancer Research, the study’s senior author.

“Moreover, patients who do have BRAF mutation and have developed resistance to BRAF inhibitors may respond to the combination of KRT-232 and BRAF/MEK inhibitors.”

The researchers also noted that KRT-232 had promising results in a small clinical trial. KRT-232 with trametinib was shown to reduce tumor size in 73% of patients without BRAF mutation. It reduced tumor size in 100% of patients with BRAF mutant tumors when combined with trametinib or dabrafenib.

Two-thirds of those patients experienced a decrease in tumor size greater than 30%. Vanderbilt-Ingram Cancer Center recruited patients for that clinical trial.

“We continue to be excited about the translational implications of this study,” said lead author Rebecca Shattuck-Brandt, M.Ed, PhD, a Vanderbilt staff scientist.

Vanderbilt co-authors on the study include Sheau-Chiann Chen, PhD, Emily Murray, Andrew Johnson, Holly Crandall, Jamye O’Neal, MS, Caroline Nebhan, MD, PhD, Kimberly Dahlman, PhD, Gregory Ayers, MS, Chi Yan, PhD, Mark Kelley, MD, MMHC, Rondi Kauffmann, MD, MPH, Mary Hooks, MD, MBA, Ana Grau, MD, and Douglas Johnson, MD, MSCI.

The research received funding from a supplement to the Cancer Center Support Grant awarded to Vanderbilt-Ingram Cancer Center.