by Tom Wilemon
A team of Vanderbilt researchers have shown in a preclinical study that the investigational drug rigosertib could be a potential booster treatment to elicit response to immunotherapies among melanoma patients.
While immune checkpoint blockade therapies are already an established first-line treatment for metastatic melanoma patients, these immunotherapies are effective for about 52% of patients. The team of researchers, utilizing mouse models and patient-derived xenografts, investigated whether rigosertib would enhance response to these immunotherapies.
Their study, published online June 6 in Molecular Cancer, indicated that rigosertib was well tolerated in mice, inhibited tumor growth by about 50% as a stand-alone treatment and by about 70% when combined with anti-PD1 and anti-CTLA-4 immunotherapies.
The investigators also found that rigosertib, or combination of the BRAF/MEK targeted therapies dabrafenib and trametinib, increased levels of a CD40 protein. High levels of this protein correlate with beneficial T-cell responses and better survival. CD40 expression by melanoma cells is also associated with therapeutic responses to immune checkpoint blockade immunotherapies.
The study reveals a novel role of RAS/RAF/P13K inhibition for inducing immunogenic cell death by inducing CD40 expression on melanoma cells as well as inducing an anti-tumor immune response. More importantly, it provides preclinical evidence for the combination of rigosertib and immune checkpoint blockade treatment as potential therapy for patients with metastatic melanoma. This is especially important since melanoma patients who do not have BRAF mutation but exhibit NRAS mutation, or have neither BRAF nor NRAS mutation, can be treated with rigosertib.
“We are very encouraged by these findings and expect a new clinical trial to launch soon combining rigosertib with anti-PD-1 for melanoma patients who are resistant to anti-PD-1 therapy alone. We are working with Drs. Doug Johnson and Caroline Nebhan to launch this trial”, said senior author Ann Richmond, PhD, professor of Pharmacology and Ingram Professor of Cancer Research.
The study’s lead author is Chi Yan, PhD, who designed the research approach with Richmond, and performed the experiments with Nabil Saleh and Jinming Yang, PhD ,with assistance from Caroline Nebhan, MD, PhD, Anna Vilgelm, MD, PhD, E. Premkumar Reddy, PhD, Joseph Roland, PhD, Douglas Johnson, MD, MSCI, Sheau-Chiann Chen, PhD, Rebecca Shattuck-Brandt, PhD, and Gregory Ayers, MS.
