Novel Therapy Partners Emerge in Melanoma Research

Jessie Villanueva, PhD

A novel combination therapy aimed at 2 processes implicated in NRAS-mutant melanoma has displayed promising activity in preclinical investigations, signaling an avenue of exploration for a new therapeutic approach for patients who currently have few options.

Researchers at the Wistar Institute in Philadelphia have paired BET and MEK inhibitors for testing in biopsy samples from patients treated for metastatic melanoma and in several types of mouse models. The responses to the combination in NRAS-mutant disease have been “striking,” according to Jessie Villanueva, PhD. The combination inhibited the growth of tumors and prolonged the survival of the mice without adverse effects such as weight loss and lethargy and without negative histopathological impact on the lung, liver, spleen, or kidney.

Villanueva presented an overview of the novel strategy during the Noreen O’Neill Melanoma Research Symposium held June 20 at the Wistar Institute. “We’re very excited about this combination,” said Villanueva, who is an assistant professor in the Molecular and Cellular Oncogenesis Program and a member of the Wistar Institute Melanoma Research Center. “We think it’s a promising strategy and we hope that it can be translated, perhaps as a salvage strategy for those patients who have failed both immunotherapy and targeted therapy.”

Dual targeted therapy approaches for the treatment of patients with melanoma have proliferated in recent years, starting in 2014 with the FDA’s approval of the combination of trametinib (Mekinist) and dabrafenib (Tafinlar) for patients with unresectable or advanced melanoma with a BRAF V600E or V600K mutation. Next, in November 2015, the FDA approved cobimetinib (Cotellic) in combination with vemurafenib (Zelboraf) for a similar patient population. Recent phase III findings support the efficacy of a third combination, encorafenib and binimetinib, which is now undergoing an FDA review for a similar patient population.

These pairings combine BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) with MEK inhibitors (trametinib, cobimetinib, binimetinib) and are aimed at patients with BRAF mutations, which have been found in 37% to 50% of melanoma samples.¹

Although these combinations attack 2 targets, both BRAF and MEK are components of the mitogen-activated protein kinase (MAPK) signaling pathway that is central to driving the proliferation of cancer cells (Figure A).² These kinases are often driven by RAS oncogenes, which have been implicated in more than 30% of all human cancers. Mutations in NRAS, a member of the RAS family, have been identified in 13% to 25% of melanomas.¹

Figure A. RAS Signaling and Downstream Targets²

There are no therapies targeting NRAS mutations, and this constitutes an urgent, unmet need for patients with melanoma, said Villanueva. “NRAS-mutant tumors are extremely aggressive,” she said. “They rapidly metastasize to the lymph nodes, glands, and other organs.”

Villanueva and colleagues, including Ileabett Echevarria-Vargas, PhD, analyzed data from The Cancer Genome Atlas and learned that BRD4, a member of the bromodomain and extra-terminal domain (BET) family of proteins, was expressed at relatively high levels in NRAS-mutant tumors. BRD4 expression correlated with patient outcomes, as lower levels were associated with higher survival rates. “BRD4 plays a major role in regulating proliferation in these cells,” said Villanueva.

To test their hypothesis, researchers used 2 investigational BET inhibitors: JQ1 and OTX015. JQ1 was discovered at the Dana-Farber Cancer Institute; the Roche Group is developing a chemically similar compound, TEN-010.³ Meanwhile, Merck is developing OTX015 under the name MK-8628. For the MEK inhibitor, investigators used PD0325901.³ Villanueva said the BET inhibitors have been well characterized in prior research (Figure B⁴) and that the MEK-targeting agent is an older drug that was commercially available.

Figure B. BET Inhibitors at Work⁴

As with other anticancer strategies, researchers found that the inhibitors were not effective as monotherapy but showed impressive preclinical activity when paired and used against NRAS-mutant melanoma with high BRD4 expression. “Targeting a single pathway or a single oncogene doesn’t really lead us to effective responses,” noted Villanueva.

BET proteins are epigenetic regulators of genetic material packaged in the form of chromatin, which is composed of negatively charged DNA wound tightly around positively charged histone proteins like thread on a spool. BRD4 is an epigenetic “reader” that binds to marks in the chromatin that signal the transcription complex, Villanueva explained in an interview with OncologyLive^®.

As a result, pairing BET and MEK represents dual targeted therapy aimed at 2 types of signaling, as opposed to 2 junctures in the same pathway offered by current combinations.

“The approach that we’re taking is slightly different in the sense that we’re hitting 2 different pathways that are somewhat interrelated,” said Villanueva. “One of them is the MAPK pathway, which is critical for melanoma. Basically, all types of melanomas depend on this pathway. We need to target that.

“On top of that, we’re targeting the BET protein, which regulates multiple transcriptional effects,” she added. “By doing that, we think we are perturbing the transcriptional profile of the cells so that the cells are not robust. They can now accept a second hit and be much more sensitive to [that] hit.”

The experiments at Wistar come at a time when epigenetic processes are attracting increasing interest in the development of anticancer therapy. At least 10 BET inhibitors are being evaluated in phase I and II trials in a range of hematologic and solid malignancies, including acute myeloid leukemia, myelodysplastic syndrome, and glioblastoma.³

Additionally, histone deacetylases, enzymes that function in the epigenetic process by repressing gene transcription, are being explored. One novel combination under study involves pairing of pembrolizumab (Keytruda), a PD-1 inhibitor, with entinostat, an HDAC inhibitor.

Today, the research conducted on the BET/MEK inhibitor combination is not directly paired with a particular drug or clinical development program, but Wistar is exploring collaboration opportunities to see these findings translated into the clinic in the future.

Wistar is a National Cancer Institute—designated Cancer Center. The symposium where Villanueva presented her findings was sponsored by the Noreen O’Neill Melanoma Foundation for Melanoma Research, which was founded by a Philadelphia executive who was diagnosed and later succumbed to malignant melanoma.

References

1. Lovly C, Pao W, Sosman J. Molecular profiling of melanoma. My Cancer Genome website. http://goo.gl/YrX6v4. Updated January 26, 2016. Accessed July 9, 2017.
2. Nussinov R, Jang H, Tsai CJ. The structural basis for cancer treatment. Oncotarget. 2014;5(17):7285-7302. doi: 10.18632/oncotarget.2439.
3. Von Schaper E. Roche bets on bromodomains. Nat Biotechnol. 2016;34(4):361—362. doi:10.1038/nbt0416-361.
4. Fu L, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6(8)5501-5516. doi: 10.18632/oncotarget.3551.