A new drug may show promise in the treatment of skin cancers that are resistant or unresponsive to current leading therapies.
In the United States, 5 million people are treated annually for skin cancer, and 9000 people die from melanoma, the deadliest form of the disease, according to the US Department of Health and Human Services.
A new compound, SBI-756, targets a specific molecular machine known as the translation initiation complex. These structures are in every cell and play the critical role of translating mRNA into proteins. In cancer cells, the complex is impaired, producing extra protein and providing a growth advantage to tumors. SBI-756 causes the translation complex to dissociate, and was shown to inhibit melanoma cell growth in the study, published in Cancer Research (doi:10.1158/0008-5472.CAN-15-0885).
“The unique target of SBI-756 makes it especially promising for use in combination therapy,” said senior author Ze’ev Ronai, PhD, scientific director of the La Jolla, California, campus of the Sanford Burnham Prebys Medical Discovery Institute (SBP). “A major issue limiting the effectiveness of current melanoma therapies is that tumors become resistant to treatment. Combining drugs that come at a melanoma from different angles may help overcome the problem of drug resistance.”
Approximately 50% of melanomas are caused by mutations in the BRAF gene. Patients with these tumors are commonly prescribed vemurafenib, a BRAF inhibitor. However, many patients experience a relapse within weeks, months, or even years because tumors evolve and become resistant to the drug. A similar phenomenon is seen in mice, where treatment of BRAF melanomas results in an initial response, but the tumors recur 3 to 4 weeks later.
The team found that if SBI-756 is co-administered with vemurafenib, the tumors disappeared and most importantly, they did not recur. Even in mice with advanced/late-stage BRAF-driven cancer, the reappearance of resistant tumors was slowed with the addition of SBI-756. These data suggest that SBI-756 provides a significant advantage in overcoming tumor resistance.
In other forms of melanoma, caused by mutations in the genes NRAS and NF1, which are known as unresponsive to BRAF drugs, administering SBI-756 alone significantly lessened the tumor load. The team is now testing whether combining SBI-756 with existing drugs used for treating these types of melanomas can make the tumors disappear.
Drugs that target the translation initiation complex have been intensely pursued in the past few years, not just for melanoma, but for a wide array of cancers. SBI-756 is considered a first-in-class drug because it is the first successful attempt to target a specific part of the elF4G1 complex.
SBI-756 is the culmination of 7 years of work in Ronai’s group, who tested and tweaked the drug’s features to help it bind to the target more readily and to make it easier to formulate.