Researchers from Sanford Burnham Prebys Medical Discovery Institute (SBP; CA, USA) have discovered a novel drug that could be a promising therapy for skin cancer resistant or unresponsive to existing therapies. The compound, named SBI-756, targets the translation initiation complex, a structure present in every cell responsible for translating mRNA into proteins. SBI-756 causes the translation complex to dissociate, inhibiting melanoma cell growth.
In the United States, 5 million people annually are treated for skin cancer, with 9000 deaths from the deadliest variant, melanoma. About 50% of melanomas are caused by mutations in a specific gene called BRAF, and patients are usually prescribed a BRAF inhibitor. However, many patients experience a relapse following treatment because tumors develop drug resistance.
"The unique target of SBI-756 makes it especially promising for use in combination therapy," explained Ze'ev Ronai, senior author of the research. "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."
The research team determined that in mice, co-administration of SBI-756 with a BRAF inhibitor caused tumors to disappear, and they did not subsequently reoccur. In other forms of melanoma, caused by different genes known to be unresponsive to BRAF inhibitors, administration of SBI-756 alone caused a significant reduction in tumor load.
SBI-756 is considered a first-in-class drug due to its unique action; it is the first successful attempt to target a specific part of the translation initiation complex, eIF4G1. "It appears that the dose we need to administer is very low. Even in the experiments where the drug was administered to mice with tumors over a significant period of time, we have not found any toxicity," Ronai confirmed. "We hope that we're going to come up with the next generation of the compound that can go into clinical trials – first in melanoma but likely in other tumors.”
Feng, Y., Pinkerton, A. B., Hulea,
L., et al. (2015). SBI-0640756 Attenuates the Growth of Clinically Unresponsive
Melanomas by Disrupting the eIF4F Translation Initiation Complex. Feng, Y., Pinkerton, A. B., Hulea,L., et al. (2015). SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex. Cancer Research. doi:10.1158/0008-5472.CAN-15-0885. doi:10.1158/0008-5472.CAN-15-0885