Sanford Burnham Prebys Medical Discovery Institute (SBP) researchers discovered a new drug, SBI-756, which inhibits melanoma cell growth in vitro, and delays disease onset and reduces the incidence of melanoma in vivo. The study, whose results show promise for treating skin cancers resistant or unresponsive to leading therapies, is titled “SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex” and appears in Cancer Research.
SBI-0640756 (SBI-756) works by inhibiting the eukaryotic Translation Initiation Factor 4 Gamma, 1 (eIF4G1), a protein that belongs to the multi-subunit protein complex eukaryotic translation initiation factor 4F (EIF4F). This protein complex is involved in the recruitment of messenger RNA (mRNA) to the ribosome, so these molecules can be translated into proteins, making this complex essential to the initiation phase of protein synthesis and tumor cell growth advantage. Disruption of the EIF4F complex, such as that observed with SBI-756, is a strategy being explored by scientists to potentiate the effect of existing cancer drugs and overcome resistance to certain drugs now in use, such as BRAF inhibitors (BRAFi). SBI-276 is considered a first-in-class drug because it is the first compound to successfully target a specific part of the EIF4F complex.
According to the Melanoma International Foundation, approximately 50% of melanoma tumor tissue tests positive for BRAF gene mutations, which accelerate tumor cell growth and metastasis. Despite therapy with BRAFi, several patients develop resistance to these drugs and experience tumor relapse. When the research team co-administered SBI-756 with vemurafenib, a BRAF inhibitor, the tumors disappeared and did not reoccur. The scientists also observed this phenomenon in mice with late-stage BRAF-driven cancer, suggesting that SBI-756 is a potential successful candidate to overcome tumor resistance. Senior author Dr Ze’ev Ronai, scientific director of SBP’s La Jolla campus, said in a press release, “The unique target of SBI-756 makes it especially promising for use in combination therapy. 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 researchers also tested the drug alone in melanomas with other genetic origins, such as those caused by mutations in the genes NRAS and NF1, observing that the compound led to significant tumor reduction. Furthermore, the team reports the necessary dose for these results was very low and no signs of toxicity were found in mice. Future plans include formulation of the next generation of the compound and clinical trials to prove efficacy and safety, first in melanoma and then in other tumors. Professor Nahum Sonenberg of McGill University further stated, “The finding of SBI-756 is also exciting for the possible treatment of diseases other than cancer, such as neurodegenerative diseases, where the activity of the translation initiation complex is reported to be higher.”