On November 7, 2016 SignalRx Pharmaceuticals Inc., a clinical-stage company focused on developing more effective oncology drugs with designed multiple target-selected inhibition profiles, reported the publication of key research supporting the use of its clinical stage drug SF1126 alone and in combination with Sorafinib for the treatment of hepatocellular carcinoma (HCC) (Press release, SignalRx, NOV 7, 2016, http://www.ireachcontent.com/news-releases/signalrx-announces-publication-of-research-results-on-sf1126-as-a-first-in-class-dual-pi3kbrd4-inhibitor-for-treating-hcc-600328031.html [SID1234517420]). The research was published in the November issue of Molecular Cancer Therapeutics journal from the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Mol Cancer Ther November 1 2016 15 (11) 2553-2562; DOI:10.1158/1535-7163.MCT-15-0976).

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Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center, led by Dr. Donald Durden, Professor and Associate Director of Pediatric Oncology and senior scientific advisor for SignalRx, report results supporting the use of SF1126 as a novel therapeutic agent for the treatment of hepatocellular carcinoma (HCC), the most common kind of liver cancer and second most common cause of cancer death worldwide.

SF1126 is an anticancer agent shown to have an excellent therapeutic window with excellent tolerability and safety in Phase I clinical trials (Clinicaltrials.gov: NCT00907205). While most anti-cancer drugs only interact with a single cancer target, SF1126 inhibits two key cancer signaling molecules in liver cancer cells, phosphatidylinositol 3-kinase (PI3K) and bromodomain-containing 4 (BRD4). SF1126 represents a "first in class" approach to treat liver cancer by hitting two central signaling nodes of the liver cancer cell with only one therapeutic agent. The published work shows that this novel strategy kills liver cancer cells and prevents the growth of liver cancer tumors in mice.

Targeting two pathways with one drug can provide a significant therapeutic advantage since this approach also reduces the risk of severe "off-target" side effects resulting from the combination of side effects associated to each of the multiple drugs used. The treatment of HCC remains a challenge with Sorafenib as the only FDA-approved drug for liver cancer since it prolongs life for an average of only 2-3 months and can have significant side effects. Work from the Durden laboratory shows that using SF1126 with Sorafenib provides a dramatically improved anticancer effect by killing liver cancer cells in synergy.

In HCC, the deregulation of the PI3K/AKT/mTOR, Ras/Raf/MAPK and c-Myc signaling pathways are of prognostic significance. While Sorafenib blocks the Ras/Raf/MAPK pathway, it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. SF1126 controls c-Myc by inhibiting BRD4, which results in blockage of c-Myc production, and by inhibiting PI3K, which leads to enhanced c-Myc degradation. Hence, a combination of SF1126 with Sorafenib offers a new mechanism-driven mode of action to inhibit/treat HCC.

In particular, the research results published in Molecular Cancer Therapeutics demonstrate that:

SF1126 (pan PI3K/BRD4 inhibitor), as a single agent or in combination with Sorafenib, inhibits cancer cell proliferation (Hep 3B, Hep G2, SK-Hep1 and Huh7 HCC cell lines) by effectively inhibiting the PI3K/AKT/mTOR and Ras/Raf/MAPK pathways.
SF1126’s active moiety LY294002 binds to and blocks BRD4 interaction with the acetylated histone-H4 chromatin mark protein and displaces the BRD4 co-activator protein from the transcriptional start site of MYC in Huh7 and SK-Hep-1 HCC cell lines.
SF1126 blocks expression of c-Myc in HCC cells.
SF1126, either alone or in combination with Sorafenib, shows significant antitumor activity in vivo.
These published results establish SF1126 as a dual PI3K/BRD4 inhibitor and the first epigenetic/kinase inhibitor in the clinic. SF1126 has completed a Phase I clinical trial in humans with good safety profile, has received Orphan Drug Designation by the FDA, and is currently in a pediatric Phase I clinical trial in children with neuroblastoma.

Taken together, this published data strongly warrants additional clinical trials of SF1126 in advanced HCC as well as a combination Phase I trial with Sorafenib.

SignalRx is seeking partners for the clinical development of SF1126 as well as the acceleration of the company’s preclinical pipeline with novel and proprietary nM potent small molecules into first-in-man clinical trials.

SignalRx’s novel dual inhibitors have a unique competitive advantage over combining separate agents in cancers where lethality requires simultaneous target inhibition for maximal effect with minimal side-effects. Because it provides a single pharmacodynamics profile the dual inhibition in a single molecule approach provides the optimal way to effect simultaneous target inhibition with significantly less toxicity than combinations of inhibitors.