RGX-202: Pioneering Creatine Transporter Inhibition for Cancer Growth and Metastasis Control

Colorectal cancer (CRC) is a significant cause of cancer-related mortality globally, with over 140,000 new diagnoses and nearly 50,000 fatalities reported each year in the United States. The liver is a common site for CRC metastasis, and creatine metabolism plays a critical role in the advancement and liver colonization of this cancer. Creatine kinase-B (CKB) is overexpressed and secreted by metastatic colon cancer cells, leading to the production of the high-energy compound phosphocreatine, which is then imported by the SLC6a8 transporter. This process supports the survival of metastatic cells in the hypoxic liver environment. Genetic depletion of SLC6a8 in colon and pancreatic cancer cells has been shown to reduce liver colonization in mice.

Our study presents RGX-202, a new small molecule that inhibits creatine uptake in cancer cells both in vitro and in vivo. When administered orally, RGX-202 triggered apoptosis in colon cancer cells and significantly reduced liver metastatic colonization and primary tumor growth in both KRAS wild-type and mutant colon cancer cell lines, as well as in human PDX mouse models. These effects were found to be reliant on the expression of SLC6a8 in the tumors. Furthermore, combining RGX-202 with 5-FU in the CT26 mouse model resulted in synergistic antitumor effects, with over 40% of treated mice showing complete tumor regression. Similarly, the combination of RGX-202 with gemcitabine in the KPC mouse model significantly slowed the growth of primary pancreatic tumors. Ongoing 28-day GLP toxicology and pharmacokinetics studies indicate that RGX-202 is well-tolerated across several animal species and exhibits a favorable pharmacokinetic profile, including bioavailability.

These findings strongly advocate for the clinical advancement of RGX-202 for gastrointestinal cancers, including CRC and pancreatic cancer, as both a standalone treatment and in combination with standard treatments.