2. Academic Validation
  3. Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels

Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels

  • Sci Adv. 2021 Oct 8;7(41):eabi7511. doi: 10.1126/sciadv.abi7511.
Isabel Kurth 1,  Norihiro Yamaguchi 2,  Celia Andreu-Agullo 1,  Helen S Tian 2,  Subhasree Sridhar 1,  Shugaku Takeda 1,  Foster C Gonsalves 1,  Jia Min Loo 2 3,  Afsar Barlas 4,  Katia Manova-Todorova 4,  Robert Busby 1,  Johanna C Bendell 5,  James Strauss 6,  Marwan Fakih 7,  Autumn J McRee 8,  Andrew E Hendifar 9,  Lee S Rosen 10,  Andrea Cercek 4,  Robert Wasserman 1,  Michael Szarek 1 11 12,  Scott L Spector 1,  Syed Raza 1,  Masoud F Tavazoie 1,  Sohail F Tavazoie 2
Affiliations

Affiliations

  • 1 Inspirna, Inc., 310 E. 67th St, New York, NY 10065, USA.
  • 2 Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
  • 3 Laboratory of Precision Oncology and Tumor Evolution, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
  • 4 Memorial Sloan Kettering Cancer Center, 275 York Ave., New York, NY 10065, USA.
  • 5 Sarah Cannon Research Institute, 250 25th Ave N, Nashville, TN 37203, USA.
  • 6 Mary Crowley Cancer Research, Building C, 7777 Forest Ln #707, Dallas, TX 75230, USA.
  • 7 City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA 91010, USA.
  • 8 The University of North Carolina at Chapel Hill, 27599 Chapel Hill, NC, USA.
  • 9 Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
  • 10 Jonsson Comprehensive Cancer Center, University of California, 10833 Le Conte Ave, Los Angeles, CA 90024, USA.
  • 11 University of Colorado School of Medicine, 13001 E 17th Pl, Aurora, CO 80045, USA.
  • 12 SUNY Downstate Health Sciences University School of Public Health, 450 Clarkson Ave, Brooklyn, NY 11203, USA.
PMID: 34613776 DOI: 10.1126/sciadv.abi7511
Abstract

Colorectal Cancer (CRC) is a leading cause of Cancer mortality. Creatine metabolism was previously shown to critically regulate colon Cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor Apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target.

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