Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-Activated prodrug in murine xenograft models of human cancer

W. Nathaniel Brennen, D. Marc Rosen, Alcides Chaux, George J. Netto, John T. Isaacs, Samuel R. Denmeade

Research output: Contribution to journalArticlepeer-review


BACKGROUND As carcinoma progresses, the stroma undergoes a variety of phenotypic changes, including the presence of carcinoma-Associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). FAP is a post-prolyl endopeptidase whose expression in a healthy adult is largely restricted to the cancer-Associated stroma. FAP-targeted prodrugs with a 100-fold greater therapeutic window over the parent compound were previously generated. METHODS Prodrugs and non-cleavable controls were incubated in the presence of FAP. Plasma and tumor half-lives (t1/2) of the full-length and active forms of the prodrugs were determined using LCMS. Biodistribution studies of prodrug activation were performed. Histopathological analysis of tissues from treated animals were compared to vehicle-treated controls. Toxicity and efficacy studies were performed in human breast (MDA-MB-231 and MCF-7) and prostate (LNCaP) cancer xenografts models. RESULTS These FAP-Activated prodrugs have a significantly slower clearance from tumor tissue than the circulation (12 vs. 4.5hr). Micromolar concentrations of active drug persist in the tumor. Active drug is detected in non-target tissues; however, histopathologic evaluation reveals no evidence of drug-induced toxicity. A FAP-Activated prodrug (ERGETGP-S12ADT) inhibits tumor growth in multiple human breast and prostate cancer xenograft models. The anti-tumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity. CONCLUSION FAP-Activated prodrugs are a viable strategy for the management of prostate and other cancers. These prodrugs exhibit less toxicity than a commonly used chemotherapeutic agent. Further refinement of the FAP cleavage site for greater specificity may reduce prodrug activation in non-target tissues and enhance clinical benefit. Prostate 74: 1308-1319, 2014.

Original languageEnglish (US)
Pages (from-to)1308-1319
Number of pages12
Issue number13
StatePublished - Sep 2014


  • carcinoma-Associated fibroblast (CAF)
  • fibroblast activation protein (FAP)
  • pharmacokinetics
  • prodrug

ASJC Scopus subject areas

  • Oncology
  • Urology


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