There is renewed scientific interest in using live or attenuated pathogenic bacteria or their products to treat cancer. The bacterium Salmonella typhimurium induces tumor regression in mice, as have combinations of anaerobic bacteria plus various chemotherapeutic agents. Microbial pathogens have been employed as cancer "vaccines" and "vaccine vectors" to induce tumor regression via activation of immune response directed toward a specific tumor type. While these approaches have, in some cases, produced tumor regression, they have also induced undesirable generalized immune responses. Furthermore, when used in combination with other chemotherapeutic agents, additional systemic toxicity has made their clinical application impractical.
CDG Therapeutics, Inc. has developed a group of proprietary peptides that represent a new class of anti-cancer agents. These peptides are derived from the cupredoxin family of copper containing, redox proteins found in pathogenic and non pathogenic bacteria and green plants. Selected family members, as well as peptides derived from them, preferentially penetrate human cancer cells when compared to histological matched normal cells. As such, they are excellent candidates, either as specific, anti-cancer therapeutic agents or therapeutic adjuncts as carriers for diagnostic imaging or standard chemotherapeutic agents and novel DNA based reagents for gene therapy. Our results provide the first report that non-virulence-related, bacterial peptides selectively enter cancer cells and significantly kill them without significant toxicity. As such, our family of peptides has significant potential to yield therapeutic agents and therapeutic adjuncts to treat regionally advanced metastatic cancers which are unresponsive to standard chemotherapies.LEAD COMPOUNDS
Our lead compound, a 28 amino acid, 2.9 kD fragment (p28) of azurin, a cupredoxin secreted by the bacterium Pseudomonas aeruginosa, submitted under IND (#77754) exerts significant, dose related, direct cell cycle inhibitory and cytotoxic (apoptotic) effects through formation of a complex with the tumor suppressor protein p53, a major regulator of cell growth, genomic stability, and cell death. p28 also enters human endothelial cells and exhibits a potent, dose related, inhibition of endothelial cell proliferation. We have explored the kinetics and mechanisms underlying the unique time and temperature dependent penetration of human cancer and normal cells by p28, how p28 mediates its pharmacologic effects through p53, which forms a common thread underlying the cytostatic and cytotoxic activity, and the anti-angiogenic effects of p28. The apoptotic and antiangiogenic properties of p28, first observed in vitro, have been confirmed in a series of in vivo studies conducted on human solid tumor xenografts in athymic mice.
Preclinical, chronic immunologic and toxicology studies have been completed in two species: mice and NHP (Cynomolgous sp.). All results indicate that p28 is a water soluble nonimmunogenic, nontoxic peptide with anticancer properties.
Stability studies of lyophilized p28 as an unformulated and formulated peptide also indicate that p28 is stable at room temperature. Pharmacokinetic (PK), pharmacodynamic (PD) and absorption, distribution metabolism (ADMET) profiles for the p28 peptide in murine and non-human primate (NHP) subjects have been completed by NCI/FDA approved contractors through an NCI/RAID collaboration. Preclinical evidence indicates that p28 is efficacious, stable and non-toxic. P28 has been approved by the FDA for Phase I clinical trial to ascertain the safety of systemically administered p28 to patient volunteers (FDA IND 77,754). Summary of the trial can be found at clinicaltrials.gov. Our initial observation in patients receiving p28 has not shown any systemic toxicity.
