DpC, a unique small molecule invented by Des Richardson and David Lovejoy at the University of Sydney has been shown to dramatically impair the growth of cancer cells in preclinical models. An overview of the research that has been performed to date, the rationale for why DpC may be an effective treatment, and development status are summarized briefly below.
A brief history of the research
Compared with normal cells, cancer cells have an increased requirement for iron, needed for the activity of key iron-containing proteins that catalyze critical reactions involved in energy metabolism, respiration, and DNA synthesis. In normal cells, iron levels are tightly controlled through both transcriptional and post-transcriptional mechanisms to maintain an appropriate iron balance, but iron homeostasis is altered in cancer cells due to re-programming of gene expression.
In a series of publications starting in 2011, researchers led by Des Richardson showed that DpC exerts pleiotropic effects in cancer cells, including mobilization of cellular iron, leading to accumulation of copper; forming highly redox active iron(III) and copper(II) complexes that generate cytotoxic reactive oxygen species (“ROS”) intracellularly; up-regulating mRNA and protein expression of N-myc downstream regulated gene 1 (“NDRG1”), a central regulator of multiple signaling pathways that modulate tumor progression; and affecting crucial thiol systems, such as glutathione, thioredoxin, and glutaredoxin, which produce reducing equivalent equivalents required for ribnucleoside reductase activity. In mice bearing DMS-53 human lung tumor or PANC-1 human pancreatic tumor xenografts, DpC treatment induced significant dose-dependent reductions in tumor volumes compared with vehicle controls, with ≥87% tumor growth inhibition. Complementing their findings, in vitro studies by the U.S. National Cancer Institute (“NCI”) Developmental Therapeutics Program showed that DpC induced cell death in 59 of 60 human tumor cell lines tested, with GI50 values ranging from <10 nM (12 cell lines; the lower limit of the NCI assay) to 300 nM. Normal fibroblasts were >1000-fold more resistant to DpC than cancer cells, suggesting a marked therapeutic window.
Moving from the laboratory into the clinic
Since licensing commercial rights to DpC, CMD has developed processes for large scale manufacturing of clinical supplies of DpC in compliance with Good Manufacturing Practices (“GMP”); completed studies to evaluate the absorption, distribution, metabolism and excretion of DpC in rodents; and completed repeated oral dose toxicology studies in rodents and non-rodents to define target organ toxicities and the starting dose for clinical trials. CMD has initiated a dose-finding study of DpC in patients with advanced solid tumors at participating sites in Australia. Details of the clinical study have been posted on www.clinicaltrials.gov (NCT02688101).
For information on DpC Clinical Trials, please email ClinicalOperations@ColMedDev.com