Stephen Lippard

Understanding and Improving Platinum Anticancer Drugs

Platinum compounds are a mainstay of cancer therapy, with more than half of all patients receiving an infusion of one of three FDA approved drugs (cisplatin, carboplatin, and oxaliplatin). The biological action of cisplatin was discovered by serendipity in the late 1960s. Our laboratory subsequently established the chemical nature of events leading up to the binding of platinum anticancer drugs to nuclear DNA, their principal target in the nucleus of cancer cells. Platination of the genome evokes cell death pathways and attempts at damage repair. Binding of high mobility group proteins to cisplatin 1,2-intrastrand d(GpG) cross-links blocks excision repair, an event that facilitates the ability of the drug to cure testicular cancer. We discovered subsequently that related platinum compounds, capable of forming only a single link to DNA, are also extremely active against cancer in vitro as well as animals when delivered in a plant virus, leading to exciting new candidates for drug development. Details of how these ‘monofunctional’ compounds work will be described. Studies of platinum(IV) pro-drugs offer several advantages in drug delivery, including the targeting of cancer cells, the ability to personalize platinum-based medicines, and the benefit of ‘multi-threat’ constructs where more than one cancer cell-specific target is attacked by the conjugate. These findings and others were used by scientists at Blend (now Placon) Therapeutics, Inc., of which the author is a co-founder, to fashion a novel, platinum-based anticancer drug that will soon enter Phase I clinical trials. From the chemical principles learned in studies of platinum anticancer drugs and drug candidates we envisioned a larger family of metal-based therapeutic candidates, including those based on osmium and rhenium. The ability of osmium complexes to selectively kill cancer stem cells in culture offers a promising approach to blocking recurrence and metastasis of the disease. The efficacy of rhenium compounds in an orthotopic model of colon cancer will be described. This work is supported by a grant from the US National Cancer Institute. The author discloses a financial interest in Placon Therapeutics, Inc.