Despite being studied for decades, the chemotherapy drug cisplatin is revealing new aspects of how it works. Researchers at Winship Cancer Institute of Emory University have identified an enzyme responsible for making tumors and cancer cell lines resistant to cisplatin, along with an experimental drug that targets that enzyme.
The results were published on July 19 in Cancer Cell.
Winship researcher Sumin Kang, PhD
Cisplatin is a DNA-damaging agent used in standard treatment for lung, head and neck, ovarian, and testicular cancers. It has a simple structure, grabbing DNA with its metallic (platinum) arms to form crosslinks. It used to be known as “cis-flatten” because of its nausea-inducing side effects. The experimental drug, lestaurtinib, has already been tested in clinical studies in combination with other chemotherapy drugs, which means it could easily go into trials against tumors displaying cisplatin resistance.
Sumin Kang, PhD, and colleagues at Winship decided to look for enzymes whose activity was necessary for cancer cells to withstand cisplatin treatment. They chose kinases, enzymes that often control some aspect of cell growth and are have plenty of existing drugs targeting them. The researchers found that in combination with a sub-lethal amount of cisplatin, “knocking down” the activity of the kinase MAST1 kills a cell. But how does that combination work?
The DNA in our cells is constantly being damaged by heat, radiation and other environmental stresses, andÂ the enzyme systems that repair DNA are critical for life. A particularly toxic form of damage is the covalent attachment of a protein to DNA, which can be triggered by radiation or by anticancer drugs.
Keith Wilkinson, PhD
Emory biochemist Keith Wilkinson and colleagues have a paper this week in the journal eLife probing how a yeast protein called Wss1 is involved in repairing DNA-protein crosslinks. The researchers show how Wss1 wrestles with a protein tag called SUMO onÂ the site of the DNA damage, and how Wss1 and SUMO areÂ involved in the cleanup process.
Three interesting things about this paper:
*The paper grew out of first author Maxim Balakirevâ€™s sabbatical with Wilkinson at Emory. Balakirev’s home base is at the CEA (Alternative Energy and Atomic Energy Commission)Â in Grenoble, France.
* Since manyÂ cancer chemotherapy drugs induce protein-DNA cross links, an inhibitor of cross linkÂ repair could enhance those drugs’ effectiveness. On the other side of the coin, mutations in a human gene called Spartan, whose sequence looks similar to Wss1â€™s, cause premature aging and susceptibility to liver cancer. Whether the Spartan-encoded protein has the same biochemical activity as Wss1 is not yet clear.
*SUMOÂ stands for â€œsmall ubiquitin-like modifierâ€. The eLife digest has an elegant explanation of whatâ€™s happening: Read more
Cancer of the colon, ovaries, appendix or other organs within the abdomen often spreads to the lining of the abdominal cavity. Experts call this condition peritoneal surface malignancy. Until recently, treatment options for this form of cancer only provided relief from symptoms.
Emory University Hospital is one of a few facilities nationwide to utilize a new combination therapy to slow or prevent recurrence of this cancer. Hyperthermic intraperitoneal chemoperfusion (HIPEC) is a procedure done immediately following surgery that delivers heated chemotherapy directly into the abdominal cavity where it can penetrate cancerous tissue. Heat at 42 C (107 F) destroys cancer cells and enhances the power of chemotherapy.
The term â€œintraperitonealâ€ means that the treatment is delivered to the abdominal cavity. â€œHyperthermic chemoperfusionâ€ means that the solution containing chemotherapy is heated to a temperature greater than normal body temperature.
Charles Staley, MD, chief of surgical oncology at the Emory Winship Cancer Institute, says by bathing the abdomen with heated chemotherapy immediately following surgery doctors can administer a higher dose of medication than would normally be tolerated by a patient if given intravenously – the traditional way chemotherapy is administered.
During surgery, Staley removes all visible tumors throughout the abdomen, a procedure known as cytoreductive surgery. Following surgery, while still in the operating room, Staley administers the new treatment, which takes about two hours. Recent studies show improved prognosis in patients treated with HIPEC after the cytoreductive surgery.
Illustration of heated, targeted chemotherapy