Dec. 8, 2000 Researchers who had been advancing a promising cancer treatment found a new obstacle looming last spring, when the international journal Nature Medicine published a study that identified a fatal flaw: The treatment destroys healthy human liver cells.
Now researchers at the University of Pennsylvania School of Medicine have discovered a solution to that crucial problem, re-opening what the lead scientist in Penn’s efforts calls “a window of opportunity” for using this powerful treatment against colon, breast, lung, ovarian and esophageal cancers.
“There are only a handful of very promising anti-cancer drugs and this one is on that list,” said Dr. Wafik El-Deiry, MD-PhD, associate professor of medicine at Penn. “Part of the reason we’ve been so excited about this treatment is because it seems to be very effective on a wide range of human cancers. It was on its way toward clinical trials, and then there was this set-back.
“But now we’ve solved the toxicity problem. Within the context of clinical trials, we should be able to protect the liver while still killing cancer cells,” said El-Deiry, who also serves as assistant investigator for the Howard Hughes Medical Institute. Findings from his recent work are published in the current issue of Cancer Research, which is scheduled for publication Monday.
The therapy consists of injecting a cancer patient with a particular ligand (a molecule that binds to receptors on the surface of cells) that scientists identify by the acronym TRAIL -- for Tumor Necrosis Factor-Related Apoptosis Inducing Ligand.
Although other related proteins such as TNF and FAS have complicated research histories because of their side-effects, TRAIL has been widely considered worth serious research efforts because it triggers a sweeping death response in its target, destroying cancerous and pre-cancerous cells.
After the Nature Medicine study appeared, El-Deiry and his colleagues set out to find the key to how TRAIL works, in order to establish a method for using it safely.
That key lies in the enzyme family known as caspases.
Working first with colon cells, the researchers learned that cancerous colon cells may be destroyed through two separate actions – one of which is triggered through a caspase-8-dependent pathway, and the other through a pathway that requires caspase 9.
Then, working with human liver cells, they found the healthy cells were destroyed mainly through the caspase-9-requiring path. The human liver cells could be protected from TRAIL if that path were blocked. “When we realized that the cells have different sensitivities to these enzymes, it immediately suggested that many malignant tumor cells will be killed, but healthy cells will be preserved, if we use a combination of TRAIL plus a caspase 9 inhibitor,” El-Deiry said. But there remained the problem that some cancerous cells may be destroyed only through a caspase 9-requiring pathway.
The researchers suggest solving that problem through timing: “What we are proposing is a schedule of treatments that would avoid using chemotherapy or radiation at the same time we use TRAIL with a caspase 9 inhibitor. That will increase the safety and strength of both therapies," El-Deiry said. "We think it could be something to add to other research in the setting of clinical trials. Now, at least, there is a feasible direction for its study.”
He was assisted in the study by Penn collaborators Nesrin Ozoren; Kunhong Kim, MD-PhD; Timothy F. Burns; David T. Dicker, and A. David Moscioni, PhD. The study was funded by the Howard Hughes institute.
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