Oncology researchers have long had TRAIL, or TNF-related apoptosis inducing ligand, in their sights as a potential anticancer agent. The molecule induces apoptosis in tumor cells, but is more specific and less toxic to normal cells than related cytokines, including TNF itself. It is in multiple clinical trials, including a joint Phase II trial by biotech giants Genentech Inc. and Amgen Inc. to test its utility, in combination with Rituximab, for the treatment of non-Hodgkin's lymphoma.
However, like other apoptosis-inducing factors, TRAIL activates molecules that inhibit its effectiveness. Such regulation is, of course, a wise strategy for healthy cells to avoid killing themselves unnecessarily; but from an oncology perspective, it nevertheless amounts to TRAIL's shooting itself in the foot. As a result, cancer cell resistance to TRAIL is an all-too-common problem.
Now, a paper in the July, 2007 issue of Cancer Cell has reported on a way to overcome such resistance, while a separate paper in the Journal of Clinical Investigation takes TRAIL further afield - toward a treatment for bacterial meningitis.
Recent research had shown that TRAIL activates NF-kappaB, which in turn increases the levels of prosurvival proteins cIAP2 and Mcl-1. In the Cancer Cell paper, authors form the University of Pennsylvania, Pennsylvania State University and the University of Texas M.D. Anderson Cancer Center described two ways to disrupt the TRAIL-induced prosurvival signalling: through the oncogene c-Myc - or the kidney cancer drug Nexavar (sorafenib) from Onyx Pharmaceutical Inc. and Bayer Healthcare Pharmaceuticals Inc.
The researchers first tested whether c-Myc could sensitize resistant cells to TRAIL, since previous research had shown that the protein is important for TRAIL sensitivity. They found that normally TRAIL-resistant cells did become sensitive if they expressed c-Myc.
In search of drugs that perform a similar cancer-cell death function to c-Myc, the researchers investigated sorafenib. The multikinase-inhibitor is approved for the treatment of kidney cancer, and Onyx and Bayer have filed for its approval for the treatment of advanced liver cancer. (See BioWorld Today, June 5, 2007.)
Researchers found that, like c-Myc, sorafenib blocked the expression of NF-kappaB and when combined with TRAIL, caused normally TRAIL-resistant colon and lung cancer cells to die in culture.
While the scientists showed data supporting the idea that sorafenib acts by eliminating the need for mitochondrial activation in order for apoptosis to occur, the drug inhibits multiple kinases including RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT and FLT-3, and it seems likely that the drug has multiple mechanisms of action. The scientists are exploring additional pathways through which sorafenib may be working to increase cellular sensitivity to TRAIL.
The researchers also noted that c-Myc could be useful as a biomarker for tumors that are sensitive to TRAIL. Mark Hall and John Cleveland from the Scripps Research Institute echoed that possibility in a related preview. "In designing the ideal therapy for cancer treatment, three criteria are highest on the list," they wrote: efficacy, selectivity and the ability to predict efficacy based on biomarkers. The studies in Cancer Cell "tackle all three of these criteria, and importantly, they do so in the setting of chemorefractory disease, which ultimately kills the patient."
In a separate study published in the July, 2007 issue of the Journal of Clinical Investigation, researchers from the Charite hospital in Berlin, study another aspect of TRAIL function - its anti-inflammatory effects, which could make the compound useful for fighting serious infections.
The researchers first found that patients with bacterial meningitis had elevated levels of TRAIL in their spinal serum, and investigated the details of TRAIL's effects in meningitis using knockout and wild-type mice with experimental meningitis.
TRAIL knockout mice had worse clinical symptoms of meningitis, as well as increased apoptosis, compared to their wild-type counterparts. Those effects were reversed by administering recombinant TRAIL. Wild-type mice also showed decreased inflammation and apoptosis if they received injections of recombinant TRAIL to the meninges, which line the brain. TRAIL injection did not change the number of bacteria, suggesting that it affects the inflammatory response, not the infection itself.
The authors concluded that "The ability of TRAIL to modify inflammatory responses and to reduce neuronal cell death in meningitis suggests that it may be used as a novel anti-inflammatory agent in invasive infections."