The researchers, led by Penn State Hershey Cancer Institute and College of Medicine, report their findings in the 6 February online issue of Science Translational Medicine.
New treatments are needed for advanced cancer, as estimates suggest more than half a million Americans will die of cancer in 2013.
Increasing Interest In Natural Tumor Suppression for Cancer TreatmentOne of the many routine tasks the immune system performs is tracking down and destroying rogue cells that can become cancerous tumors.
The immune system's surveillance process looks for rogue cells that aren't behaving normally and flags them up to the tumor suppression process, which includes a natural protein called TRAIL (recombinant tumor necrosis factor-related apoptosis-inducing ligand) that triggers cell suicide (apoptosis).
However, once cancer progresses, the immune system loses this ability to suppress tumors, and so the rogue cells continue to grow uncontrolled allowing tumors to spread.
Researchers looking for new ways to tackle cancer are becoming increasingly interested in the cell suicide pathway. One of the attractions of this route, apart from it being an existing natural process, is that it is a clean way to kill cancer cells.
Once cells start down the suicide path, their membranes change, and this is picked up by macrophages, the waste collectors of the immune system, that swallow up the whole cell, without leaving any debris. Other ways of killing cancer cells tend to leave bits of cell waste in the tumor microenvironment, which can trigger an inflammatory response and lead to further tissue damage.
Problems with Trying to Make Drugs Based on TRAILThere have been several attempts to duplicate TRAIL's ability to pick out only cancer cells and get them to kill themselves.
Some trials are trying to do this with artificially produced TRAIL, or with antibodies that mimic what it does.
But, while use of the TRAIL protein as a drug is safe, there are some practical problems. For instance, in drug form the protein is unstable and expensive. And it does not easily distribute throughout the body to reach the target tumors, especially if they are in the brain.
Senior author Wafik El-Deiry, professor of medicine and chief of the hematology/oncology division at Penn State College of Medicine, says in a statement:
"The TRAIL pathway is a powerful way to suppress tumors but current approaches have limitations that we have been trying to overcome to unleash an effective and selective cancer therapy."
The Cell Death Pathway Looks Like a Better OptionEl-Deiry says they turned to the "TRAIL biochemical cell death pathway", because it "naturally lends itself as a drug target to restore anti-tumor immunity".
In their paper he and his colleagues describe how they identified a compound called TIC10, short for TRAIL-inducing Compound 10, that appears able to boost the natural tumor suppression ability of TRAIL.
Using mice, they tested TIC10's ability to boost TRAIL's tumor suppression in both normal tissue and in tumors, including in the brain.
A Small Molecule with a Big EffectTIC10 is a small, organic compound that binds to a protein and changes its behavior. When it binds to TRAIL it stimulates the protein to kill rogue cells both in tumors and in normal tissue.
In normal tissue, normal cells appear to help the stimulated TRAIL protein to trigger cancer cell death via a process known as the "bystander effect", where the healthy cells pass on the cell suicide message to the rogue cells.
The researchers tested TIC10 in both cancer cell samples and in cell lines that had proved resistant to conventional anti-cancer therapies.
El-Deiry says he was "surprised and impressed" that they were able to do this.
"Using a small molecule to significantly boost and overcome limitations of the TRAIL pathway appears to be a promising way to address difficult to treat cancers using a safe mechanism already used in those with a normal effective immune system."
"This candidate new drug, a first-in-its-class, shows activity against a broad range of tumor types in mice and appears safe at this stage."
Next StepEl-Deiry says they now have enough preclinical evidence to justify testing TIC10 in the clinic.
The drug appears to be non-toxic to normal cells. Even at doses ten times stronger than what would be regarded as a therapeutic dose did not harm live mice.
But the researchers say more work needs to be done to satisfy US Food and Drug Administration (FDA) requirements before clinical trials can start.
Funds from the American Cancer Society, Penn State Hershey Cancer Institute and the National Institutes of Health helped finance the study.
In another novel approach to target tumor suppression with small molecules, researchers writing in the journal Cell in October 2012, report how cold virus proteins hijack molecular mechanisms inside healthy cells to silence cancer-fighting genes and overpower cellular agents of growth and cancer suppression. They hope the discovery will help scientists create small drug molecules that destroy tumors by binding to and disrupting large cellular components that allow cancer cells to proliferate unchecked.
Written by Catharine Paddock PhD