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TORONTO — Researchers have found the closest thing to an off-switch for cancer: a specific protein section that has the ability to trigger the death of a cancer cell.
A team from the UC Davis Comprehensive Cancer Center has identified an epitope on a CD95 cell receptor that is able to kick off a chain reaction that instructs cells to essentially self-destruct, something researchers believe could be leveraged for new therapeutics to stop cancer cells in their tracks.
Scientists have long been aware that the CD95 receptor, known as Fas, holds the key to killing cells — it’s often called a “death receptor.”
But until now, researchers say, they haven’t been able to do much with that knowledge. Their findings are described in a paper published earlier this month in the peer-reviewed Nature journal Cell Death & Differentiation.
“We have found the most critical epitope for cytotoxic Fas signaling, as well as CAR T-cell bystander anti-tumor function,” Jogender Tushir-Singh, a senior author of the study and an associate professor in the department of medical microbiology and immunology at UC Davis Health and School of Medicine, said in a press release.
“Previous efforts to target this receptor have been unsuccessful. But now that we’ve identified this epitope, there could be a therapeutic path forward to target Fas in tumors.”
An epitope is a group of amino acids or chemicals, usually part of a protein, which sits on the surface of a molecule and can be recognized by the body’s immune system, specifically by an antibody, B-cell receptor or T-cell receptor. When specific immune cells interact with the right epitope, it’s similar to lighting a fuse to an explosive, causing proteins to activate — and, in the case of this crucial epitope on Fas, leading to cell death.
Researchers believe that they can now start developing antibodies that selectively use this newly identified epitope to bind to and activate Fas in cancer cells in solid tumours, sparking cell death.
Researchers also believe this work may have identified a way in which current treatments could be made more efficient and cause cancer cell death as a side effect while targeting other areas of the cancer.
The complications of cancer treatment
There are many therapies to try and tackle cancer, but if a cancer returns despite surgery, chemotherapy and radiotherapy, doctors often will try immunotherapies, which are therapies that boost the immune system to help the body destroy the cancer.
One example of this is CAR T-cell-based immune therapies, in which researchers edit a patient’s T-cells by grafting a specific tumor-targeting antibody onto them to guide them to attack the tumour cells.
This therapy has shown promise in fighting leukemia and other blood cancers, but hasn’t made much ground in solid tumors such as ovarian cancer, breast cancer and lung cancer before because of the completely different environments they have.
“These are often called cold tumors because immune cells simply cannot penetrate the microenvironments to provide a therapeutic effect,” said Tushir-Singh. “It doesn’t matter how well we engineer the immune receptor activating antibodies and T-cells if they cannot get close to the tumor cells. Hence, we need to create spaces so T-cells can infiltrate.”
That doorway into solid tumors that researchers have been looking for could be Fas, the death receptor. Drugs which boost the activation of death receptors could not only kill more cancer cells, but create the opening needed to deliver more therapeutics into the tumor itself.
And the identification of this crucial epitope may have just unlocked that doorway.
Researchers are hoping that they will be able to develop antibodies that target this epitope to spark cancer cell death, while also identifying the presence of this epitope in a patients’ cells to give them a better idea of how to leverage CAR T-cell immune therapy.
A drug targeting this specific epitope could generate a “bystander effect” in conjunction with the CAR T-cell immune therapy, in which any cancer cells lacking the molecule that the CAR T-cell therapy is designed to destroy can get taken out by the drug targeting this newly identified epitope.
In previous studies, the bystander effect hasn’t worked because receptors that inhibit cell death have been better at binding to therapies attempting to target Fas. Targeting antibodies to this epitope could change that.
The study also found that patients who had a mutated version of this specific epitope on their Fas receptors didn’t respond to CAR T-cell immune therapy at all, signaling that this epitope can also serve as a biomarker for the effectiveness of this existing therapy.
“We should know a patient’s Fas status — particularly the mutations around the discovered epitope — before even considering giving them CAR T,” Tushir-Singh said. “This is a definitive marker for bystander treatment efficacy of CAR T therapy. But most importantly, this sets the stage to develop antibodies that activate Fas, selectively kill tumor cells, and potentially support CAR T-cell therapy in solid tumors.”
So far, no antibodies developed to target Fas have made it to clinical trials. Researchers hope that with this new knowledge for how to best activate these death receptors, we could see that change soon.
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