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In 1997, Dr. Wafik El-Deiry’s cancer research laboratory discovered a gene called death receptor 5, or TRAIL receptor 2. TRAIL is a protein that activates the cell death process, or apoptosis. This TRAIL pathway via death receptor 5 gives rise to the body’s innate immune system and is capable of suppressing cancer cells by inducing their apoptosis.
After this discovery, researchers considered enhancing the body’s own immune response by increasing the production of TRAIL may have a safe therapeutic benefit in the treatment of cancer. The team searched for small molecules capable of upregulating the TRAIL gene. This led to the 2013 discovery of the therapeutic compound TIC10—known today as ONC201. ONC201 is now a well-tolerated drug currently being evaluated in advanced clinical trials for the treatment of various malignant solid tumors, including breast cancer.
Researchers in Dr. El-Deiry’s laboratory have continued to investigate this drug to learn more about how it works and what tactics or combinations may be used in order to produce better results for cancer patients. In a 2017 study, the researchers learned that ONC201 produces heterogeneous results in different tumor types.
“The question is, with this specific drug, what is the pattern of response, what determines that, and how can we get it to work a little bit better,” Dr. El-Deiry said in a recent Oncotarget interview.
Led by first-author Dr. Marie Ralff, researchers based out of Temple University, Fox Chase Cancer Center, Brown University, and the El-Deiry Cancer Research Laboratory wrote a paper detailing their latest study on ONC201. The paper was published by Oncotarget in 2020 and entitled, “TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic.”
The researchers previously found that ONC201 induces differential responses across various breast cancer tumor subtypes. When they compared in vivo and in vitro results from this compound, they found that tumors showing pro-apoptotic effects translated to efficacy, while the tumors showing anti-proliferative effects did not. The team then decided to investigate strategies to convert TRAIL-resistant breast cancer cell response to ONC201 from anti-proliferative, to apoptotic.
“We saw that in some of these tumor types (the triple-negative breast cancer type in particular) the compound was having a pro-apoptotic effect, and in other [breast cancer] tumor types, it was having an anti-proliferative effect,” Dr. Ralff said.
In the current study, researchers began searching for strategies that make ONC201 more effective by investigating two known mechanisms of TRAIL resistance in breast cancer that are also affected by ONC201: death receptor 5 and anti-apoptotic proteins. The researchers primed the TRAIL-resistant cancer cells to undergo apoptosis through the TRAIL pathway with ONC201. They then introduced a TRAIL receptor agonist antibody to potently induce apoptosis.
“If we pretreat TRAIL-resistant breast cancer cells with ONC201, the level of surface death receptor 5 goes up and the intracellular levels of anti-apoptotic proteins go down, thereby priming the cells to undergo death through the TRAIL pathway. So, if we then add in a TRAIL receptor agonist, it induces apoptosis in a very potent way,” Dr. Ralff said.
“The concept is, when cells are treated with the small molecule compound, not a whole lot happens. When cells are treated with TRAIL, not a whole lot happens. When you put them together, it’s like flipping a switch. The cells now undergo potent cell death,” Dr. El-Deiry said.
The potential efficacy of this therapeutic combination was strengthened by study results showing that ONC201 paired with the TRAIL receptor agonist antibodies is non-toxic to fibroblasts. The researchers also showed that natural killer cells were only active against breast cancer cells that have been exposed to ONC201. Mouse model studies reaffirmed the safety of this combination in vivo.
“These findings may have clinical relevance as ONC201 is currently being tested in patients with breast cancer, and we believe that this newly identified combinatorial strategy has the potential to induce tumor regressions in patients with limited response to ONC201 monotherapy.”
Click here to read the full research study, published by Oncotarget.
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