Specifically, NLRP3 promotes inflammation by inducing the maturation and release of interleukin-1-beta, a cytokine that causes inflammation as part of the normal immune response to infection. In cancer, however, inflammation can cause tumors to grow and spread.
“NLRP3 is a member of a larger family that is involved in detecting danger signs,” said Marchetti. “It is a receptor that watches over the intercellular compartment of a cell, looking for dangerous molecules or pathogens.
Upon recognizing these signals, NLRP3 leads to the activation of caspase-1, a protein involved in the processing and maturation of interleukin-1-beta in its active biological form, causing an intense inflammatory response. We found that in melanoma, this process is unregulated, resulting in tumor growth. “
The oral NLRP3 inhibitor used in his study (Dapansutrile) has already been shown to be effective in clinical trials to treat gout and heart disease, and is currently being tested on COVID-19 as well.
CU cancer researchers are now trying to find out if this NLRP3 inhibitor can be used successfully in melanoma patients who are resistant to checkpoint inhibitors.
“Checkpoint inhibitors increase the effectiveness of the immune system to kill tumors, but sometimes tumors become resistant to this treatment,” says Marchetti. “A large part of cancer research now is finding therapies that can be combined with checkpoint inhibitors to improve their effectiveness.”
With the hypothesis that an NLRP3 inhibitor is one of these therapies, researchers at the CU Cancer Center are studying the effects of the drug on melanoma, as well as breast and pancreatic cancer.
In addition to improving the immune response, the NLRP3 inhibitor can also help reduce the side effects of checkpoint inhibitors. Marchetti says that this research can make a big difference for melanoma patients who don’t respond only to checkpoint inhibitors.
“This was a very collaborative project that involved many members of the university and we are very excited about it,” he says.
This project is important because it also shows that NLRP3-mediated inflammation plays a critical role in the progression of melanoma and opens up new strategies to improve patient care. “