Interest continues to grow in the role mitochondria play in the development of cancer, the progression of cancer and the resistance of cancer cells to chemotherapy. DEF Research Director Dr. M. Cristina Kenney is currently working with DEF-supported researcher Dr. Lata Singh, who has been studying several cancer types: retinoblastoma, which is a childhood cancer of the eye; uveal melanoma, which is a melanoma that occurs in the eye; and chronic lymphocytic leukemia (CLL). In cells with each of these cancers, they have found that the mitochondria and mitochondrial DNA are damaged, and the cancer cells can be less receptive to chemotherapy.
At the same time, DEF-funded researcher Dr. Mithalesh Singh has been studying the role of ferroptosis, which is a newly discovered mode of cell death that involves the presence of iron.
Together, Kenney, Singh, Singh and several other researchers submitted a proposal to the UCI Chao Family Comprehensive Cancer Center Anti-Cancer Challenge. In July 2023, they were awarded funds to continue their work looking at the role of mitochondria in cancer. They will study the importance of mitochondria in ferroptosis with the hypothesis that increasing mitochondria-mediated ferroptosis can overcome chemo-resistance in cancer cells.
Specifically, they will look at neuroblastoma (NB), which is one of the most common and deadly tumors in children under 5 years of age. When NB cancer cells have higher levels of ferroptosis, the cells are more receptive to chemotherapy drugs. When ferroptosis levels are low, cancer cells are resistant to chemotherapy drugs.
“Approximately half the NB tumors make a protein that causes the tumor cells to become resistant to chemotherapy drugs and more deadly,” Kenney says. “The protein causes the mitochondria to fuse together, which leads to lower levels of ferroptosis and, thus, less resistance to cancer.”
Ferroptosis is an important area of research. It plays a role in retinoblastoma, uveal melanoma, pancreatic ductal adenocarcinoma, gastric cancer, colorectal cancer, lung cancer, breast cancer, glioblastoma, head and neck cancer, age-related macular degeneration, diabetic retinopathy, and glaucoma.
“We will be also applying our work to all these other diseases,” Kenney says. “The idea is you need ferroptosis to be occurring in cancer cells for the cells to be receptive to chemotherapy and susceptible to death. Sometimes, the cancer cell produces a factor that blocks ferroptosis, making the cancer cell resistant to chemotherapy instead.
“We believe the mitochondria are playing a role in the blocking of ferroptosis. This grant will allow us to compare cancer cells that have the mitochondria with those that have inactivated mitochondria. We’re showing that if you don’t have the mitochondria, the entire ferroptosis pathway is altered, and cell are negatively affected. This type of information will help us identify potential targets for therapies.”
“This work illustrates the importance of getting initial funding from DEF,” says Dr. Anthony Nesburn, DEF’s medical director. “DEF funds pilot research to get preliminary data, then researchers can build on that work to get grants from larger foundations. That’s what happened here.”
“This whole field is opening up,” Kenney adds. “No one would be studying this if it hadn’t been for DEF giving the initial funding that allowed us to see the importance of the mitochondria in these diseases.”