Ovarian cancer causes more deaths than any other cancer involving the female reproductive system. Although new targeted treatments help some patients, about three-quarters of women with advanced ovarian cancer will relapse within five years.
With targeted treatments, doctors look to the genes within a tumor to match patients to the drug that is most likely to work for their particular tumor. This is more personalized than the one-size-fits-all approach of the past, but in practice, many patients receive a targeted therapy and are then switched to a different one if their cancer stops responding to it. Stefani Thomas, PhD, from the Masonic Cancer Center at University of Minnesota, is taking a new approach. With V Foundation funding, she is studying protein expression, rather than genes, to predict treatment sensitivity and resistance.
“Proteins are the primary molecules responsible for carrying out biological functions,” Thomas said. “This is an exciting time because advances in proteomic technologies such as mass spectrometry are allowing us to discover new insights into the mechanisms of human health and disease, including cancer.”
The work could eventually lead to a blood-based diagnostic test that lets doctors use a patient’s protein profile to determine their likelihood of responding to a certain drug or combination of treatments. This could help patients avoid wasting critical time – and suffering unnecessary side effects – in an extensive trial-and-error search for the right treatment.
Early results showed that certain biological pathways were suppressed after cancer cells were treated with the PARP inhibitor Rucaparib but not when the same cells were treated with a different PARP inhibitor. Because both drugs target DNA damage response, these findings suggest that different PARP inhibitors have additional, previously unknown, mechanisms of action, which could help explain why some patients respond to them while others do not. The researchers observed similar results when cancer cells received a different targeted treatment known as histone deacetylase inhibitors.
“Between these two studies, we have solid evidence that targeted therapies for high-grade serous ovarian cancer have impacts on pathways that are not related to their initially intended purposes, which was to perturb the DNA damage response pathway,” said Thomas.
The researchers are now performing animal-based studies and are examining whether histone deacetylase inhibitors could help sensitize tumors to PARP inhibitor treatment. Eventually they want to use their findings to help equip doctors to use the right drug for the right patient based on their protein profile rather than their genomic profile alone.
An investment in the future
Thomas says that the V Foundation support was critical in supporting the graduate students and undergraduate trainees who performed this work and helping their team build up the expertise and infrastructure needed to perform proteomic studies.
“The discovery-based analyses we are doing form a very important foundation for deciding what questions to pursue in targeted follow-up studies,” said Thomas. “However, it can be difficult to get funding for discovery studies. Receiving a V Foundation grant also demonstrated to other funders that that my research is a good investment and is following a positive trajectory.”
Outside of the lab, Thomas’s training as a dancer offers inspiration and reinforces the importance of keeping a steady focus. “I’ve been a member of several professional dance companies and am currently in a company that specializes in traditional drumming and dance from Guinea in West Africa,” said Thomas. “Having that creative outlet not only keeps me balanced, but it also helps me approach difficult questions from different perspectives.”