One of the most impactful advancements during the past decade in treating ovarian cancer is the use of PARP inhibitors (short for poly adenosine diphosphate-ribose polymerase). PARP inhibitors are a type of cancer drug that blocks the PARP enzyme from helping to repair DNA damage in cancer cells.
PARP inhibitors are an important ovarian cancer treatment, but patients can commonly develop resistance to them. This resistance and how to overcome it are an area of research that Benjamin Bitler, PhD, CU Cancer Center member and assistant professor of reproductive sciences, has pursued with research partners across the CU Anschutz Medical Campus and the country.
Now, his ongoing research is supported by a seven-year R37 MERIT Award, given by the National Institutes of Health to provide long-term support to investigators whose research competence and productivity are deemed superior.
The award originally was a five-year R01 grant, but was converted to the R37 award in July, Bitler says. It will fund research and development of therapeutic treatments to overcome PARP inhibitor resistance disease, focusing on how to target Wnt signaling in therapy-resistant ovarian cancer.
“Between cells and within cells, there’s a form of communication that provide cues to the cells for them to grow, when to take up nutrients, and other cell functions,” Bitler explains. “This communication network within cells is mediated by multiple stimuli and one of the stimuli that activates this network is Wnt. Wnts are stimuli that basically trigger the signaling network within the cell to make the cell less sensitive to chemotherapies as well as PARP inhibitors.”
Working to overcome therapy resistance
Bitler first began researching PARP inhibitors as a post-doctoral student at the Wistar Institute, when they were an emerging therapy. PARP inhibitors initially were developed for patients with BRCA1 and BRCA2 mutations, which account for about 30% of ovarian cancers. The use of PARP inhibitors has evolved so that “now almost all ovarian cancer patients will receive PARP inhibitor when they’re being treated here at the University of Colorado,” Bitler says. “Unfortunately, most of these patients eventually develop resistance to PARP inhibitors.”
In 2015, he and other researchers began developing unique models to combat PARP inhibitor resistance disease.
“What we discovered is that Wnt signaling is one of the major mechanisms of PARP inhibitor resistance,” he says. This groundbreaking discovery, published in 2019, demonstrated that a mechanism of PARP inhibitor resistance is an elevation of the Wnt signaling pathway.
“That paper set the stage for us now to say we have these unique models of PARP inhibitor resistance, we have a description of the mechanism of how these patients are potentially developing therapy resistance,” Bitler explains. “The next step is what are the therapeutic options we can develop to treat PARP inhibitor resistance disease?”
Potential to treat multiple types of cancer
Research in Bitler’s, as well as other labs, found that Wnt signaling promotes an immune suppressive microenvironment, which aligns with ovarian cancer as a cancer that doesn’t respond well to immunotherapies.
The goal, he says, is to develop a Wnt inhibitor that will stop survival pathways from being activated – to stop Wnt signaling from telling cancer cells not to die and to repair their DNA, and making the cells less sensitive to chemotherapies and PARP inhibitors. Bitler and his co-researchers are working closely with Elmar Nurmemmedov, PhD, of the John Wayne Cancer Center in California, who reached out to Bitler with a promising Wnt inhibitor he was developing.
“Where we stand right now is we’re going through some of the paces with (Nurmemmedov’s) drug,” Bitler explains. “We’ve seen PARP inhibitor resistant cells in the tissue culture dish die following treatment with the Wnt inhibitor. We’re ramping up to use more complex models in the next couple of months, which is a good place to be at considering we’re only one month into a seven-year award.”
Bitler said he is working closely with Bradley Corr, MD, CU Cancer Center member and assistant professor of gynecologic oncology, to plan animal studies that will allow the research team to develop and open clinical trials at the CU School of Medicine.
An effective Wnt inhibitor could have potential beyond treating PARP inhibitor resistant ovarian cancer, Bitler says, and sees it being used in treatment of breast, prostate, and pancreatic cancers. The Wnt inhibitor research also dovetails with research he is doing on multi-spectral immunohistochemistry (mIHC) (LINK Previous article?), which is a way of characterizing a tumor’s composition. The University of Colorado Ovarian Cancer Group, including Dr. Bitler, has a pending grant application which proposes to use mIHC to provide precision medicine to patients.
“We’re looking at the tumor microenvironment as an organism itself,” Bitler says. “I think this is an area cancer research has often overlooked by just focusing on cancer cells, but with multi-spectral IHC we’re appreciating the heterogeneity of the tumor microenvironment. Tumors are not just made up of cancer cells, so we think, based on previous literature, that the immune microenvironment of the tumor is also being deregulated by this Wnt pathway within immune cells such as T cells and macrophages.
“Our hypothesis is that using a Wnt inhibitor will kill tumor cells and reprogram immune cells to produce an anti-tumor immune response, and that has the potential applications for treating multiple kinds of cancer,” he says.