Researchers at the University of Colorado (UC) Denver, Anschutz Medical Campus, have discovered a novel combination treatment strategy that could offer new hope to ovarian cancer patients who stop responding to existing PARP inhibitor (PARPi) therapies.
The strategy combines a PARP inhibitor, a targeted drug used to treat certain types of ovarian cancer, with a novel indirect WNT inhibitor, SM08502 (cirtuvivint), to attack cancer from two directions. SM08502 is a dual CDC-like kinase and dual-specificity tyrosine phosphorylation–regulated kinase inhibitor. In a newly reported study, the researchers report on tests evaluating therapy combining SM08502 with PARPi in multiple resistant models of homologous recombination–deficient high-grade serous carcinoma (HGSC). The team has also advanced from the laboratory to a Phase I clinical trial on the campus.
“I began my career focused on understanding why ovarian cancer becomes resistant to therapy. PARP inhibitors have been a cornerstone of my research, but resistance remains a major challenge,” said Benjamin Bitler, PhD, associate professor and the D. Thomas and Kay L. Dunton Endowed Chair in Ovarian Cancer Research at CU Anschutz. “Early on, we characterized therapy-resistant cell lines, and this research represents the next step—developing strategies to help patients who may have no other options.”
Bitler is senior author of the team’s published paper in Cancer Research Communications, outlining preclinical studies. In the paper, titled “SM08502-Mediated β-Catenin Repression Synergizes with Olaparib to Inhibit Tumor Progression,” the researchers concluded that their study “… provides strong preclinical evidence that SM08502, in combination with PARPi, may be an effective strategy to overcome PARPi resistance.”
Ovarian cancer, particularly high-grade serous ovarian cancer, is notoriously difficult to treat. PARP inhibitors, used as a treatment for ovarian cancer for more than a decade, have transformed care for patients with a BRCA genetic mutation or homologous recombination deficiency (HRD), significantly extending survival rates. However, many ovarian cancer patients eventually develop resistance to PARP inhibitors. “PARPi resistance is a major clinical challenge, and subsequent therapeutic options for patients with resistant disease remain limited,” the authors stated.
The CU Cancer Center experts discovered that when cancer cells become resistant to PARP inhibitors, they switch on WNT signaling as a “backup survival system.” This helps the cancer keep growing in certain patients, even when PARP drugs should stop it. “Elevated WNT signaling and T-cell factor (TCF) transcriptional activity contribute to PARPi resistance; however, directly targeting WNT signaling is challenging due to on-target adverse events,” they pointed out.
For their newly reported study, the team tested a new therapy, SM08502, which is an indirect WNT inhibitor. Instead of directly blocking WNT signaling, which can cause bad side effects, this small molecule pan-inhibitor of CDC-like kinase (CLK1-4) and dual-specificity tyrosine kinase (DYRK) changes how certain cancer genes are processed (spliced), which indirectly shuts down WNT signaling.
The researchers found that SM08502 by itself slowed tumor growth in lab tests, showing the drug has an anti-cancer effect. SM08502 in combination with a PARP inhibitor (such as olaparib) killed more cancer cells, caused more DNA damage (which makes it harder for cancer to survive), and reduced immune suppression (meaning the body’s immune system can fight cancer more effectively). “Using several human and murine PARPi-resistant HGSC models, we observed that SM08502 significantly reduces TCF transcriptional activity, induces elevated DNA damage, and synergizes with olaparib to enhance antitumor activity in two independent immune-intact murine models as well as a patient-derived xenograft (PDX) immune-compromised model,” the team wrote. “These findings strongly support the clinical use of SM08502 against PARPi-resistant HGSC.”
This is the first combination therapy that targets two different cancer survival mechanisms: PARP and WNT signaling. This means the cancer has fewer ways to survive, making the treatment more effective.
The treatment approach has now progressed into clinical development. “A Phase I clinical trial (NCT06856499) is currently open to patients with BRCA/HRD platinum-resistant HGSC to evaluate the safety profile of olaparib in combination with SM08502 (cirtuvivint),” the authors wrote. “This achievement exemplifies true bench-to-bedside innovation entirely done at CU Anschutz,” stated first author Bradley Corr, MD, associate professor and director of clinical research in gynecologic oncology at CU Anschutz. “To the best of our knowledge, this is the first clinical trial to successfully combine these classes of drugs. While the concept has been discussed before, no one has moved it into the clinic until now. That’s what makes this approach truly novel.”
Bitler credits CU Anschutz’s collaborative ecosystem—and the partnership with clinicians like Corr—for turning this milestone into reality. The authors suggest that their approach has the potential to reach beyond ovarian cancer to other tumors with similar resistance mechanisms. Both drugs are oral, making treatment more accessible, and the combination may even help reduce risks associated with long-term PARP inhibitor use.
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