Researchers at the University of Colorado Cancer Center have discovered a novel therapy combination that could offer new hope to ovarian cancer patients who do not respond to existing treatments. Conducted entirely at the University of Colorado Anschutz , this research has advanced from the laboratory to a Phase 1 clinical trial on the campus.
The findings, published today in Cancer Research Communications , outline a promising strategy that combines a PARP inhibitor, a targeted drug used to treat certain types of ovarian cancer, with a novel therapy, SM08502, to attack cancer from two directions. This innovative approach boosts the effectiveness of the treatment, even for patients who are no longer responding to PARP inhibitor therapy.
"This achievement exemplifies true bench-to-bedside innovation entirely done at CU Anschutz," said the paper's 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."
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, leaving few treatment alternatives.
The CU Cancer Center experts discovered that when cancer cells become resistant to PARP inhibitors, they switch on a "backup survival system" called WNT signaling. This helps the cancer keep growing in certain patients, even when PARP drugs should stop it.
Because of this outcome, they decided to test a new therapy called SM08502 (Cirtuvivint). They found that instead of directly blocking WNT signaling (which can cause bad side effects), this drug changes how certain cancer genes are processed (spliced), which indirectly shuts down WNT signaling. This resulted in impressive findings:
- SM08502 by itself slowed tumor growth in lab tests, showing the drug has an anti-cancer effect.
- When combined with a PARP inhibitor (such as Olaparib), it 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).
- 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.
"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. 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," said senior author Benjamin Bitler, PhD, associate professor and the D. Thomas and Kay L. Dunton Endowed Chair in Ovarian Cancer Research at CU Anschutz.
Bitler credits CU Anschutz's collaborative ecosystem - and the partnership with clinicians like Corr - for turning this milestone into reality.
The authors mention this 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.
To explore enrollment in this clinical trial, visit www.clinicaltrials.gov/study/NCT06856499 .
