Cholesterol Drug Repurposed as Investigational Therapy for HPV+ Cancers at University Hospitals Seidman Cancer Center in Nation’s First-Ever Clinical Trials

CLEVELAND, Ohio - A team from University Hospitals Seidman Cancer Center is launching the nation’s first-ever clinical trials evaluating the cholesterol drug fenofibrate (Triglide, Fibricor, Lipofen) as an investigational and potential treatment for patients with HPV+ cervical and HPV+ head and neck cancer (HNSCC). Published pre-clinical results show fenofibrate restores function of key tumor suppressor gene in these cancers.

The group’s pre-clinical research in cell lines and mouse models of HPV+ cancers shows that fenofibrate performed as well against these cancers as the conventional chemotherapy drug cisplatin. Specifically, fenofibrate appears to overcome the effects of HPV+ oncoproteins and helps restore the function of the p53 tumor suppressor gene – often referred to as the “guardian of the genome.”

“It stands to reason that if we can prevent the HPV-associated oncoproteins from lowering p53 levels, we should be able to restore the potent anti-cancer activity of this gene,” says Wendi Quinn O’Neill, MS, DDS, Research Scientist at UH Seidman Cancer Center and Assistant Professor of Otolaryngology at the Case Western Reserve University School of Medicine, and lead author of the recent study. “And that's what we've seen in our pre-clinical studies. When we compare tissue samples from mice that have been treated with fenofibrate and mice that haven't received the drug, we see much greater expression of p53 in the treated mice. This drug puts the guardian of the genome back to work. These are really exciting findings, and now we're in the process of moving forward with a number of investigator-initiated clinical trials to look at whether we can potentially use this drug in cancer patients.”

The research team recently published its pre-clinical results in the journal Cancers. Co-authors include: Quintin Pan, PhD, Deputy Director of Research at UH Seidman Cancer Center and Professor of Otolaryngology at the Case Western Reserve University School of Medicine and holder of the Dr. Lester E. Coleman, Jr. Chair of Cancer Research & Therapeutics, and Theodoros Teknos, MD, President & Scientific Director of UH Seidman Cancer Center, Professor of Otolaryngology at the School of Medicine and holder of the Jane and Lee Seidman Chair in Cancer Innovation, among others.

Interestingly, Dr. O’Neill says, fenofibrate also seems to “re-program” the micro-environment of the HPV+ tumor in a way that could prove to be beneficial.

“We really don’t understand the precise mechanism responsible, but when we treated the mice with fenofibrate, we found that the tumors had collections of immune cells infiltrating the tumor,” she says. “In a few cases, we saw just a bit of fibrous tissue and inflammatory cells where the tumor had been. In one case there was no detectable sign of the original tumor. Fenofibrate seems to reactivate the host’s immune cells and we can see them attacking the tumor.”

The research team from UH Seidman Cancer Center is the first to document the anti-cancer potential of fenofibrate to reactivate p53 in HPV+ cancer cells, Dr. O’Neill says. To leverage and implement these important findings, two Phase 1 “window” trials, one enrolling patients with HPV+ cervical cancer and the other with HPV+ HNSCC, will soon launch at UH Seidman Cancer Center. Patients will receive the investigational drug fenofibrate in the window between diagnosis and definitive surgical treatment, and then their excised tissue will be analyzed to determine whether the changes in cellular signaling pathways seen in previous lab experiments are also present in actual patients. Neither clinical trial is testing fenofibrate at a therapeutic dose – that will come if results from the initial window trials are promising, Dr. O’Neill says.

Much is still unknown. However, if proven effective, treatment with fenofibrate has the potential to be a more targeted and less toxic therapy for patients with cancers linked to HPV – as opposed to those with head and neck cancer linked to smoking and alcohol. Such targeted therapeutic approaches are currently lacking, Dr. O’Neill says.

“Despite the many distinctive features of HPV+ HNSCC, current treatment options for both forms of the disease are the same irrespective of HPV status,” she says. “But HPV+ HNSCC is really a distinct disease with a very specific driver, which are these HPV- associated oncoproteins. In theory, we should be able to treat it with a targeted approach that specifically impacts the viral oncoproteins that drive the disease process. This way, we can directly target the cause of the cancer with less toxicity and better patient outcomes.”

It's possible fenofibrate may also have a role to play in preventing these cancers, Dr. O’Neill says.

“Treatment with fenofibrate alone or in combination with cisplatin or an anti-PD-1 checkpoint inhibitor could provide a means of targeting the unique biology of HPV+ cancers, while reducing the toxicity and morbidity associated with current standard of care treatments,” she says. “Moreover, given its excellent safety record, fenofibrate offers the exciting potential for long-term use as a preventative agent for individuals at high risk for developing primary or recurrent HPV+ cancers.”

The Kathy and Les Coleman Clinical Trials Center at UH Seidman Cancer Center offers more than 400 clinical trials for cancer patients.

To search for clinical trials at University Hospitals, visit clinicaltrials.uhhospitals.org