A clinical trial from a team at the University of Michigan Rogel Cancer Center uses innovative basic science research methods to offer hope and a new treatment to glioblastoma patients, according to a news release.
A collaborative team of Rogel physicians, led by Daniel Wahl, MD, PhD, hopes that grounding their trial in rigorous and innovative biology from the very beginning will help this approach succeed where so many other potential glioblastoma treatments have failed.
Exploring these types of advances in glioblastoma treatment is urgent. The aggressive brain tumor is largely resistant to current treatment, almost always recurs, and comes with a grim prognosis. Further, many new therapies fail to cross the blood-brain barrier, making drugs that would otherwise be effective often unable to reach the cancer cells. This reality of glioblastoma, and the lack of new effective treatments in the last 15 years, motivates Wahl and his team.
The clinical trial, which began in August 2020, has its foundation in Wahl’s medical training and PhD studying metabolism, all performed at U-M. While taking care of glioblastoma patients during a residency in radiation oncology, Wahl saw firsthand the consequences of these aggressive treatment-resistant brain tumors. Most glioblastoma patients live less than a year-and-a-half from diagnosis, and fewer than 5% live five or more years.
“Radiation is one of the few treatments that work for glioblastoma, but it doesn’t work well enough,” Wahl explained. “Because of how important metabolism is for so many biologic functions, and how different metabolism is in cancer cells compared to the normal body, I thought metabolic pathways might be partly to blame for this resistance.”
First, Wahl needed to understand the relationship between metabolites—small nutrients like sugars, amino acids, and fats—and tumor treatment response. Measuring a variety of tumor models, Wahl’s team searched for a correlation between the high levels of different metabolites and the tumor models with the highest radiation resistance. Toward the end of his post-doctoral fellowship, he and his team found what they were looking for. “Purines, the metabolites that are the building blocks of DNA, were really, really high in the brain tumors that were most resistant to radiation.”
But how important was this finding? When more purines were added into a glioblastoma cell, did the cells become more resistant to radiation? If purine levels were decreased, did the tumor become more sensitive to radiation? The answers were a resounding yes.
“Not only were high purines associated with treatment resistance, they also caused treatment resistance,” said Wahl.
With this, Wahl set out to see if this causal relationship between high purine levels and glioblastoma radiation resistance could be leveraged to make clinical treatments more effective. He looked for FDA-approved drugs on the market that altered purine levels and found mycophenolate mofetil, a purine blocker used to prevent organ rejection in transplant patients. Moreover, mycophenolate eliminated guanosine triphosphate, the main purine responsible for radiation resistance.
In the lab, Wahl’s team explored using mycophenolate mofetil on glioblastoma tumors grown in mouse models. To their delight, the drug made radiation work better. “When we saw those lab results, we knew we had to write a clinical trial.”
To do so, Wahl partnered with Yoshie Umemura, MD, a Neuro-oncologist at the Rogel Cancer Center and expert in clinical trial writing and design, and Wajd Al-Holou, MD, a Neurosurgeon specializing in Oncology. Together they have developed the Michigan Medicine Multidisciplinary Brain Tumor Clinic, the first multi-disciplinary treatment-focused brain tumor clinic at the University of Michigan.
In this clinic, Wahl, Umemura and Al-Holou see patients and determine treatment plans together. It was this clinic that “allowed us to develop ideas as a team to tackle this difficult problem,” said Al-Holou.
The clinical trial started in August 2020 for patients with recurrent glioblastoma tumors who’d previously received radiation but whose tumors had returned. In the trial, these patients receive mycophenolate mofetil alongside additional radiation treatment. To date, the team has treated about a dozen patients, and has since expanded the bounds of the trial to include patients with new glioblastoma diagnoses, incorporating updated laboratory results showing that mycophenolate also made chemotherapy more effective. This arm of the trial started in late 2021 and five patients have been treated at the time of publication.
“It’s all still ongoing and too early to tell, but so far, treatment has been really safe with no serious toxicities,” said Wahl.
For Umemura, the strength of this trial lies in the symbiotic relationship between clinical care and lab research, and the collaboration amongst researchers.
“This trial has a rigorous basic science backbone to support the addition of an inexpensive drug that is widely available. If we can prove there is an added benefit in treatment efficacy—which would be the next step after we can show it’s safe— then this treatment regimen is likely readily incorporated into clinical care without challenges in cost or accessibility for patients.”
