Promising Drug Treatment for Brain Tumors

Meningioma is cancer of the membrane surrounding the brain and spinal cord. It is the most common intracranial tumor in humans and accounts for approximately half of all primary brain tumors in dogs. Surgical removal is the treatment of choice but is not always possible due to tumor size and location or overall patient health. Therefore, new drug treatments are needed.

Investigators from the National Cancer Institute's Comparative Oncology Program (NCI-COP) and select veterinary universities are collaborating to evaluate a new chemotherapy treatment for meningioma. This includes AKC Canine Health Foundation (CHF) funded investigator Dr. Timothy Fan at the University of Illinois College of Veterinary Medicine. (CHF Grant 02321: Clinical Trial of Procaspase-3 Activator (PAC-1) in Combination with Hydroxyurea for Treatment of Canine Meningioma) The drug under investigation is Procaspase Activating Compound-1 (PAC-1), a small molecule that activates programmed cell death in many cancer cells. PAC-1 targets a process that is upregulated or overexpressed in cancer cells, including 70% of human and 92% of canine meningiomas.

PAC-1 was combined with two other chemotherapy drugs to enhance its effect – hydroxyurea (HU) or temozolomide (TMZ). In cell cultures, PAC-1 + TMZ showed some combined effect, but PAC-1 + HU worked synergistically to kill meningioma cells. When tested in a handful of dogs with naturally occurring brain tumors, the opposite was true – PAC-1 + TMZ decreased tumor burden, while PAC-1 + HU only stabilized the disease and did not change the rate of programmed cell death in the tumor.

A novel drug that activates programmed cell death in many cancer cells was well tolerated in dogs and may be effective against meningioma – cancer of the membrane surrounding the brain and spinal cord.

As part of this study, investigators also tested a new indicator of programmed cell death – an injectable compound that is measured by PET-CT scan. Levels of the tracer documented during this study matched the tumor burden visualized on MRI, proving that this appears to be a valuable tool for cancer studies in dogs and humans. A clinical trial is already underway to assess the safety of this tracer in humans.

Results of this study demonstrate the importance of using natural disease models during drug discovery. What happens in cell cultures does not always hold true in natural disease. Investigators recommend including canine clinical trials early in drug discovery, as the results will not only benefit participating canine patients but will demonstrate which drugs do not impact natural disease as expected earlier in the process.

Since only a handful of canine meningioma patients were recruited for this clinical trial, additional study is needed to refine the dose and effect of PAC-1 on this cancer. However, results do show that the combination of PAC-1 plus TMZ appears effective and was well tolerated in dogs. CHF and its donors remain committed to finding new and more effective treatments for many cancers that affect dogs and humans. Collaboration and this One Health approach to drug discovery ensure that both dogs and their people can live longer, healthier lives.

Learn more about CHF’s canine cancer research at akcchf.org/caninecancer.


Reference:
Tonogai, E. J., Huang, S., Botham, R. C., Berry, M. R., Joslyn, S. K., Daniel, G. B., Chen, Z., Rao, J., Zhang, X., Basuli, F., Rossmeisl, J. H., Riggins, G. J., LeBlanc, A. K., Fan, T. M., & Hergenrother, P. J. (2021). Evaluation of a procaspase-3 activator with hydroxyurea or temozolomide against high-grade meningioma in cell culture and canine cancer patients. Neuro-Oncology, noab161. https://doi.org/10.1093/neuonc/noab161