Painful neuropathy affects quality of life – sometimes long-term for cancer patients

BUFFALO, NY — A powerful chemotherapy drug, monomethyl auristatin E (MMAE), can be very effective in treating certain kinds of cancers, especially when it’s delivered directly to cancer cells. However, about half of patients suffer from a significant side effect ­— nerve damage.

The tingling, pain and weakness, particularly in the hands and feet, that are hallmarks of peripheral neuropathy can become so severe that physicians sometimes have to reduce a patient’s dosage or stop cancer treatment altogether. And in some cases, the neuropathy can become a long-term issue, notes Jason Sprowl, PhD, associate professor of pharmaceutical sciences in the University at Buffalo School of Pharmacy and Pharmaceutical Sciences.

Sprowl, who has studied cancer drugs over his academic career, was recently awarded more than $410,000 from the National Cancer Institute to study how the body processes and responds to MMAE in order to understand why it can cause nerve damage. The co-principal investigator on the study is Donald Mager, PharmD, PhD, professor and chair of the Department of Pharmaceutical Sciences.

While many studies have focused on making MMAE work more effectively, this project focuses on understanding why it causes side effects and how those side effects might be prevented.

“Even people getting the same exact drugs for the same type of cancer are going to respond differently,” Sprowl says. “And while approximately 50% of the patients treated with MMAE won’t experience neuropathy, the other 50% aren’t as lucky.”

Particularly in breast and lung cancer, the goal is to get MMAE directly to the tumor by conjugating it to an antibody, but it does cause nerve toxicity in quite a few patients.

“Cancer patients are going through enough as it is, and then they have the concern of whether their nervous system is going to suffer, and subsequently, their quality of life,” Sprowl says. “For instance, musicians need fine motor skills, which can be impacted by neuropathy.”

The first goal is to find out if the loss or modulation of a certain protein, permeability glycoprotein or P-gp, alters the adverse response to MMAE. And then that can help guide clinicians in avoiding certain drug interactions.

“There is a potential chance of reducing the neurotoxicity of antibody drug conjugates by manipulating permeability glycoprotein, a multidrug resistant protein that pumps many foreign substances out of cells,” Sprowl says. “This poses a good possibility of reducing or eliminating nerve damage in cancer patients.”

During the two-year study that began this summer, the researchers will evaluate two animal models­ ­­— one of which has the protective protein and one that does not — to look at genetic and drug interaction factors.

“This mimics genetic deficiencies in humans,” Sprowl explains. “Some people don’t have a functional version of this protein or they can be on multiple drugs which interferes with that protein. This can be a big deal for cancer patients.”

A second goal of this research is to evaluate how different gene and protein expression levels change after exposure (or in response) to MMAE. Along with using pharmacokinetics, looking at how the body processes and eliminates the drug, the study will employ computer models and biological data to help understand how different organs, cells and pathways interact to produce the drug’s effects and side effects.

Mager has expertise in the development and validation of quantitative structure-property relationships and network pharmacology modeling to optimize drug design, development, and therapeutic application of anti-cancer compounds.

“If specific genes or proteins are found to be associated with neuropathy, we could potentially develop new drugs or repurpose existing drugs that would prevent these changes and stop nerve damage symptoms,” Mager says.

Jeffrey Miecznikowski, PhD, professor and associate chair of strategic initiatives in Department of Biostatistics in the School of Public Health and Health Professions, is providing support on the genetic analysis piece of the study, and Vivian Xu, a doctoral candidate in pharmaceutical sciences, will assist with the lab research.

“I think we’ve got so many drugs that are very effective, but then they’re limited by these side effects,” Sprowl says. “If we can alleviate the side effects, then we don’t have to lower dosages or stop treatment, which of course, would be a huge benefit to cancer patients.”