NCI-funded study targets P-gp to reduce MMAE-induced neuropathy in cancer patients
核心洞察
Monomethyl auristatin E (搜索) (MMAE), a potent chemotherapy payload used in antibody-drug conjugates, causes peripheral neuropathy (搜索) in roughly 50% of treated patients, sometimes requiring dose reduction or treatment discontinuation.
University at Buffalo researchers received more than $410,000 from the National Cancer Institute to investigate why MMAE causes nerve damage and how it might be prevented.
The two-year study will examine whether modulating permeability glycoprotein (搜索) (P-gp) can reduce neurotoxicity, using animal models that mimic human genetic deficiencies and drug interactions.
A potent chemotherapy agent, monomethyl auristatin E (搜索) (MMAE), can be highly effective against certain cancers when delivered directly to tumor cells, yet roughly half of treated patients develop a significant side effect: nerve damage. Jason Sprowl, PhD, associate professor of pharmaceutical sciences in the University at Buffalo School of Pharmacy and Pharmaceutical Sciences, has received more than $410,000 from the National Cancer Institute (NCI) to study how the body processes and responds to MMAE, with the goal of understanding why it causes peripheral neuropathy (搜索) and how that toxicity might be prevented. Donald Mager, PharmD, PhD, professor and chair of the Department of Pharmaceutical Sciences, serves as co-principal investigator.
The tingling, pain, and weakness—particularly in the hands and feet—that characterize peripheral neuropathy (搜索) can become so severe that physicians sometimes must reduce a patient's dosage or stop cancer treatment altogether. In some cases, the neuropathy can become a long-term issue. "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 deliver MMAE directly to the tumor by conjugating it to an antibody, but the approach still causes 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."
While many prior studies have focused on making MMAE work more effectively, this project focuses instead on understanding why it causes side effects and how those side effects might be prevented.
Investigating permeability glycoprotein (P-gp)
The first goal of the research is to determine whether the loss or modulation of a specific protein—permeability glycoprotein (搜索), or P-gp—alters the adverse response to MMAE. Such findings could 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, which began this summer, the researchers will evaluate two animal models—one possessing the protective protein and one lacking it—to examine 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."
Modeling gene and protein expression changes
A second goal of the research is to evaluate how different gene and protein expression levels change after exposure to, or in response to, MMAE. Along with pharmacokinetics—examining how the body processes and eliminates the drug—the study will employ computer models and biological data to understand how different organs, cells, and pathways interact to produce the drug's effects and side effects.
Mager brings 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 the Department of Biostatistics in the School of Public Health and Health Professions, is providing support on the genetic analysis component of the study, and Vivian Xu, a doctoral candidate in pharmaceutical sciences, will assist with the laboratory research.
Clinical implications
The ultimate aim is to alleviate the side effects that currently limit otherwise effective therapies. "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."