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Discovery Could Take the Guesswork out of When Meds Will Work Best

Drugs delivered during their molecular target’s daily downtime often do more harm than good, which is why biologists have struggled to pinpoint the precise timing of these molecules’ delivery systems

by Virginia Tech
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Carla FinkielsteinA recent discovery by Carla Finkielstein's research group could dramatically improve quality of life for cancer patients, allowing chemotherapeutics to be delivered in timed doses that ensure maximum benefits and minimal negative side effects.Photo credit: Virginia Tech

An uncomfortable truth of modern medical science: chances are nobody knows when your drugs are working.

This gap in our collective knowledge frequently compels patients to take larger-than-necessary amounts of medication throughout the day while suffering a range of severe side effects.

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Many of the best-selling medications on the market today, including Tamiflu, Ritalin, and Viagra, vary in effectiveness depending on the availability of their molecular targets in our cells. These molecules ebb and flow on a daily cycle, controlled by the body’s internal clock or “circadian rhythm.”

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Drugs delivered during their molecular target’s daily downtime often do more harm than good, which is why biologists have struggled to pinpoint the precise timing of these molecules’ delivery systems.

An international team of researchers, led by scientists at Virginia Tech, has just made the case for timely delivery of medication even more compelling. Their findings, recently released in Proceedings of the National Academy of Sciences, outline the circadian-regulated delivery system for an essential tumor-suppressing molecule called p53.

This discovery could vastly improve the effectiveness of common chemotherapy drugs and host of other time-dependent treatments.

“Knowing when and where target molecules like p53 are available in our cells could take all the guesswork out of when we should receive treatment,” said Carla Finkielstein, an associate professor of biological sciences in the College of Science, a fellow in the Biocomplexity Institute, and a Fralin Life Science Institute affiliate. “Timed, targeted doses would replace the current, standard treatment model of flooding the patient’s system with drugs throughout the day, just to ensure their medicines and molecules meet up.”

Treatment that syncs with the body’s natural rhythms, also known as “chronotherapy,” has a range of proven benefits, including higher drug efficacy and fewer harsh side effects.

These are especially relevant in the context of p53’s cancer treatment applications, where reduced quality of life is a leading cause of patients choosing to end their course of treatment early.

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Under normal conditions, p53 is one of the body’s most effective tools for halting the reproduction of cancer cells. It signals the cell when genetic damage is detected and triggers a self-destruct sequence if it can’t be repaired, making it a prime target for the current generation of chemotherapeutic drugs.

Each cell’s main supply of p53 spends most of the day stored outside of the nuclear compartment, its primary area of activity. The Virginia Tech team’s latest discovery reveals how those reserves of p53 are transported and kept to a regular schedule: a circadian-regulated helper molecule called Period 2 (PER2.)

“PER2 acts like a personal assistant for p53, making sure it’s in the right place at the right time of day, ready to get the job done,” said Tetsuya Gotoh, a research associate in the Finkielstein Research Group and lead author on the new publication. “When PER2 is shuttling it into the body of the cell, p53 is largely inactive, but its timely release triggers a number of events that prime p53 to perform its tumor-suppressing duties”  

This breakthrough came to light through a unique combination of experimental research and the advanced computational modeling efforts of Jae Kyoung Kim, a leading systems biologist researcher at the Korea Advanced Institute of Science and Technology.

Kim’s algorithm simulated all the factors capable of affecting p53’s localization in our cells, narrowing down thousands of probable mechanisms to a handful of distinct premises that helped the team hone in on PER2. Building on their initial success, the team believes this model could be adapted to uncover how and when other target molecules are kept to a daily schedule.

“Chronotherapy is an incredibly powerful principle for developing effective medications, yet it’s considered in less than 0.2 percent of all ongoing clinical trials in the world,” said Finkielstein. “Our model may be able to help change that. The earlier researchers understand how timing impacts the efficacy of their drugs, the sooner we can all start to experience their benefits.”

These discoveries are the result of a long-term collaboration between several Virginia Tech researchers.

In addition to those mentioned above, the research team included John Tyson, a distinguished professor of biological sciences in the College of Science; Marian Vila-Caballer, a former postdoctoral student; JingJing Liu, a former graduate student and current postdoctoral fellow at University of Pennsylvania; and Philip Stauffer, an undergraduate microbiology student in biological sciences.