Fishing for Answers

Tuesday, March 24, 2015

Cancer researchers are constantly searching for innovative ways to develop life-saving therapies as quickly as possible. The possible key to unlocking these cures can be found at any pet store throughout the world.

It’s only about four centimeters long and a few grams in weight, but thanks to a wide variety of genetic and biological factors, it has emerged as an invaluable member of the scientific research community.

What is this wonderful organism?

The zebrafish.

Scientific articles in many top peer-reviewed journals have touted the zebrafish’s effectiveness and versatility for nearly two decades, but recently, a group of University of Arizona researchers has applied the zebrafish’s unique research capabilities toward discovering potential solutions for chemotherapy-related hearing loss (ototoxicity).

Chemotherapy-induced damage to the inner ear can rob patients of their hearing and even balance function. At the University of Arizona Cancer Center, researchers are looking to an unlikely ally in their fight to find drugs that prevent hearing loss.

“Zebrafish orient themselves in water much like the way the human’s inner-ear cells evolved to orient themselves to sound waves,” said Abraham Jacob, MD. “When we simulate ototoxicity with zebrafish, we are able to generate so much more data than with any other model.”

In recent years, the zebrafish has been found to serve as an effective model for a number of human cancers, as well as post-treatment side effects. According to the National Institutes of Health, “major technical advances have been essential for the generation of zebrafish cancer models relevant to human diseases. These models develop tumors in various organ sites that bear striking resemblance to human malignances, both histologically and genetically.

Further exploration of the zebrafish cancer models not only will generate unique insights into underlying mechanisms of cancer but will also provide platforms useful for drug discovery.”

Before zebrafish entered the picture, these experiments required higher-order species, such as birds or mice. These projects were costly and time consuming — so much so that it was next to impossible to generate the amount of data required to make any statistically relevant conclusions, let alone develop any effective interventions.

Zebrafish changed all that. Information that took years to gather could be done in weeks. For example, thousands of zebrafish larvae can be used each month to test promising hearing-protective drugs.

“We have the data to show that a change in the zebrafish’s behavior is a biomarker for inner-ear damage,” Dr. Jacob said. This information is presented in a journal article titled “A High Throughput Ototoxicity Assay in Zebrafish: Drug Development Platform Targeting Hearing Loss.”

So what is the potential impact?

Hearing loss has become one of modern cancer therapy’s most prevalent side effects. In fact, hearing loss is among the most underreported, yet potentially devastating, side effects endured by many chemotherapy patients. Often, these patients don’t realize that their hearing has been compromised until it is too late to receive treatment.

Dr. Jacob started the Hearing Conservation Program to educate chemotherapy patients about their risks for hearing loss, while suggesting possible interventions to prevent hearing loss or to recover a patient’s hearing. 

Dr. Jacob is an Associate Professor with Tenure and Vice Chair of the Department of Otolaryngology, as well as a member of the University of Arizona Cancer Center and the BIO5 Institute.

“It doesn’t even occur to most cancer patients that their treatment could impact their hearing,” said Dr. Jacob, who, in addition to his role with the UA Cancer Center, is the director of the University of Arizona Ear Institute, which is dedicated to the prevention, detection, treatment, and rehabilitation of ear disease through clinical care, research and education.

Postdoctoral Research Associate Maki Niihori, PhD, is responsible for much of the data analysis, and says that these fish can start to tell a story once you observe them long enough.

“It’s remarkable how consistent their behavior remains from test to test,” Dr. Niihori said. “They’re ideal for this kind of research.”

Dr. Niihori’s experience with experimental fish analysis dates back to her days as a student at the Graduate School of Humanities and Sciences at Ochanomizu University in Tokyo, Japan. She was among those studying the development and swimming activity of Japanese rice fish (referred to as “medaka fry”) during spaceflight aboard the Space Shuttle Columbia.

These experiments took place as part of JUSTSAP — the Japan-US Science, Technology and Space Application Program — during the early 2000s, with their findings published in 2003 and 2004.

All About Zebrafish

The zebrafish, Danio rero, is named for the five horizontal stripes on the side of the body, which resemble a zebra’s stripes. A full-grown zebrafish is typically 2 to 4 inches long, and can live as long as five years.

This breed of fish didn’t become part of the scientific community until the early 1970s, when researchers in the Pacific Northwest discovered that these fish — natives of the Southeast Himalayan region — could potentially serve as ideal models for disease examination.

What makes the torpedo-shaped zebrafish so special?

First and foremost, the zebrafish has a backbone. Unlike the majority of smaller, high-volume test subjects (insects, larvae, etc.), the zebrafish is a vertebrate, which makes a world of difference when it comes to translating these research findings into possible human applications.

In addition, zebrafish live healthy, happy lives in close proximity with one another. The ease of breeding makes it possible to run large tests on statistically significant numbers, while keeping the zebrafish’s response to stimuli consistent across the board.

It’s a smart, resilient fish that adapts almost immediately to its surroundings. All of the studies conducted in Dr. Jacob’s ototoxicity study are completely safe and comfortable for the fish.

Dr. Niihori’s background in small fish study has helped make this current chemotherapy-related hearing-loss study one of the most exciting and innovative projects at the University of Arizona. She joined the UACC in April 2012, with the zebrafish program beginning just a few months later.

“We’ve built this program from the ground up,” Dr. Niihori said.

Collaboration has been crucial to the success of this program. Dr. Jacob’s lab is working closely with Donna Zhang, PhD, and Eli Chapman, PhD, of the University of Arizona College of Pharmacy to develop clinical trials that would test the efficacy of various therapeutic interventions that could help save a cancer patient’s hearing.

Further collaborations with Jeffrey Rodriguez, PhD, in the University of Arizona College of Engineering, Marvin Slepian, MD, at Sarver Heart Center, and personnel in the University of Arizona Cancer Center’s Bioinformatics Shared Resource will go a long way toward translating this data from a spreadsheet full of numbers into personalized patient care.

“Now that the data gathering is so much more streamlined, we can apply that to therapeutic development, as we can quickly administer, test, and rank the various drug combinations in ways we never could without these zebrafish,” Dr. Jacob said.

With more and more people living full, rich lives well beyond that initial cancer diagnosis, survivorship care will continue to move toward the forefront of cancer research. These zebrafish find themselves in a unique position to assist with cutting-edge research in every facet of our fight against cancer.

-Nick Prevenas, March 24, 2015 (all photos by csrichards.com)