Fishing for cures: New zebrafish model identifies drugs that kill pediatric cancer cells

April 25, 2019

A new animal model developed by Massachusetts General Hospital (MGH) investigators promises to be less expensive, easier to use and to improve personalized therapies for cancers and potentially other diseases. In their paper published online in Cell, the investigators describe using their immunodeficient zebrafish model to visualize drug responses at single-cell resolution in live animals. They also identify a promising new treatment for rhabdomyosarcoma, a muscle cancer that primarily develops in children.

"We have created the first immune-compromised zebrafish model that can robustly engraft and grow human cancers", says David Langenau, PhD, of the MGH Molecular Pathology Unit and the MGH Cancer Center, senior author of the report.

Chuan Yan, PhD, of Langenau's team, first author of the report, adds, "These immune-compromised zebrafish are optically clear, allowing us to visualize cellular characteristics and therapeutic responses of single cancer cells over time. The model has the potential to transform the scale of personalized therapy and for the first time provides unprecedented ability to image a variety of cancer processes at single-cell resolution."

Although transplantation of human cancer cells into animal models has helped to define mechanisms that drive tumor growth, metastasis and response to therapy, traditional mouse models have significant limitations, including the cost and space required to maintain them and the difficulty visualizing tumor cells implanted beneath the animals' fur-covered skin. Doing so requires the creation of pre-implanted "windows," which do not allow following the dissemination of cancer cells throughout an animal's body.

Previous studies have implanted human tumor cells into two-day-old zebrafish larvae that had not yet developed immune systems. But such implants are eventually rejected by the immune system, preventing the assessment of long-term therapeutic responses. In addition, two-day-old zebrafish cannot grow at the same temperature as human cells, which prevents the accurate recapitulation of tumor development in these models.

The mutant zebrafish strain developed by Langenau's team is transparent into adulthood and is deficient in two genes, resulting in a lack of T cells, B cells and NK (natural killer) cells. The researchers were able to engraft several types of cancer cells - both solid and blood system tumors - into their model, where they developed into tumors similar to those found in humans. Cells taken directly from patients with tumors such as melanoma, glioblastoma, breast cancer and rhabdomyosarcoma were also successfully grown in adult fish for more than 28 days, with many animals dying from cancer progression.

The team used their model to investigate whether a combination of two drugs - olaparib and temozolomide, which are currently in a clinical trial for Ewing's sarcoma - could inhibit rhabdomyosarcoma growth. Their experiments using both the new zebrafish model and mouse models showed that, while treatment with either drug alone had limited effectiveness against either cancer, the combination treatment eliminated rhabdomyosarcoma cells from both types of animal models, with the zebrafish model allowing single-cell visualization of treatment response.

"The work is particularly exciting for two reasons," says Langenau, an associate professor of Pathology at Harvard Medical School and faculty member of the Harvard Stem Cell Institute. "First, we identified a potential new therapy for a devastating childhood cancer. Second, we now show that a wide variety of human tumors can grow in immune-deficient zebrafish. The model has the potential to change how we assess drugs prior to moving into the clinical setting - reducing the cost and time required, allowing rapid assessment of combination therapies, and directly visualizing drug responses at single-cell resolution. The model will be truly transformative for cancer biology."

The investigators now are working with clinical trial teams at the MGH and Dana-Farber Cancer Institute, along with the involved pharmaceutical companies, to refine the existing clinical trial to include rhabdomyosarcoma, which would be the first phase 2 cancer drug trial based on studies in zebrafish. Langenau's team is also exploring potential uses for the model in immunotherapy, stem-cell biology and regenerative medicine.
-end-
Dalton Brunson, Qin Tang, PhD, and Daniel Do - also of the MGH Cancer Center and Molecular Pathology are co-second authors of the Cell paper. Additional co-authors of the paper include Shyamala Maheswaran, PhD, Nick Dyson, PhD, and Daniel Haber, MD, PhD, MGH Cancer Center; and John Rawls, PhD, Duke University School of Medicine. The work was facilitated by close collaboration with the laboratories of Michael Dyer, PhD, and Elizabeth Stewart, MD, St. Jude Research Hospital and the Childhood Solid Tumor Network. Support for the study includes National Institutes of Health grants R24 OD016761, R01 CA154923, R01 CA215118, R01 CA211734, and R01 CA226926; and grants from the Alex's Lemonade Stand Foundation, the Liddy Shriver Sarcoma Initiative, and the MGH Research Scholars Program. The Massachusetts General Hospital has a patent pending for the work described in this paper.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2017 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.