Breaking News
February 19, 2019 - Scientists untangle how microbes manufacture key antibiotic compound
February 19, 2019 - Greater primary care physician supply associated with longer life spans
February 19, 2019 - HIV-1 protein suppresses immune response more broadly than thought
February 19, 2019 - For 2020 Dem Hopefuls, ‘Medicare-For-All’ Is A Defining Issue, However They Define It
February 19, 2019 - KU professor discusses promise of brain-computer interface to aid, restore communication
February 19, 2019 - Early marker of cardiac damage triggered by cancer treatment identified
February 19, 2019 - Antidepressant drug could save people from deadly sepsis, research suggests
February 19, 2019 - CRISPR technology creates pluripotent stem cells that are ‘invisible’ to the immune system
February 19, 2019 - Midlife Systemic Inflammation Linked to Later Cognitive Decline
February 19, 2019 - Therapy derived from parasitic worms downregulates proinflammatory pathways
February 19, 2019 - Antimicrobial reusable coffee cups are less likely to become contaminated with bacteria, study shows
February 19, 2019 - Harnessing the evolutionary games played by cancer cells to advance therapies
February 19, 2019 - AHA News: Heart Transplant Survivor Gets Wedding Proposal at Finish Line
February 19, 2019 - HIV hidden in patients’ cells can now be accurately measured
February 19, 2019 - Research finds reasons for sudden cardiac death in patients with stable ischemic disease
February 19, 2019 - New protocol could help physicians to rule out bacterial infections in infants
February 19, 2019 - Women experiencing miscarriage should be offered treatment choices
February 19, 2019 - New protocol can help identify febrile infants at low risk for serious bacterial infections
February 19, 2019 - Innovative way to block HIV runs into a roadblock
February 19, 2019 - Springer Nature with BCRF conduct pilot project to make their research datasets more accessible
February 19, 2019 - Study finds neuromelanin-sensitive MRI as potential biomarker for psychosis
February 19, 2019 - Improvements in cardiovascular care for elderly save billions in health care costs
February 19, 2019 - Chilean food regulations are changing food perceptions and purchasing habits, study suggests
February 19, 2019 - Index endoscopy results are crucial for assessment of Barrett’s patients
February 18, 2019 - Breast cancer screening age should be lowered to 35
February 18, 2019 - Brain synchronization depends on the language of communication
February 18, 2019 - Drug Company Payments Over Time May Influence Rx Practices
February 18, 2019 - Despite socioeconomic gains, black-white ‘health gap’ remains
February 18, 2019 - Researchers report progress in the treatment of aggressive brain tumors
February 18, 2019 - Scientists discover trigger that turns strep infections into devastating disease
February 18, 2019 - Scanning children’s teeth may predict future mental health issues
February 18, 2019 - Health Highlights: Feb. 14, 2019
February 18, 2019 - New knowledge could help predict and prevent depression
February 18, 2019 - More primary care physicians leads to longer life spans | News Center
February 18, 2019 - Study examines link between supply of primary care physicians and life expectancy
February 18, 2019 - New study assesses screen time in young children
February 18, 2019 - Patented IU discovery to treat ARDS has been optioned to Theratome Bio
February 18, 2019 - Software found to be four times better at monitoring ovarian cancer
February 18, 2019 - Male Y chromosomes not ‘genetic wastelands’
February 18, 2019 - Hormone therapy during gender transition may increase risk for cardiovascular events
February 18, 2019 - NICE renews accreditation for Advanced
February 18, 2019 - FDA Grants Orphan Drug Designation to Amplyx Pharmaceuticals for APX001 for Treatment of Cryptococcosis
February 18, 2019 - Molecule effective in killing tuberculosis bacteria
February 18, 2019 - Columbia researchers unravel why some glioblastomas respond to immunotherapy
February 18, 2019 - Men who are able to do ten push-ups are less likely to have a stroke
February 18, 2019 - Blood-brain barrier disruption could lead to age-related cognitive decline
February 18, 2019 - Combination of PARP inhibitor and immunotherapy results in tumor regression in SCLC mouse models
February 18, 2019 - Heavy smoking could lead to vision loss, study finds
February 18, 2019 - New diagnostic test for malaria uses spit, not blood
February 18, 2019 - New therapeutic molecules show promise in reversing memory loss related to depression, aging
February 18, 2019 - Darla Shine joins anti-vaccination campaigners
February 18, 2019 - New study outlines sex-specific issues in ischemic heart disease
February 18, 2019 - Drug combinations could become first-line treatment for metastatic kidney cancer
February 18, 2019 - Lifetime adversity, increased neural processing during trauma combine to intensify core PTSD symptoms
February 18, 2019 - HRQoL Scores Decrease With Treatment Line in Multiple Myeloma
February 18, 2019 - Convincing evidence that type 2 diabetes is a cause of erectile dysfunction
February 18, 2019 - Study offers implications of advanced age in evaluation, management of ischemic heart disease
February 18, 2019 - Children from homes with flame-retardant sofa have high SVOC concentration in their blood
February 18, 2019 - Art Institute of Chicago announces results of research on five terracotta sculptures
February 18, 2019 - New PET/CT tracer shows high detection rate for diagnosis of acute venous thromboembolism
February 18, 2019 - Smoking may blight immune response against melanoma and reduce survival
February 18, 2019 - How Inactivity and Junk Food Can Harm Your Brain
February 18, 2019 - Diabetes tops common conditions for frequent geriatric emergency patients
February 18, 2019 - Longer-lived sperm produces offspring with healthier lifespans
February 18, 2019 - New dental adhesive prevents tooth decay around orthodontic brackets
February 18, 2019 - New eHealth tool shows potential to improve quality of asthma care
February 18, 2019 - New Australian initiative helps emergency clinicians to improve patient care
February 17, 2019 - Apellis Pharmaceuticals’ APL-2 Receives Fast Track Designation from the FDA for the Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria
February 17, 2019 - Researchers identify faulty ‘brake’ that interferes with heart muscle’s ability to contract and relax
February 17, 2019 - Support from trusted adults can reduce risk of dying in suicidal teens, finds study
February 17, 2019 - Heart attack awareness improved since 2008
February 17, 2019 - Exercise gives a better brain boost to older men than women
February 17, 2019 - New research disproves previous assumptions of how looks influence personality
February 17, 2019 - Cannabis use as a teenager linked to depression later in life
February 17, 2019 - Sinks by Toilets in ICU Patient Rooms Harbor Harmful Bacteria
February 17, 2019 - Cancer cells’ plasticity makes them harder to stop
February 17, 2019 - Young cannabis users have increased risk of depression and suicidal behavior
February 17, 2019 - Tasmanian Devils Likely to Survive Cancer Scourge
February 17, 2019 - Neoadjuvant PD-1 blockade seems effective in glioblastoma
February 17, 2019 - Personal, social factors play role in enabling sustainable return to work after ill health
New research suggests power of zebrafish as tool for cancer drug discovery

New research suggests power of zebrafish as tool for cancer drug discovery

image_pdfDownload PDFimage_print

The lab of Leonard Zon, MD, at Boston Children’s Hospital has long been interested in making blood stem cells in quantity for therapeutic purposes. Looking for a way to test for their presence in zebrafish, their go-to research model, they turned to the MYB gene, a marker of blood stem cells. To spot the cells, Joseph Mandelbaum, a PhD candidate in the lab, attached a green fluorescent tag to MYB, easily visible in transparent zebrafish embryos.

“It was a real workhorse line for us,” says Zon, who directs the Stem Cell Research Program at Boston Children’s.

The line has also proved valuable for discovering cancer drugs. In addition to being a marker of blood stem cells, MYB is an oncogene.

About five years ago, Zon was at a cancer meeting and serendipitously met Jeff Kaufman, who was also interested in MYB. Kaufman was excited to hear about Zon’s fluorescing MYB zebrafish, which reproduce quickly, can be studied at scale and are surprisingly similar to humans genetically. He asked if Zon had ever heard of adenoid cystic carcinoma — and a collaboration was born.

Targeting a cancer driver

Kaufman had founded the Adenoid Cystic Carcinoma Research Foundation with his wife, Marnie, in 2005, after she felt a lump under her jawline and was diagnosed with the rare, often deadly malignancy. (ACC usually starts in the salivary glands, but can also appear in the larynx, trachea, lacrimal gland, breast and vulva.) Finding very little ongoing research on ACC, the Foundation began creating tissue repositories and funding studies.

“What we’ve learned over 12 to 13 years is that MYB is the main driver of ACC,” Kaufman says. He asked Zon, “Do you think you could shut off the MYB gene by giving chemicals to your zebrafish?”

Zon and his colleagues agreed to try, with the Foundation providing grant support. Their findings, reported last week in the Journal of Experimental Medicine, have laid the groundwork for a clinical trial in patients with ACC at the Dana-Farber Cancer Institute. More broadly, they suggest the power of zebrafish as a tool for cancer drug discovery.

Turning off the green

Despite more than 30 phase II clinical trials since 1985, there is no standard chemotherapy or drug regimen for ACC. About half of all patients develop metastatic disease, and no drug therapy has been shown to prolong overall or progression-free survival.

Zon, Mandelbaum and colleagues set up a high-throughput drug screening system. They loaded tiny zebrafish blastomeres — very early embryos consisting of just a few cells — into 384-well plates. Each embryo’s MYB genes were tagged with green fluorescent protein. The team then systematically exposed the blastomeres to 3,840 small molecules. Using an automated cell imaging system, they looked to see if any chemical would “shut off the green.”

“We could have done the screen in whole embryos, but the cell culture system was so much faster,” says Zon. “We were able to do a screen in six months, versus what might’ve taken one and a half years with whole embryos.”

In the end, 22 chemicals shut off MYB, of which retinoic acid or derivatives of retinoic acid were the most potent. Retinoic acid, best known as acne treatment, is a derivative of vitamin A.

Slowing tumor growth

The team further validated retinoic acid’s efficacy in human tumor cells. Since no one has been able to create a viable ACC cell line, the team turned to a human myeloid leukemia line, which also expresses MYB at high levels. Retinoic acid not only downregulated MYB, but did so within just one hour.

Finally, through the Foundation, the team collaborated with South Texas Accelerated Research Therapeutics (START) to test retinoic acid in “primagraft” models — live mice bearing tumors derived from actual ACC patients. They showed that retinoic acid (specifically, a preparation called ATRA) slowed tumor growth.

“With the tumor, the gas pedal is all the way down,” says Zon. “When you give retinoic acid, it takes the foot off the pedal.”

Finally, the team worked out how retinoic acid works. In ACC, a chromosome rearrangement brings MYB adjacent to another gene, NFIB, which has an “enhancer” region. The genes bind together and NFIB’s enhancer causes MYB to get stuck “on,” so more and more of the oncogene is made in the cell. But Zon’s group found that when the cell’s retinoic acid receptors are triggered by retinoic acid, they bind to the NFIB enhancer and shut down most MYB production.

“Len’s work is incredibly exciting, because this is really the first drug that appears to directly target MYB, and we really haven’t had any drug that has effectively done that before,” says Kaufman. “Through our preclinical drug screening program and mouse models of ACC, we have screened over 100 anticancer agents, and we’ve very seldom seen a drug as active as retinoic acid.”

Clinical trial on deck

Mandelbaum and Zon, part of the Division of Hematology/Oncology at Boston Children’s and Dana-Farber, presented the study results at a meeting of Dana-Farber head and neck oncologists. They were equally excited. “We’re all in agreement to do a clinical trial,” says Zon.

Source:

https://vector.childrenshospital.org/2018/09/zebrafish-reveal-potential-cancer-treatments/

Tagged with:

About author

Related Articles