Scientists work to bring about a new treatment for rare childhood cancer

March 7, 2016

Neuroblastoma is a rare cancer that develops in very early forms of nerve cells in the embryo or fetus, and it accounts for the most pediatric deaths for any tumor outside of the brain. The most lethal form of this tumor is often associated with amplification of the gene MYCN, and now scientists at VCU Massey Cancer Center and the VCU Philips Institute for Oral Health Research may have developed a combination therapy that uses this gene to kill the cancer, instead of making it grow.

In a study featured on the cover of last month's edition of the journal Cancer Cell, Anthony Faber, Ph.D., and a team of scientists demonstrated that MYCN-amplified neuroblastoma cells are highly sensitive to an called ABT-199 that is currently being evaluated in clinical trials for another disease. After determining why ABT-199 was so effective in MYCN-amplified neuroblastoma, they began a process of looking for other drugs that increased its effectiveness. Eventually they discovered that another investigational drug called MLN8237 complements ABT-199 and is very effective at killing neuroblastoma tumors in laboratory experiments and advanced mouse models.

"The positive preclinical activity and safety profile of this targeted therapy combination will hopefully set the stage for in a subset of neuroblastoma patients who urgently need new, more effective therapies," says Faber, assistant professor at the Philips Institute for Oral Health Research at the VCU School of Dentistry and a member of the Developmental Therapeutics research program at VCU Massey Cancer Center.

ABT-199 targets the protein B-cell lymphoma 2 (BCL2), which regulates a form of cell suicide known as apoptosis. Faber's team found that ABT-199 kills neuroblastoma cells only in the presence of amplified MYCN. They found this selectivity was due to paradoxical upregulation (cellular increase) of the pro-apoptotic (suicidal) protein NOXA in this type of . The process is paradoxical because amplified MYCN is responsible for the formation and growth of these high-risk tumors and would not ordinarily be associated with promoting . Their strategy was therefore to "turn MYCN against itself," finding vulnerabilities specific to this cancer, such as MYCN-upregulated NOXA, and treating the cancer with a drug that exploits the vulnerability.

The addition of a second investigational drug, MLN8237, to ABT-199 led to widespread cell death in the experiments. The researchers attributed this outcome to a further imbalance in the BCL-2 family member proteins, which govern cell death. The toxic effects of the two drugs were only seen in MYCN-amplified neuroblastoma cells; the was not effective against neuroblastomas without amplified MYCN.

"Fortunately, our primary collaborator, Yael Mossé at the Children's Hospital of Philadelphia (CHOP), treats a high volume of these patients and has been a trailblazer for developing targeted therapies, including MLN8237, in neuroblastoma. We also have a good relationship with the drug maker, Abbvie, that produces ABT-199; therefore, we believe we are in a good position to hopefully bring the ABT-199/MLN8237 combination into the clinic at CHOP," says Faber. "In addition, we are also exploring ABT-199 as a chemosensitizer (makes cells more sensitive to chemotherapy) in MYCN-amplified neuroblastomas with Dr. Mosse's team. Overall, it seems there may be a place for BCL-2 specific inhibitors in the future care of these patients, and we are excited about that.

"These advances would not have been possible without the financial contributions of our supporters, including the Massey Cancer Center, and our private donors, who have been true blessings to our work and include Alex's Lemonade Stand, Rally/The Truth 365 and Wipe out Kids' Cancer. We greatly appreciate their support."

Explore further: Biomarker may identify neuroblastomas with sensitivity to BET bromodomain inhibitors

More information: Jungoh Ham et al. Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination, Cancer Cell (2016). DOI: 10.1016/j.ccell.2016.01.002

Related Stories

Biomarker may identify neuroblastomas with sensitivity to BET bromodomain inhibitors

February 21, 2013
Neuroblastoma, the most common malignant tumor of early childhood, is frequently associated with the presence of MYCN amplification, a genetic biomarker associated with poor prognosis. Researchers have determined that tumors ...

Genetic biomarker may help identify neuroblastomas vulnerable to novel class of drugs

April 9, 2013
An irregularity within many neuroblastoma cells may indicate whether a neuroblastoma tumor, a difficult-to-treat, early childhood cancer, is vulnerable to a new class of anti-cancer drugs known as BET bromodomain inhibitors, ...

Researchers take new approach to stop 'most wanted' cancer protein

November 7, 2014
Researchers at Dana-Farber/Boston Children's Cancer and Blood Disorders Center have found a way to defeat one of the most tantalizing yet elusive target proteins in cancer cells - employing a strategy that turns the protein's ...

A way to target the Achilles heel of neuroblastoma

November 4, 2015
Australian scientists have identified a critical molecular 'feedback loop' that helps initiate and drive neuroblastoma, a cancer of the nervous system in children that is triggered in embryonal nerve cells.

Study identifies potential drug combination for mantle cell lymphoma and chronic lymphocytic leukemia

September 23, 2014
Using the molecularly targeted drug ibrutinib (Imbruvica) together with the investigational anticancer agent ABT-199 may improve outcomes for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), ...

Recommended for you

CAR-T immunotherapy may help blood cancer patients who don't respond to standard treatments

October 20, 2017
Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis is one of the first centers nationwide to offer a new immunotherapy that targets certain blood cancers. Newly approved ...

Researchers pinpoint causes for spike in breast cancer genetic testing

October 20, 2017
A sharp rise in the number of women seeking BRCA genetic testing to evaluate their risk of developing breast cancer was driven by multiple factors, including celebrity endorsement, according to researchers at the University ...

Study shows how nerves drive prostate cancer

October 19, 2017
In a study in today's issue of Science, researchers at Albert Einstein College of Medicine, part of Montefiore Medicine, report that certain nerves sustain prostate cancer growth by triggering a switch that causes tumor vessels ...

Gene circuit switches on inside cancer cells, triggers immune attack

October 19, 2017
Researchers at MIT have developed a synthetic gene circuit that triggers the body's immune system to attack cancers when it detects signs of the disease.

One to 10 mutations are needed to drive cancer, scientists find

October 19, 2017
For the first time, scientists have provided unbiased estimates of the number of mutations needed for cancers to develop, in a study of more than 7,500 tumours across 29 cancer types. Researchers from the Wellcome Trust Sanger ...

Researchers target undruggable cancers

October 19, 2017
A new approach to targeting key cancer-linked proteins, thought to be 'undruggable," has been discovered through an alliance between industry and academia.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.