image: This is a picture of Anthony Faber, Ph.D. view more
Credit: Virginia Commonwealth University
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 investigational drug 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 clinical trials 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 cancer. 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 cell death. 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 combination therapy 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."
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In addition to pursuing clinical trials with collaborators at CHOP, Faber is partnering with Massey researchers Hisashi Harada, Ph.D., assistant professor at the Philips Institute for Oral Health Research and member of the Cancer Cell Signaling research program at Massey, and Geoffrey Krystal, M.D., Ph.D., professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine, chief of oncology at the Hunter Holmes McGuire VA Medical Center and member of the Developmental Therapeutics research program at Massey, whose prior research shed light on the important link between NOXA and BCL-2 inhibitors exploited in the current study. And because MYC family members are amplified in several other cancers, including about 25 percent of small cell lung cancers, the potential of future findings may extend beyond neuroblastoma.
"Drs. Harada and Krystal have made important advances in the biology of NOXA and its relationship with BCL-2 inhibitors in tumors. Indeed, their previously published work helped guide us in the right direction," says Faber.
In addition to Harada, Faber collaborated on this research with Shirley M. Taylor, director of the Biological Macromolecule Core and member of the Cancer Molecular Genetics research program at Massey and associate professor in the Department of Microbiology and Immunology at the VCU School of Medicine; Iain M. Morgan, director of and professor in the Philips Institute of Oral Health Research and member of the Cancer Molecular Genetics research program at Massey; Madhu Gowda, pediatric oncologist at Massey and the Children's Hospital of Richmond at VCU and assistant professor in the Department of Pediatrics at the VCU School of Medicine; Jungoh Ham, Neha Patel, Konstantinos Floros, Mark Hughes, Daniel. Heisey, Justin Ferrel, Molly Bristol, Craig Yates, Mark A. Hicks and Brad Windle, all from the Philips Institute of Oral Health Research; Mikhail Dozmorov, Ph.D., member of the Cancer Molecular Genetics research program at Massey and assistant professor in the VCU Department of Biostatistics; Renata Sano, Kateryna Krytska and Yael Mossé, M.D., all from the Division of Oncology and Center for Childhood Cancer Research at the Children's Hospital of Philadelphia; Carlotta Costa, Erin Sennott, Anahita Dastur, Maria Gomez-Caraballo, Aaron Hata, Charles Jakubik, Ryan March, Cyril Benes and Jeffrey Engelman, all from Massachusetts General Hospital Cancer Center and the Department of Medicine at Harvard Medical School; Ultan McDermott and Mathew Garnett from the Sanger Institute, UK; and Wataru Nakajima from the Department of Molecular Oncology at the Institute for Advanced Medical Services, Nippon Medical School.
Funding for this research was provided by the Rally Foundation for Childhood Cancer Research and the Truth 365, an Alex's Lemonade Stand Innovation Grant, a Wipe Out Kids Cancer Research Grant, the Wellcome Trust, the George and Lavina Blick Research Fund, a VCU Massey Cancer Center Pilot Project grant, and, in part, by Massey's National Institutes of Health-National Cancer Institute Cancer Center Support Grant P30 CA016059.
The full manuscript of this study is available online at: http://www.cell.com/cancer-cell/fulltext/S1535-6108(16)00031-3
Journal
Cancer Cell