Neuroblastoma Drug Candidates Target Key Henchmen of a Supervillain Oncogene

The oncogene MYC is a supervillain of the cancer world. This gene is known to power the activities of cancer cells in many types of tumors in children and adults. Its variant MYCN, which is active in the childhood cancer neuroblastoma, is associated with the most high-risk forms of the disease. Although many scientists have tried to fight cancer by attacking MYC, the gene is active in so many different ways that it has so far managed to evade such direct attacks. As a result, many researchers are also trying to stop MYC by attacking some of its henchmen instead.

A recently published study by researchers at The Children’s Hospital of Philadelphia showed promising preclinical results with just such an approach, blocking the synthesis and speeding the breakdown of molecules that MYCN uses, called polyamines. Some of the drug candidates they studied are already in Phase 1 and 2 clinical trials for neuroblastoma.

“Polyamines have been an area of growing interest in the last several decades,” said Nicholas Evageliou, MD, an attending physician at CHOP. “Previous data in lymphomas and also in colon cancer suggested that these molecules were good targets for cancer therapies.”

Dr. Evageliou, who is now medical director of the Hematology/Oncology Clinic at CHOP’s Specialty Care Center in Voorhees, New Jersey and an assistant professor of Clinical Pediatrics in Hematology and Oncology at the Perelman School of Medicine at the University of Pennsylvania, is first author of the new study published in the September issue of Clinical Cancer Research. He worked on the project during his fellowship in the lab of Michael Hogarty, MD, a CHOP pediatric oncologist and associate professor of Pediatrics at the Perelman School of Medicine.

Before the start of the project, Dr. Hogarty’s and several other labs had performed in vitro studies showing that drugs blocking polyamine synthesis also had potential in neuroblastoma, a cancer of the peripheral nervous system that is one of the deadliest childhood cancers. Then, over a span of several years, Dr. Hogarty, Dr. Evageliou, and colleagues put several of these drugs through their paces, alone and in combination, on a variety of in vitro and in vivo preclinical models of neuroblastoma.

They tested two drugs that block MYC-regulated enzymes that are needed for synthesis of polyamines, difluoromethylornithine (DFMO) and SAM486, and one drug, celecoxib, that induces an enzyme that breaks polyamines down. DFMO is already approved by the Food and Drug Administration (FDA) for an infectious disease, African sleeping sickness, and celecoxib has FDA approval for treating pain and inflammation, typically in arthritis.

In the team’s in vitro studies, the drugs were effective at killing MYCN-driven neuroblastoma cells. In in vivo studies, the combination of DFMO and SAM486 delayed onset of neuroblastoma in mice predisposed to the cancer. The drugs also regressed the tumors in mice that already had cancer, and DFMO did so even more strongly when given in combination with known-effective chemotherapy drugs.

Combining DFMO with the drug celecoxib added to its effectiveness at regressing or slowing tumors in the mouse model, and the pair of drugs did so even more strongly when combined with standard chemotherapy treatments. The researchers suggested that by limiting uptake of polyamine molecules from the environment outside the cell, celecoxib could keep polyamine levels in the tumor cells low even if those cells tried to compensate for DFMO blocking their synthesis.

The researchers were especially enthusiastic about the findings when they repeated these experiments and saw similar results in mice grafted with human neuroblastoma tumor cells. Similar drug combinations were not only effective on MYCN-driven grafted tumors, but also in a variety of neuroblastoma tumors representing the different genetic subtypes that clinicians typically see.

A Phase 1 clinical trial for DFMO and celecoxib combined with chemotherapy is underway, sponsored by the New Approaches to Neuroblastoma Therapy consortium (NANT). Discussions of how to proceed with a Phase 2 trial are ongoing with both NANT and the Children’s Oncology Group (COG). A key question that will shape the design of the ideal Phase 2 trial of these drugs is whether they have the most potential to kill cancer cells directly when given in high doses alongside chemotherapy, or to do so indirectly in more moderate doses to help an immunotherapy work better. Dr. Hogarty and COG are carefully reviewing the available data about the drugs’ activity mechanisms to determine the best path forward for clinical testing.

Dr. Hogarty also cautioned that, although he is enthusiastic about the strength of the preclinical findings with these drugs, he is far from certain that this success will translate to clinical effectiveness.

“I think it’s humbling to see how difficult it is to predict what drugs will work in the clinic,” Dr. Hogarty said. “But compared to a lot of other potential new drugs, we know a lot about DFMO’s safety, we know a lot about its impact on children’s bodies because it’s been used as an infectious disease drug for a long time, and we have, in my experience, as much depth and breadth of preclinical data of any drug that I’ve been associated with. It’ll have to prove itself in the clinic, but it has a good running start.”

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