A new approach to treating neuroblastoma that could enable therapy with fewer side-effects has been heralded as "promising" by experts. Researchers from the University of Cambridge said their discovery, published in Developmental Cell, could lead to "kinder" treatments for the "devastating" childhood cancer that is responsible for 15% of childhood cancer deaths.
The research team explained that neuroblastoma arises from "developmentally stalled" neural crest-derived cells. In normal development, sympathoadrenal precursor cells derived from the neural crest differentiate into cell types including sympathetic neurons, adrenal chromaffin cells, and Schwann cells. But in neuroblastoma, these sympathetic precursor cells fail to differentiate, and are locked into an immature state that drives tumour growth.
The disease varies in aggressiveness depending on the maturity of cells within the tumour, with the most mature or differentiated tumours being the least aggressive, and the least differentiated carrying the highest risk of relapse and death. Current chemotherapy regimens are punishing – they can impair immunity to the extent of causing life-threatening infections or second tumours, and carry a significant risk of long-term complications, including hearing impairment, growth restriction, and infertility.
Reactivating Latent Differentiation Ability a Promising Approach
It was known that a subset of tumours can undergo spontaneous remission linked to tumour cell differentiation. So, reactivating this "latent ability" to undergo differentiation to normal non-dividing cells represented a promising potential new therapeutic approach. With the right cues, the team hoped, neuroblastoma might be driven to re-enter a post-mitotic differentiated state.
They first tested palbociclib (Ibrance, Pfizer), a CDK4/6 inhibitor and anti-proliferative agent used in treatment of some breast cancers, for its ability to drive the latent differentiation potential in a variety of genetic backgrounds.
Treatment with palbociclib on various neuroblastoma cell lines over 5 days resulted in a significant decrease in proliferation, they reported. Collection and sequencing of RNA from the cell lines demonstrated strong downregulation of target genes, with "a robust reprogramming of the transcriptome" towards reduced proliferation, and induction of neuronal differentiation in all three neuroblastoma cell lines tested.
"We surmised that the dual anti-proliferative and pro-differentiation effects of palbociclib we observed in vitro could provide a therapeutic opportunity," they said. They therefore tested the drug in vivo in a genetically engineered mouse model mirroring many clinical features of high-risk neuroblastoma.
The drug was well-tolerated and had "a significant survival benefit", the research team reported. It also effectively restrained tumour growth in immunocompromised mice xenografted with a human neuroblastoma cell line. They concluded that palbociclib "is able to restrain neuroblastoma growth in vivo and is an effective and tolerable cytostatic agent".
However, although palbociclib alone significantly re-engaged differentiation, complete cell cycle arrest was not achieved. So they then tested palbociclib in combination with retinoic acid, already used as a differentiating agent in maintenance therapy for neuroblastoma patients at most risk of relapse. They hoped that the combination might "further enhance the acquisition of a post-mitotic differentiated state".
Clinical Trials of the Drug Combination Planned
The combination indeed further inhibited cell cycling and, on RNA sequencing analysis, facilitated genome-wide changes favouring reduced proliferation and enhanced differentiation of adrenergic neuroblastoma cells, with a much greater effect on gene expression than palbociclib alone.
The research was "still at an early stage" the team said, but trials in children are now planned. The team is seeking patent protection on the use of the drug combination in neuroblastoma.
Research leader Anna Philpott, professor of cancer and developmental biology at Cambridge, said that neuroblastoma could be "a particularly gruelling disease" for families to manage. "Its outcomes are very variable. Some children can be cured with surgery or chemotherapy, but others will need to receive a very high dose of chemotherapy – and some of them then relapse and require further treatment."
Joint first author Dr Sarah Gillen, from Professor Philpott's lab, said: "Children will still need chemotherapy to kill the main tumour, but once that treatment is out of the way, we think the combination of palbociclib and retinoic acid should be enough to stop any remaining neuroblastoma cells in their tracks. And because these drugs don't need to kill the tumour cells, only to guide them back to the right path, it should be a much kinder treatment with fewer side-effects."
Prof Philpott noted that because both drugs had already been shown to be safe, and one of them was already used in children, the clinical trial process should be much faster. "If it's successful, then we could see this new treatment being used within the next decade."
Asked to comment by Medscape News UK, Professor Andy Pearson, trustee of Neuroblastoma UK, said: "Currently only 50% of children survive with high-risk neuroblastoma, so there is an urgent need for new drugs specifically to treat high-risk neuroblastoma, and new drug combinations to kill any remaining cells at the end of treatment. It is promising to see this new research and we look forward to the next step of how this can be incorporated into clinical trials to really see the impact and effect for children."