Preclinical research from VCU Massey Cancer Center published recently in the Proceedings of the National Academy of Sciences shows that the combination of two existing drugs can kill aggressive neuroblastoma cancer cells by exploiting their metabolic ‘hunger’.
A cancer of the nervous system, neuroblastomas are one of the deadliest childhood cancers, and if the MYCN gene is overexpressed, the prognosis is even worse. Although paediatric blood cancers are more treatable thanks to medical advancements, it has been much harder to treat neuroblastomas mostly due to the difficulty of targeting MYCN.
“MYCN is a transcription factor, and it’s very difficult to drug transcription factors,” said study senior author Anthony Faber, PhD, co-leader of the Developmental Therapeutics research programme and Natalie N and John R.Congdon, Sr. Endowed Chair of Cancer Research at VCU Massey Cancer Center and associate professor in the Philips Institute for Oral Health Research at the VCU School of Dentistry. “So, the next best thing is to target what MYCN does in the cell. One thing it does is to crank up metabolic activity – what it’s doing to keep the cell alive – and we can work that against itself.”
Since these ravenous cells burn cellular energy stores as quickly as they can be replenished Prof Faber’s team looked for a method to kick their metabolism over the edge without harming normal cells.
Screening 20 metabolic drug combinations in cancer cells originating from nearly 1000 different patients, the researchers found that neuroblastoma with high MYCN expression was particularly sensitive to a cocktail containing two drugs: phenformin and AZD3965..
Phenformin was developed in 1957 to treat diabetes. It blocks complex I on the surface of mitochondria, the organelle where energy production occurs.
Although phenformin was taken off the US market in the 1970s after a number of deaths, it’s still in use elsewhere in the world and is finding new application in the US as a cancer drug. Right now, phenformin is being tested in phase I clinical trial for melanoma.
Meanwhile, AZD3965 is a much newer type of drug under phase I clinical investigation. It works by blocking MCT1 rectors on the surface of cells, in this case as a cancer treatment. MCT1 receptors ferry lactate, another energy source, out of the cell. Blocking MCT1 causes lactate to accumulate, causing the cell to stop using it to make energy.
Simultaneously targeting energy production with the two different pathways used by the drugs should result in disruption of the cellular power supply, stressing and finally killing the cells.
This idea was put to the test by using mice seeded with MYCN-amplified neuroblastoma patient cells. Greater tumour reduction was seen from the cocktail than either drug given alone, with the cocktail being well tolerated.
“The data we got with AZD3965 in combination with phenformin might get people to reconsider phenformin,” said study lead author Krista Dalton, MEng, PhD Student, Virginia Commonwealth University Philips Institute for Oral Health Research. “In combination, where we can use lower doses, phenformin might have better tolerability than it previously did on its own.”
Source: News-Medical.Net
Journal information: Dalton, K. M., et al. (2021) Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2009620118.
