Two-pronged Attack on Neuroblastoma
How inhibiting both polyamine synthesis (with DFMO) and uptake (with new small molecule AMXT 1501) could delay tumor development.
Jonathan James | | Quick Read
The MYCN oncogene – highly upregulated in neuroblastoma – has long been regarded as an attractive target for therapy, but successful translation into the clinic has proven challenging (1). Attention thus turned to downstream pathways and, now, a multinational team of researchers has demonstrated the feasibility of targeting two aspects of a crucial pathway in cancer growth: polyamine synthesis and uptake (2).
The team were acutely aware that targeting the polyamine pathway was going to be a challenge. Difluoromethylornithine (DFMO), a drug developed in the 1970s designed to block polyamine in neuroblastoma, proved disappointing in clinical trials, although it’s seen wide use as a therapy for sleeping sickness (3). Michelle Haber, Executive Director of the Children’s Cancer Institute in Sydney, Australia, led the new study, and she attributes DFMO’s failure to the adaptive nature of cancerous cells. “In addition to synthesizing their own polyamines, cancer cells can also import or absorb polyamines from their surrounding microenvironment,” she says. The team decided to focus on tackling the problem from multiple avenues. “We’ve been investigating simultaneously blocking the synthesis, as well as the uptake, of polyamines, in combination with currently used chemotherapeutics,” says Haber.
Step one was to identify the proteins involved in polyamine uptake; “We’d previously identified a protein – SLC3A2 - as a key transporter in neuroblastoma,” says Haber. “Genetic knockdown of this gene leads to reduced polyamine uptake.” Conversely, DFMO treatment increases SLC3A2 – seemingly confirming the adaptive nature of cancer cells to acquire polyamines.
Meanwhile, colleagues at USA-based drug development company Aminex Therapeutics developed a new small molecule drug – AMXT 1501 – that was able to completely block polyamine uptake in neuroblastoma cells. The next logical step was to test the two drugs – DFMO and AMXT 1501 – in combination – and the results left Haber optimistic. “This treatment is highly potent in inhibiting the growth of neuroblastoma in all our mouse models, suggesting that this may be a valuable therapeutic approach in the treatment of aggressive neuroblastoma,” she says.
A phase 1 trial of AMXT 1501 is currently underway in the US – the goal to gather the necessary data to support the development of a formulation suitable for use in children (4). But this may be just the beginning. “MYCN is highly homologous to c-MYC, and this latter oncoprotein is believed to be dysregulated in over 50 percent of all adult cancers,” Haber says. “As our research has also shown that c-MYC regulates the polyamine pathway, this polyamine depletion strategy may have broad application in a range of adult cancers.”
- SB Whittle et al., “Overview and recent advances in the treatment of neuroblastoma,” Expert Rev Anticancer Ther, 17, 369-386, (2017) PMID: 28142287.
- L D Gamble et al., “Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma,” Sci Transl Med, 30:11, (2019) PMID: 30700572
- P Babokhov et al., “A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis,” Pathog Glob Health, 107, 242-252 (2019) PMID: 23916333
- ClinicalTrials.gov, “Oral AMXT 1501 Dicaprate in Combination with DFMO” (2019) Available at: bit.ly/2OsxVjL.