Novel Neuroblastoma Driver Could Be Target for Therapeutics

Researchers at the University Medicine Halle have identified a novel, feasibly druggable pathway that is involved in initiating neuroblastoma tumor growth. The scientists’ studies in human neuroblastoma samples, xenografts and in mouse models, provide what they say is the first evidence that a gene called IGF2BP1 acts as a novel driver of neuroblastoma, effectively behaving as the cancer-initiating spark. A feedforward loop involving transcriptional/post-transcriptional synergy between IGF2BP1 and MYCN then promotes  what they term “an oncogene storm” that fosters expression of 17q oncogenes such as BIRC5. The results of preclinical studies showed how IGF2BP1 inhibition (IGF2BP1i) using a small molecule BTYNB effectively extinguished this spark, and impaired tumor growth.

“If we succeed in developing a suitable molecule, this will not only be relevant for neuroblastomas,” said Stefan Hüttelmaier, PhD, director of the Institute of Molecular Medicine at University Medicine Halle.” Studies show that IGF2BP1 also plays a key role in other tumors.” Hüttelmaier is senior author of the team’s published paper in Molecular Cancer “IGF2BP1 induces neuroblastoma via a druggable feedforward loop with MYCN promoting 17q oncogene expression,” in which they concluded, “We reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1.”

Neuroblastomas are tumors of the nervous system. They can form in many places in the body and are the most common cause of cancer-related deaths in young children. “High-risk neuroblastoma (HRN) accounts for approximately 15% of all cancer-related death in infants and despite intensive multimodal therapy > 50% of HRN relapse,” the authors noted.

Neuroblastoma is commonly associated with genomic abnormalities including amplification of MYCN—which located on chromosome 2p—and 17q gain, which is “the most frequent (> 50%) chromosomal aberration,” the team continued. “In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1, and MYCN amplification at chromosome 2p are associated with adverse outcome,” they noted, although “genetic synergies of 2p and 17q remain largely unknown.”

The protein IGF2BP1 ensures that cells grow rapidly during embryonic development. Later on, its presence is linked to various tumors. “IGF2BP1 is de novo expressed in several cancers and shows conserved association with poor prognosis, disease progression and metastasis,” the investigators stated. However, it’s not known if IGF2BP1 is an oncogene in human cancers, how it synergizes with MYCN in neuroblastoma, and if targeting IGF2BP1 may have potential as an anticancer strategy.

For their newly reported study the researchers analyzed the genetic characteristics of the neuroblastoma tumors from 100 children, and performed extensive cell culture experiments and tests in mouse models. They found that in synergy with MYCN, IGF2BP1 initiates and promotes HRN by transcriptional/post-transcriptional feedforward regulation. “MYCN is a versatile transcriptional driver of oncogene expression,” they noted, “most prominently in MNA neuroblastoma.” Added Sven Hagemann, PhD, lead author and biochemist at the Institute of Molecular Medicine at University Medicine Halle, “In short, IGF2BP1 causes that another protein is produced in abundance. Both proteins can activate various, currently unresolved, processes at the genetic level that have a strong cancer-causing effect under these abnormal circumstances.”

The result is an out-of-control conflagration in the cell, which causes neuroblastomas to form, survive, grow and spread. “MYCN/IGF2BP1 feedforward regulation culminates in an oncogene storm, which likely contributes to severe genome destabilization.” The study has shown for the first time that IGF2BP1 on its own is enough to trigger this tumor; all of the mice in which the protein IGF2BP1 was induced developed a neuroblastoma.

Encouragingly, a small molecule called BTYNB was able to disrupt this oncogene storm, impairing tumor growth in neuroblastoma cell and xenograft models. “Consistent with devastating consequences of MYCN/IGF2BP1 synergy, our studies highlight potential therapeutic prospects of IGF2BP1i … In neuroblastoma cell and xenograft models, IGF2BP1 deletion and inhibition by the small molecule BTYNB impair tumor growth. BTYNB robustly disrupts MYCN/IGF2BP1 synergy …”  Hüttelmaier added, “It would be very promising to specifically inhibit IGF2BP1, since it is not normally produced after infancy—except in cancer cells.”

The team has now successfully tested such a molecule in close cooperation with the Institute of Pharmacy at Martin Luther University Halle-Wittenberg. “Our drug candidate has so far shown no adverse effects in initial preclinical trials and can be used as the basis of further developments. In the future, the targeted treatment of neuroblastomas could prevent patients from experiencing the severe side effects of chemotherapy,” says Hüttelmaier. However, it will take a few more years to clarify unresolved questions before clinical trials can begin. It is unclear, for example, why IGF2BP1 is present in the first place, or how the drug can best be delivered to where it is needed in the body.

Professor Hüttelmaier has been studying the protein IGF2BP1 for more than 20 years: “We began by studying neurons until we suddenly stumbled upon the fact that this protein is particularly prevalent in cancer.” Based on clinical data, Professor Hüttelmaier’s team was able to demonstrate in 2015 that IGF2BP1 plays a role in the development of neuroblastomas. “We have now succeeded in uncovering further pieces of evidence and, for the first time, we have identified a possible therapeutic approach. If we succeed in developing a suitable molecule, this will not only be relevant for neuroblastomas. Studies show that IGF2BP1 also plays a key role in other tumors.”

In their paper the team concluded, “Our studies unravel that impairing IGF2BP1-RNA association by the small molecules BTYNB disrupts this oncogene storm and provides benefits in combined treatment with MYC/N inhibition via BRD inhibitors, most prominently Mivebresib, as well as inhibitors of MYCN/IGF2BP1-driven oncogenes like BIRC5.”

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