Scientists Unearth A Potent Weapon Against Neuroblastoma

Neuroblastoma is a tumor of nerve tissue that develops in infants and children and can occur in many areas of the body. It develops from the tissues that form the sympathetic nervous system (which controls body functions such as heart rate and blood pressure, digestion and levels of certain hormones).

It is a rare form of cancer that with an estimated incidence of 1 case per 100,000 children. In the United States, about 800 new cases of neuroblastoma are diagnosed each year. NB accounts for about 12% of cancer-related deaths in children under 15.

Now, oncology researchers at the Children’s Hospital of Philadelphia studying high-risk children’s cancers have identified a protein that offers a likely target for immunotherapy of high-risk neuroblastoma and other childhood cancers.

“We have built a strong foundation for developing a completely new and hopefully much less toxic treatment for neuroblastoma, the most common cancer in infants,” said study supervisor John M. Maris, MD, a pediatric oncologist at Children’s Hospital of Philadelphia (CHOP). “Furthermore, our findings may also lend support to the development of other immune-based therapies, such as CAR T cells, in children with multiple aggressive cancers in addition to neuroblastoma


During the course of the study, the team analysed molecules that are much more commonly found on the surface of neuroblastoma cells than on normal cells using sophisticated sequencing tools. “Our rationale was to identify a cell-surface molecule that an immune-based therapy could target without damaging healthy tissues,” said first author Kristopher R. Bosse. “Using this approach, we identified a protein called glypican-2, or GPC2.” GPC2 is one of a family of glypicans — cell-surface proteins that interact with growth factors and cell surface receptors, influencing many intracellular signaling pathways important in development and cancer.

By using comparing RNA sequencing data from 126 high-risk primary neuroblastomas, with RNA sequences from samples across 31 normal tissue types, the scientists could narrow down their search to the extracellular glycosylphosphatidylinositol (GPI)-anchored signalling co-receptor glypican 2 gene. GPC2 is one of a family of six (GPC1-6) GPI-anchored, extracellular proteoglycan signalling coreceptors that play diverse roles in growth factor signalling and cancer cell growth.

This implied that a compound that acted against GPC2 might kill cancer cells, spare healthy cells, and limit the possibility of these tumors developing “immune escape” mechanisms, in which cancer cells resist an immunotherapy by shedding the target.

Direct analysis of tissue samples and cultured cells identified elevated GPC2 in high- and intermediate-risk neuroblastoma primary tumors, patient-derived xenografts (PDXs) derived from high-risk human primary tumors, and the majority of neuroblastoma cell lines evaluated.

The researchers then confirmed that GPC2 protein was only present at very low levels, if at all, in the cell surface membranes of a wide range of normal pediatric tissues, and neural- and neural-crest-derived tissues.

They next developed an antibody-drug conjugate (ADC) called D3-GPC2-PBD, which combined a very specific antibody that recognizes GPC2 with a potent chemotherapy drug that is internalized specifically by cancer cells.

The drug payload damages DNA in tumors, while sparing healthy tissues from its toxic effects.

This drug in cell cultures and mouse models of neuroblastoma was found to robustly kill neuroblastoma cells with no discernible toxicity to normal cells.

“These findings establish that this type of immunotherapy could be potentially safe and effective against neuroblastoma,” said Maris. “Our next steps will be to further evaluate this ADC and also develop other immune-based therapies directed against GPC2. Because other glypicans in addition to GPC2 are overexpressed in other childhood cancers, it may also be possible to apply this approach across various types of high-risk pediatric cancers.”

Disha Padmanabha
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