A new study published in Nature Communications heralded some fascinating findings on the future of drug development for neuroblastoma treatment. Cancer that forms in developing nerve cells, neuroblastoma can begin in various parts of the body, including the adrenal glands, abdomen, chest, or the spine. Neuroblastoma occurs most commonly in children under five.
The standard treatment for neuroblastoma includes a nutrient called retinoic acid (RA). Our bodies generate RA from vitamin A, which we consume through foods or supplements. RA regulates cellular growth, and the body only requires small amounts of RA To stay healthy and function optimally. Synthetic forms of RA made in a laboratory have other indications, including skin conditions.
The efficacy of RA for high-risk neuroblastoma has led to a long-standing question emerging from the facts that while RA has minimal impact on primary tumors, it has become highly effective for reducing neuroblastoma metastasis when included in maintenance therapy regimens, particularly preventing control of metastasis to the bone marrow. The researchers of the current study set out to investigate this discrepancy.
In the laboratory, the researchers treated various types of neuroblastoma cells with RA and looked for differences in response. They found that the cells most sensitive to RA underwent mechanisms of either apoptosis, cell death occurring through a series of molecular steps, or senescence, a process of aging that results in active yet non-dividing cells. On the other hand, the cells less responsive to RA predominantly underwent differentiation, a biological process during which immature cells mature and develop specific functions.
Further analysis using CRISPR technologies, laboratory tools that can “edit” DNA, allowing researchers to “knock out” specific genes to study their role in processes like cancer development and response to treatment, identified bone morphogenic protein (BMP) as a key regulator. BMP plays a crucial role in determining if cells favor apoptosis/senescence or differentiation following RA treatment. In addition, the researchers found BMP signaling upregulated in samples from patients who experienced metastasis to bone marrow, the same biological location where RA works optimally. This discovery enlightens us about the intricate mechanisms at play in neuroblastoma treatment.
The study, for the first time, demonstrates the influence of the cellular microenvironment on RA's pro- and anti-tumor control. These findings, which provide valuable information for doctors and researchers studying neuroblastoma, also offer promising targets for future drug development.
Sources: Nature Commun, NEJM
