Overcoming Drug Resistance in Childhood Neuroblastoma: Progress in Neuro-Oncology

A new study from Luxembourg could one day lead to personalized treatments for neuroblastoma, a notoriously drug-resistant form of cancer.

Image: By Abby Tabor | Science Writer at NASA's Ames Research Center

New findings from Luxembourg cancer lab LBMCC have the potential to help young children afflicted with a deadly form of cancer of the nervous system, called neuroblastoma. A third of these patients, who are usually no more than 5 years old, suffers from a variety of the disease that is highly resistant to standard cancer drugs, putting them especially at risk. The researchers now understand better why that is—and how a natural substance with cancer-fighting properties could help overcome that resistance.

New findings from Luxembourg cancer lab LBMCC have the potential to help young children afflicted with a deadly form of cancer of the nervous system, called neuroblastoma.

The researchers have just published their results in the prestigious journal Oncogene from Nature Publishing Group, in collaboration with the non-profit organization Een Haerz fir kriibskrank Kanner (A Heart for Childhood Cancer).

One-third of these patients, who are usually no more than 5 years old, suffers from a variety of the disease that is highly resistant to standard cancer drugs, putting them especially at risk. The researchers now understand better why that is—and how a natural substance with cancer-fighting properties could help overcome that resistance.

The team at the LBMCC (Laboratoire de Biologie Moleculaire et Cellulaire du Cancer) is working to understand what happens with neuroblastoma at multiple levels: that of the different cell populations making up a tumor, of the individual cancer cells, and of the molecules by which they operate. This line of research will be necessary for developing treatments that can be tailored to each patient’s specific case.

Cleaning Cellular House Lets Cancer Escape Death

What puts certain neuroblastoma patients at such high risk is that the local environment of the tumor within the body is made up of a highly mixed population of neuroblastic (N-) cells of the tumor itself and stromal (S-) cells. The S-cells make up the connective tissue surrounding the tumor and the LBMCC’s results show that they respond differently to cancer treatments than the N-cells, revealing the origin of drug resistance seen with neuroblastoma.

Dr. Flavia Radogna, first author of the study, tested on these two cellular populations the effect of an anti-tumor compound called UNBS1450. This work is supported by a grant from Een Haerz fir kriikskrank Kanner, an association of parents of neuroblastoma patients, which sees promise in the approach.

As part of their normal processes, cells break down and clear away any damaged parts, through a process called autophagy (“self-eating”). This also occurs when cancer cells are hit with a toxic drug, in an attempt to avoid the programmed cell death (apoptosis) that would otherwise result from such significant damage. The LBMCC team, led by Prof. Marc Diederich, found that the tumor cells treated with UNBS1450 were no longer able to dispose of their damaged mitochondria, a structure within the cell that produces energy. This defective autophagy then triggered apoptosis, in the N-cells—a favorable result for cancer therapy.

Neuroblastoma N-cells: untreated (left) and treated with UNBS1450 (right).
After treatment with the anti-tumor compound, the cells are unable to clear away efficiently
the damaged mitochondria (indicated in yellow), marking them for programmed cell death.
(Image: LBMCC)

 

The situation was quite different in the S-cells, however. Here, too, the UNBS1450 treatment was harmful to mitochondria, but these cells were able to dispose of those damaged elements, thus avoiding the apoptotic fate of N-cells. Maintaining this specific type of autophagy, called mitophagy, appears to be the principal mechanism responsible for stromal cells’ avoidance of apoptosis and, thus, neuroblastoma’s resistance to chemotherapy. At high enough doses, UNBS1450 was able to kill S-cells, but via necroptosis, an alternative and promising cell death pathway.

Predicting and Personalizing for Neuroblastoma Treatment

From these findings, the researchers conclude that the level of mitophagy could be used to predict each patient’s sensitivity to treatment, allowing for personalization of their therapy. Certain neuroblastoma patients, for instance, might respond well to a drug encouraging apoptosis in cancer cells, coupled with an inhibitor of autophagy; otherwise, the autophagy mechanism could well rescue cells from the cell death program.

Combining therapies, though, will require determining precisely the events taking place in the tumor and stromal cell populations, as well as their interactions.

The drug studied in this research, UNBS1450, makes use of a substance found in the tropical plant Calotropis procera. Originally used to treat cardiac problems, its anti-tumor activity is receiving more and more attention. The LBMCC recently revealed its mode of action in killing multiple types of cancer cells. Given its other benefits, like the ability to selectively kill cancer cells, not healthy neighbors, and its efficacy at low doses, Prof. Diederich says his team will continue to unravel how exactly this promising cancer drug candidate works. Understanding its action on the molecular level will bring it closer to the point of helping the young victims of neuroblastoma with a personalized treatment adapted to their needs.

 

You can support further work by the LBMCC in the fight against cancer by making a donation to the non-profit organization Een Haerz fir kriikskrank Kanner.

 

Original study: 

Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in neuroblastoma

F Radogna, C Cerella, A Gaigneaux, C Christov, M Dicato and M Diederich

Oncogene advance online publication, December 7, 2015; doi:10.1038/onc.2015.455

Overcoming Drug Resistance in Childhood Neuroblastoma: Progress in Neuro-Oncology

Overcoming Drug Resistance in Childhood Neuroblastoma: Progress in Neuro-Oncology

A new study from Luxembourg could one day lead to personalized treatments for neuroblastoma, a notoriously drug-resistant form of cancer.

New findings from Luxembourg cancer lab LBMCC have the potential to help young children afflicted with a deadly form of cance...

Related Publication

Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in neuroblastoma

Flavia Radogna Claudia Cerella Anthoula Gaigneaux C. Christov Mario Dicato Marc Diederich

Published in Oncogene

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