Physical Health United States Project #19809

Pursuing new treatments for Neuroblastoma children

by Cure First

Project Report | Dec 17, 2015
Neuroblastoma: how to ehance Claravis's effects

By Rachele Rosati | Cure First Research Fellow

Claravis, pills with RA

To keep you constantly posted on the Neuroblastoma project here our most updated achievements:

The International Neuroblastoma Risk Group classification defined half of the Neuroblastoma (NB) as high risk and statistical analysis revealed that the 15% of the childhood cancer-related mortality is caused by Neuroblastoma. In the last few months I continued the Neuroblastoma study to identify new combinations for the Claravis/Accutane (also commonly referred to as 13-cis Retinoic Acid or Isotretinoin) therapy, currently in the maintenance standard care of children with High Risk Neuroblastoma after recovery from myeloablative chemotherapy and stem cell rescue. (http://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq#section/_214)
My goal is to inhibit gene expression in NB cells with silencing RNAs and to discover promising drug targets for use in a combined therapy with Claravis.

Interestingly the three different Neuroblastoma cell lines in my research are representative of common neuroblastoma types. One has amplification of the MYCN oncogene and it carries mutations in the TP53 and NF1 genes, another one has TP53 and N-RAS mutations, and the last one has BRAF gene amplification and ALK and PTPN11 mutations. Starting from 49 genes of panel of kinase genes I was able to narrow the number down to four target genes for the MYCN amplified and three target genes for MYCN non amplified cell lines.

In the second figure, in addition to selective genes for each type of NBs, I also identified common genes between two cell lines. In both cell lines, MYCN amplified and not amplified, the inhibition of certain DNA repair pathways can enhance the effect of Claravis (RA).

We are also pleased to announce that our new Cure First lab is set up, all worked hard to get it set up before the end of the year and we are proud to inform that we are ready to receive new samples and new inputs for our research and to continue the current project.
As mentioned in the previous Neuroblastoma report our Director, Dr. Carla Grandori, has started a collaborative project with Dr. John Maris, from CHOP (Children Hospital of Philadelphia). Next week we will receive 10 Neuroblastoma samples, I will be in charge to keep them alive and let them expand in vitro. This is a new endeavor and a new frontier because until now scientists and researchers are keeping biopsy sample alive in Patient Derived Tumor Xenograft (PDTX) model. This project has been initiated thanks to a generous donation by the Soupy for Loopy foundation. I will soon begin testing a library of 320 drugs in Neuroblastoma Patient derived cells!

Combination of RA and targeted siRNAgene silencing

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Sep 17, 2015
New drug targets to use in combination with Retinoic Acid for Children with Neuroblastoma

By Rachele Rosati | Cure First Research Fellow

Performing experiments with NB cells

Within the past few months, I have advanced the neuroblastoma (NB) project targeting the identification of novel drug targets that can be used in combination with retinoic acid (RA). RA is currently one of the more effective and less toxic compounds used in the treatment of children with NB. Although high-risk NB is still difficult to treat, the addition of RA in the consolidation phase of therapy has given good results, significantly improving the rate of survival. However, there is more we can do. Cure First believes that by using high-throughput screening (HTS), technology that employs robotic tools, we can accelerate the discovery of new RA combination therapies.

Thus far, I have optimized the crucial methods of culturing and transfecting NB cell lines with siRNA molecules targeting hundreds of genes, which are potential future drug targets. I use siRNA technology to silence each individual gene and measure NB cell survival its absence. This allows me to select candidates that will enhance the effectiveness of RA when they are used together in combination. Our ultimate goal is to eliminate the risk of recurrence during RA therapy. Through this functional genomic approach, we will also be able to learn a great deal about the driving pathways and potential vulnerabilities of NB.

Finally, we are pleased to announce that our director, Dr. Carla Grandori, will soon launch a collaborative project with Dr. John Maris. Dr. Maris is a world expert physician and researcher on NB. We plan to test at least 10 patient-derived NB samples with a collection of hundreds of novel drugs. I will execute this project, by culturing the NB cells in vitro and carrying out the high throughput screening starting next fall.

I am looking forward to these exciting new projects!! I want to thank you for supporting our NB research project through Global Giving, and I hope that my work will lead to identifying less toxic and more effective drugs for children affected by NB.

Rachele Rosati, Cure First Research Fellow

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Jun 15, 2015
Pediatric Neuroblastoma

By Dr. Carla Grandori | President and Scientific Director

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