Physical Health United States Project #19809

Pursuing new treatments for Neuroblastoma children

by Cure First

Project Report | Apr 17, 2020
Validation in vivo of in vitro effective and novel neuroblastoma drug combinations

By Rachele Rosati | Lead Scientist at Cure First

PDOs, NB model with DNA repair deficiency

Dear Project Neuroblastoma Supporters,

I would like to extend to you my gratitude for your support of Project Neuroblastoma (NB). Your generous contributions have enabled the incredible improvements and outstanding results that the project has achieved in the past months. Thank you for believing in our mission and for your enduring support.

Despite a wide variety of treatment approaches for neuroblastoma, children with this high-risk disease have poor prognoses. Many children diagnosed with neuroblastoma are faced with a multifaceted, intense treatment approach including surgery in combination with several rounds of chemotherapy, radiation, stem cell transplantation and immunotherapy with isotretinoin. These standard-of-care treatment options are highly toxic and often yield little clinical benefit. Our mission is to find less-toxic drugs for high-risk neuroblastoma patients. By testing hundreds of drugs in patient-derived organoids ex vivo, we have avoided the harmful side effects and blind matching of drugs to patients inherent in traditional clinical trials.

We are excited to share that the Project Neuroblastoma team has identified the most effective in vitro drug combinations for three different neuroblastoma patient-derived organoid (PDO) models, each from a different patient with unique DNA alterations. One model has deficiency in a DNA repair pathway. Another has an ALK mutation, which has been associated with genomic predisposition to neuroblastoma. The third model has a KRAS gene alteration that is more common in other cancer types, such as colorectal and pancreatic cancers. Our discovery of these unique alterations has allowed us to propose a new combination of drugs to battle this devastating cancer.

While we believe that this new treatment options could prove to be the light at the end of the tunnel for at least some of the children with high-risk neuroblastoma, further in vivo testing in mouse models will need to confirm these results. Each organoid model was highly sensitive to the selected combination, indicating that patients with different genomic alterations could be potentially treated with the same drug combination.

The next step, in coordination with our collaborators at Children Hospital of Philadelphia, is the validation of our results in avatar mice.

We are thrilled to announce that the in vivo study for one of the patient-derived organoid models was begun at the end of February. While we hoped to begin the in vivo study for the other two models in March, we have had to postpone this work due to the spread of coronavirus. We look forward to sharing our results from the initial in vivo model in our next GlobalGiving report and hope to begin work on the second two models soon.

With warm thanks and best wishes,

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Dec 17, 2019
Personalized Drug Combinations for Cancer

By Rachele Rosati, MS | Lead Scientist and Team Member

December 15, 2019

Dear Project Neuroblastoma Supporters,

Our research to identify individually tailored treatments for children battling Neuroblastoma (NB) utilizing patient-derived tumor organoids has advanced tremendously in the last few months. Neuroblastoma is the second most common solid tumor in the pediatric population, where standard of care therapies often yield debilitating side effects and poor outcomes. With up to 40% of high-risk pediatric neuroblastoma patients succumbing to the disease, the time to act is now. Using leading edge laboratory technologies, we will identify personalized, targeted and less toxic treatments for pediatric cancers.

Earlier this spring, we met with our collaborator Dr. John Maris at Children’s Hospital in Philadelphia to evaluate three NB organoid models, each derived from a different patient with unique DNA alterations. We have been at work amplifying the neuroblastoma organoids in amounts sufficient for high-throughput drug combination testing and screen result analysis. Each model was exposed to hundreds of different drug combinations to find the best treatment for each patient.

Now that we have found the best drug combinations for each cancer model (see Figure attached), we will proceed to test them in avatar mice carrying neuroblastoma. This research will establish if these novel combinations will be effective to block tumor growth and assess their safety in a living organism. We are excited and hopeful because our research found potentially effective drugs for tumor samples that otherwise were resistant to standard of care therapies. Further research will evaluate these therapies for use in clinic for pediatric cancer care.

Our exciting progress in fighting this disease would not have been possible without the generous contributions of our donors. We have raised over $22,697 to date, yet it will take up to an additional $67,303 to complete this project. We appreciate your consideration in contributing toward our efforts to improve overall outcomes and quality of life for children battling high-risk neuroblastoma. Your enduring support will allow us to continue the fight against this tragic disease.

With thanks and warm wishes,

Rachele Rosati, MS, Lead scientist and Cure First Team

Attachments:

Neuroblastoma_Figure.pdf (PDF)

1 Attachment

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Sep 16, 2019
Mini-Cancers in a Dish

By Rachele Rosati | Cure First Lead Scientist

GLOBAL GIVING SEPTEMBER 2019 REPORT

Dear Cure First and Project Neuroblastoma Supporters,

Our progress on finding new treatments for children with Neuroblastoma (NB) continues as we focus on re-purposing existing targeted drugs used in adults with other cancer types as well as drugs currently under experimentation. Our work to date indicates that indeed existing FDA-approved drugs could prove effective in treating this terrible childhood cancer and their use in potential novel combinations could enhance their effectiveness even further.

Cure First’s utilization of patient-derived tumor organoids also continues. These “mini-cancers in a dish,” which maintain the heterogeneity and genomic profile of the original tumor from one child’s body, can reveal significant drug responses which match a respective organoid’s genomic features. We are also able to record novel drug sensitivities which cannot be anticipated by genomics alone. The process basically allows us to perform “in vitro” trials. It is far less costly than working with avatar mice and allows the opportunity to test hundreds if not thousands of drug combinations on cancer cells from a single individual.

Over the summer, our work was focused on the validation of our findings on multiple samples of tumor-organoids derived from various patients with NB. We are working hard to assemble all the data and figures from this project for a future publication so that the scientific and biomedical community can be aware of how cancer medicines developed for adults can be beneficial to children with neuroblastoma.

None of this progress would have been achieved without your help and your support.

Thanks to you, we have raised more than $22,500. And we recently received a challenge match of $10,000! As you know, cancer research is expensive. The reagents and materials which keep NB cells alive for testing are costly. This year our fundraising target is $100,000 dollars. While we are already 1/10^th of the way there, we hope you can help us achieve our goal so that we can continue to validate new specific medicines for neuroblastoma before proposing these drugs for clinical trials.

Thank you again for your interest in our research which is devoted to improving the quality of life for children with high-risk neuroblastoma.,

Rachele Rosati, Lead Scientist, MS, and the Cure First Team

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