DIPG-07. HIGH THROUGHPUT DRUG SCREENING IDENTIFIES POTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs)
Autor: | Nicole Yeung, Caitlin Ung, Patrick Reynolds, Dannielle Upton, Aaminah Khan, Sandra George, Jie Liu, Isabella Orienti, Anahid Ehteda, Santosh Valvi, Giovanna Farruggia, Han Shen, Maria Tsoli, Laura Franshaw, David S. Ziegler, Christa E. Nath |
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Přispěvatelé: | Dannielle Upton, Santosh Valvi, Jie Liu, Nicole Yeung, Sandra George, Caitlin Ung, Aaminah Khan, Laura Franshaw, Anahid Ehteda, Han Shen, Isabella Orienti, Giovanna Farruggia, Christa Nath, Patrick Reynolds, Maria Tsoli, David Ziegler |
Rok vydání: | 2020 |
Předmět: |
Drug
Oncology Cancer Research medicine.medical_specialty antineoplastic agents brain tumors 1-phosphatidylinositol 3-kinase auranofin cell death . child death down-regulation drug screening fenretinide ivermectin mefloquine platelet-derived growth factor alpha receptor safety neoplasms cytotoxicity. proto-oncogene proteins c-akt phosphoinositide 3-kinase vorinostat mtor serine-threonine kinases amplification diffuse intrinsic pontine glioma business.industry media_common.quotation_subject MTOR Serine-Threonine Kinases Diffuse Midline Glioma/DIPG Internal medicine medicine AcademicSubjects/MED00300 AcademicSubjects/MED00310 Neurology (clinical) business Platelet-Derived Growth Factor alpha Receptor media_common |
Zdroj: | Neuro-Oncology |
ISSN: | 1523-5866 1522-8517 |
Popis: | DIPGs are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12 months. There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,500 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds- auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine- that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in-vitro. To determine whether the in-vitro efficacy could be replicated in-vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different Fenretinide formulations (LYM-X-Sorb and NanoMicelle) which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG. |
Databáze: | OpenAIRE |
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