Rare-08. Potential New Therapies for Diffuse Intrinsic Pontine Gliomas Identified Through High Throughput Drug Screening

Abstract

Diffuse Intrinsic Pontine Gliomas (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 3,570 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, auranofin 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 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.

Fenretinide in Cancer and Neurological Disease: A Two-Face Janus Molecule

“…As reported in the previous sections, fenretinide nanomicelles, administered by intravenous injection at the dose of 30 mg/kg in animal models of neuroblastoma, provided high drug intratumor concentrations due to the nanomicelles' ability to accumulate in solid tumors, by extravasation, through the discontinuities of the angiogenic tumor capillaries [48,49]. In brain tumor (DIPG-05 and RARE-08) animal models, the same intravenous doses of fenretinide nanomicelles increased overall survival, indicating their ability to cross the BBB [50,51]. By oral route, fenretinide nanomicelles showed significant efficacy at 100 mg/kg due to increased gastrointestinal fenretinide bioavailability that raised plasma levels and fenretinide concentrations in solid tumors [47].…”

“…The same nanoformulation also showed significant therapeutic efficacy in brain tumor models (DIPG-07 and RARE-08), indicating its ability to cross the blood-brain barrier (BBB) [50,51].…”

Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines

“…With the aim to overcome these limitations and obtain supra-physiological levels of spermidine in tumor cells, we prepared nanospermidine by encapsulation of spermidine in nanomicelles that we had previously demonstrated to be suitable carriers for fenretinide in tumor cells [21][22][23][24]. Next, we evaluated the effect of nanospermidine in two neuroblastoma cell lines: NLF (with MYCN amplification) and BR6 (without MYCN amplification, with TrKA expression).…”

“…Moreover, we evaluated the combination of nanospermidine with nanofenretinide to assess if the contribution of a drug able to increase intracellular ROS levels [17][18][19][20] could improve the cytotoxic effect of nanospermidine on tumor cells. Indeed, we had previously demonstrated that nanofenretinide was highly active in neuroblastoma and DIPG tumor models, and the effects were mediated by ROS increase [21][22][23][24].…”