Journal Article

HDL nanoparticles targeting sonic hedgehog subtype medulloblastoma

Goldman, Stewart, Eckerdt, Frank, Bell, Jonathan B., Rink, Jonathan S., Clymer, Jessica, Platanias, Leonidas C., Thaxton, C. Shad

2018

Overview

Medulloblastoma is the most common paediatric malignant brain cancer and there is a need for new targeted therapeutic approaches to more effectively treat these malignant tumours, which can be divided into four molecular subtypes. Here, we focus on targeting sonic hedgehog (SHH) subtype medulloblastoma, which accounts for approximately 25% of all cases. The SHH subtype relies upon cholesterol signalling for tumour growth and maintenance of tumour-initiating cancer stem cells (CSCs). To target cholesterol signalling, we employed biomimetic high-density lipoprotein nanoparticles (HDL NPs) which bind to the HDL receptor, scavenger receptor type B-1 (SCARB1), depriving cells of natural HDL and their cholesterol cargo. We demonstrate uptake of HDL NPs in SCARB1 expressing medulloblastoma cells and depletion of cholesterol levels in cancer cells. HDL NPs potently blocked proliferation of medulloblastoma cells, as well as hedgehog-driven Ewing sarcoma cells. Furthermore, HDL NPs disrupted colony formation in medulloblastoma and depleted CSC populations in medulloblastoma and Ewing sarcoma. Altogether, our findings provide proof of principle for the development of a novel targeted approach for the treatment of medulloblastoma using HDL NPs. These findings present HDL-mimetic nanoparticles as a promising therapy for sonic hedgehog (SHH) subtype medulloblastoma and possibly other hedgehog-driven cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/100 / 13/106 / 13/31 / 14/19 / 14/34 / 14/63 / 38 / 631/67/1922 / 639/925/352/2733 / Antineoplastic Agents - chemistry / Antineoplastic Agents - metabolism / Antineoplastic Agents - pharmacology / Biomimetics / Brain cancer / Brain tumors / Cell Line, Tumor / Cell proliferation / Cerebellar Neoplasms - genetics / Cerebellar Neoplasms - metabolism / Cholesterol / Cholesterol - metabolism / Ewing's sarcoma / Gene Expression Profiling / Hedgehog protein / Hedgehog Proteins - metabolism / High density lipoprotein / Humanities and Social Sciences / Humans / Lipoproteins, HDL - chemistry / Lipoproteins, HDL - metabolism / Lymphocytes B / Medulloblastoma / Medulloblastoma - genetics / Medulloblastoma - metabolism / multidisciplinary / Nanoparticles / Nanoparticles - metabolism / Physical growth / Protein Binding / Receptors, Lipoprotein - metabolism / Sarcoma / Scavenger receptors / Scavenger Receptors, Class B - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Stem cells / Tumors