UNIVERSITY OF MASSACHUSETTS

Rachael Sirianni, PhD
Professor, Department of Neurological Surgery, UMass Chan Medical School

Medulloblastoma is the most frequently diagnosed brain tumor that affects children. In many instances, particularly for the Group 3 subtype of medulloblastoma, malignant cells move away from the primary tumor and metastasize to the surfaces of the brain and spinal cord. This phenomenon is known as leptomeningeal metastasis (LM), and it remains very difficult to treat. LM cannot generally be surgically resected, and it is often unresponsive to traditional chemotherapy.  The Sirianni laboratory has for many years been focused on the development of drug loaded nanoparticles that can be administered directly to the cerebrospinal fluid (CSF) that flows across the surfaces and brain and spinal cord. This approach can achieve high levels of drug in the cerebrospinal fluid while minimizing peripheral exposure. However, despite this progress, they have also observed that drug access to deeper regions of the tumor and metastatic lesions remains incomplete. In this 2024 WhatIFF Project, they propose an innovative new drug delivery approach termed CSF Flow Enhancement (CFE). This strategy involves a simple, safe manipulation to stimulates the body to produce new CSF. This freshly secreted CSF flows quickly across and throughout brain and spinal cord tissues. Importantly, the fluid movement that is generated by CFE carries advantages for drug delivery to LM: fast flow means more opportunity for nanoparticle systems to engage with and target metastatic cells, and the increased volume of fluid generated by this method enables nanoparticles to reach tissues that cannot otherwise be accessed. Funding provided for this work supported the development of CFE approaches for delivery of nanoparticles to LM. Their recent data provide early but exciting evidence that this method will be useful to enable nanoparticles to better access the brain, including deeper tissue regions that are often difficult to treat. As this project comes to a close, their ongoing work is focused on optimizing this method for drug loaded nanoparticles, with next steps to test therapeutic efficacy in preclinical models of medulloblastoma exhibiting LM. They hope to harness the body’s endogenous physiology to enable better, safer treatment of these otherwise devastating pediatric brain tumors.