Developing Targeted Chemotherapeutics for Malignant Brain Tumors Using an Innovative Blood-Brain Barrier Organoid Platform
Abstract
Advanced brain tumors, including glioblastoma (GBM) are incurable. Once diagnosed, patients usually do not have long to live (average about 14 months) even after aggressive chemo/radiotherapy after surgery. Current standard-of-care treatment has not substantially improved patient survival over the past few decades. This is largely because aggressive brain cancer cells tend to invade into the surrounding normal brain tissue and cannot be completely removed by surgery. These cells are protected from systemic chemotherapeutics by the blood-brain barrier (BBB) that separates brain tissues from circulating blood. Furthermore, patients also generally suffer severe side effects from treatment, as chemotherapy is very toxic to healthy tissues. We have recently pioneered a technology, known as the BBB organoid model, which has proven to be a valuable tool for facilitating efficient analysis of drug delivery to the brain. The proposed research describes the development of a novel tumor-BBB organoid platform for modeling how brain tumor cells interact with the BBB, as well as evaluating drug delivery to brain tumor cells. For the objective of treating brain tumors, we rationalize that molecules that can deliver therapeutics across the BBB (like a Trojan horse) and target tumor cells (missile therapy) could simultaneously improve tumor killing and reduce side effects. In our efforts to search for such molecules, we have recently identified a peptide, called BTP-7 that can both cross the BBB and home to brain tumor cells in culture and in animal models. We propose to chemically generate a variation of new therapeutics derived from the BTP-7 peptide. We will utilize the tumor-BBB organoid platform to assess the effectiveness of the new BTP-7-derived therapeutics to destroy brain tumor cells without affecting normal healthy tissues. With state-of-the-art platforms and ample resources at world-leading institutions, we plan to continue optimizing and testing the new therapeutic variants, with a clear goal and vision towards clinical trials and translation. The Principal Investigator (PI), Dr. Choi-Fong Cho, an Instructor at the Brigham and Womens Hospital (BWH), Harvard Medical School (HMS) is leading a research team to address the clinical challenges in brain cancer therapy. Funding from the Department of Defense Career Development Award will provide major support for the salary of the PI, as well as cover majority of the experimental costs, and is a significant stepping stone for the PIs career and research. Findings from the proposed research can lead to the development of safe and efficacious anti-tumor medicines that can significantly benefit patients with advanced brain tumors. The ability to specifically target the tumor could lead to reduced side effects caused by chemotherapy, which would help improve the quality of life of patients and their families. The team aims to conduct clinical trials to test the benefits of these inventions in brain cancer patients within the next 5 years. Furthermore, the development of the tumor-BBB organoid model can facilitate many researches in the neuroscience and neuro-oncology field in the development of better brain cancer therapeutics. All together, the proposed work can significantly advance the way we tackle aggressive brain cancer in the future. Veterans and active soldiers are in greater danger of being diagnosed with (or die of) advanced brain cancer due to their increased risk of traumatic brain injury and exposure to hazardous environments and chemicals (such as nerve agents) while serving in the army. Because of this, our proposed research can significantly benefit military personnel.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910791
Entities
People
- Choi-fong Cho
Organizations
- Brigham and Women's Hospital
- United States Army