The absence of effective treatment options for patients with brainstem tumors and other highly aggressive, unresponsive CNS tumors emphasizes the need for innovative strategies that combine advanced imaging techniques, minimally invasive delivery methods, and targeted therapeutic agents. Current challenges to successful tumor treatment include the intrinsic chemoresistance of tumor cells and an intact blood-brain barrier (BBB), which effectively impedes the delivery of most therapeutic molecules. More specific, tailored therapeutic agents are emerging, however, even the most potent therapeutic molecules identified from in vitro experiments will be ineffective if they cannot penetrate the BBB to reach the cancer cells. The study of drug distribution, therefore, is crucial to determining a drug's efficacy. Otherwise, potential drugs will be regarded as ineffective, while they are in fact being inadequately delivered to the tumor. We have successfully developed a unique MRI-guided neurointerventional platform for predictable, local intra- arterial (IA) delivery of therapeutic agents to the brainstem after focal BBB disruption (BBBD). We are able to precisely document trans-catheter perfusion using real-time GE-EPI MRI and pre-define an area for selective BBBD and subsequent super-selective therapeutic agent administration. While our current methodology utilizes the chemotherapy drug melphalan, this delivery strategy can be applied to a variety of therapeutic agents including other chemotherapy drugs, siRNA, microRNA, aptamers, and future discoveries. In this proposal we will compare the differences in drug distribution after BBBD with and without the aid of predicting the targeted area in advance. We will determine the cellular neurotoxicity after IA BBBD and chemotherapy via the basilar artery, both in terms of severity of injury and time course for development. We will also assess the feasibility of glial progenitor cells (GRPs) engraftment to determine their role in repair afte chemotherapy. This information can be readily translated into our ongoing Phase I trial, Intra-arterial Chemotherapy for the Treatment of Progressive DIPG, (NCT01688401). We have assembled a team of basic science and clinical experts across the disciplines of pediatric neuro-oncology, interventional neuroradiology, and MRI research for this project. While our proposal is generally targeted for brainstem pathologies, this MRI-guided neurointerventional platform can be applied to various other CNS tumors and neurovascular pathologies that require selective, targeted therapeutic delivery.
We aim to determine the cellular neurotoxicity, both in terms of extent and time course for development, after focal blood brain barrier disruption and intra-arterial chemotherapy via the basilar artery. We will also assess the reparative role of regenerative stem cells (glial progenitor cells (GRPs)) in our rabbit model.
|Chu, Chengyan; Liu, Guanshu; Janowski, Miroslaw et al. (2018) Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice. Front Neurol 9:921|
|Qin, Huamin; Janowski, Miroslaw; Pearl, Monica S et al. (2017) Rabbit Model of Human Gliomas: Implications for Intra-Arterial Drug Delivery. PLoS One 12:e0169656|