Brain Tumor Stem Cell Lab

Overview

Brain Tumor Stem Cell Lab (the Wakimoto Lab) aims to develop new effective therapeutic approaches for malignant tumors in the central nervous system through understanding the complex biology of the tumors and investigating the potential of biological and pharmacological agents. We leverage patient-derived stem cell models and murine models to achieve the goal of translating research discoveries to the clinic. Our research is focused on four tumor types: glioblastoma, IDH (isocitrate dehydrogenase)-mutant glioma, cancer brain metastasis, and high-grade meningioma.

Research Projects

Patient-derived glioblastoma stem cell models

Glioblastoma (GBM) is an aggressive primary brain tumor, and effective treatments are needed. GBM stem cells are considered to resist therapies and drive GBM recurrence. We have led and achieved the generation of a large panel of stem-like and xenograft-forming GBM cells that we isolated from patients. Representing patient tumors, these tumor models are ideal to study cancer stem cell biology and test new therapies. Because of this utility, our models have been widely distributed to neuro-oncology investigators to help their research projects.

Oncolytic virus therapy for GBM

Genetically engineered viruses such as oncolytic herpes simplex virus (oHSV) and oncolytic adenovirus (oAd) are attractive biological agents as they can selectively kill cancer cells and stimulate anti-cancer immunity. In collaboration with Drs. Samuel Rabkin and Robert Martuza, we are the first to show that oHSVs carrying particular virus genome modifications display the ability to replicate and kill GBM stem cells. In other collaborations, we showed that expression of a secretable form of the protein TRAIL empowers oHSV to prevent GBM recurrence in mouse models of human GBM stem cells-derived GBM. We demonstrated that an oAd capable of degrading tumor extracellular matrix hyaluronan combines with immune checkpoint blockade to augment anti-tumor immunity and eradicate mouse GBM. Furthermore, we recently proposed the concept of “photo-dynamic oncolytic virus (PD-OV)” therapy that combines oHSV and PD therapy through photosensitizer expression by oHSV to enhance anti-cancer effects.

Targeting vulnerability of IDH-mutant glioma

IDH-mutant gliomas affect people in their 30s-50s, impacting the patients’ quality of life despite the disease’s initial slow growth. We showed that IDH-mutant gliomas that progressed upon acquiring driver genetic mutations had the ability to establish orthotopic xenografts in mice. In close collaboration with Drs. Daniel Cahill and Julie Miller, we have identified NAD+ metabolism as a survival vulnerability uniquely found in IDH-mutant gliomas and proposed pharmacological therapeutic strategies that exploit this IDH-specific molecular biology.

Targeted agents for cancer brain metastasis

Cancer therapy has improved, but once cancer metastasizes the brain, treatment is challenging. In close collaboration with Dr. Priscilla Brastianos, we have been testing molecularly targeted agents that block aberrant signaling pathways that are defined by cancer genomics (such as mutant KRAS oncogene and CDKN2A/B loss) in mouse models. These efforts are accelerating bench-to-bedside clinical translation, facilitating early clinical trials of promising drug therapies that are much needed for patients with cancer brain metastasis.

Therapeutic strategies for high-grade meningiomas

Meningiomas arising from the meninges are mostly benign and can be treated by surgery alone. However, recurrent or high-grade (WHO grade 2 and 3) meningiomas are often difficult to treat. We have established patient-derived xenografts of malignant meningioma and showed the activity of oHSV in animal models. Additionally, in collaboration with Dr. Brastianos, we have been actively investigating molecularly targeted agents with the goal of timely clinical translation. In collaboration with Meningioma Mommas, we have shown that the PD-OV therapy is efficacious in human malignant meningioma xenografts.

Research Team

Hiroaki Wakimoto, MD, PhD
Principal Investigator

Dr. Wakimoto leads the lab

Tomoyuki Nakano, MD, PhD
Research Fellow

Dr. Nakano is a board-certified neurosurgeon (Japan) and a research fellow, studying primary brain tumors.

Louise Leparc, MS
Graduate Student

Louise Leparc is a PhD student from University of Liege, studying GBM.

Publications

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