The Nathanson Lab focuses on malignant brain tumors, in particular glioblastoma (GBM) – one of the most lethal of all cancers. We take an interdisciplinary approach to understand the biology of brain cancer and to develop innovative therapeutics to ultimately improve on patient outcomes

RESEARCH

FUNCTIONAL BIOLOGY OF BRAIN CANCER

Cancers, including malignant glioma, have hijacked and rewired many normal cellular functional processes in order to grow and survive.  These cancer “hallmarks” – as defined by Hanahan and Weinberg (Cell 2011) – include resisting cell death and deregulated metabolism. Notably, reprogramming of these functional pathways in cancers is a direct consequence of aberrant oncogenic signaling emanating from the loss of tumor suppressors and/or mutations in oncogenic drivers. Accordingly, our lab has hypothesized that investigating the interplay between oncogenic signaling and metabolism/cell death pathways can reveal novel therapeutic vulnerabilities.

DRUG DISCOVERY AND DEVELOPMEnt of brain-penetrant therapies

The effective treatment of brain tumors requires that drugs get into the brain to target the tumor. However, the vast majority of FDA approved drugs do not cross the blood brain barrier (BBB) – a physical barrier that is highly selective for what can cross into the brain. Through collaborations with Dr. Michael Jung (Distinguished Professor of Chemistry, Co-Inventor of two FDA approved drugs for cancer), we have established a drug development program that is focused on synthesizing and testing new, potent and brain-penetrant drugs that specifically target malignant glioma cells.

Developing Innovative Pre-clinical Models of brain tumors

The translation of therapeutic strategies for treating several malignancies have been hampered by the lack of robust pre-clinical models that accurately reflect the human disease. This is particularly relevant in malignant gliomas, where the genetic and functional properties of conventional cell lines show dramatic divergence from the original patient samples. This has major implications for understanding the biology of these tumors and the development of new therapies. To address this, we have created a novel patient-derived, orthotopic glioma xenograft library (termed GliomaPDOX). This library captures the vast molecular diversity of GBM.

MOLECULAR Diagnostics OF BRAIN TUMORS

Although all gliomas originate in the brain, the molecular alterations are often unique between each patient’s tumor. These distinctions can have profound implications for diagnosis and therapeutic response. Our laboratory uses next generation sequencing – including RNAseq and exome sequencing – of patient and GliomaPDOX tumors to precisely define the molecular abnormalities that are driving each glioma. To complement this, we also employ non-invasive molecular imaging, such as positron emission tomography (PET), to examine how imaging can predict tumor response to therapeutics targeting specific molecular alterations in glioma patients and models.

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