The Brain Tumor Unit at TGen studies cancers that originate in the brain and cancers that metastasize to the brain. Specific anatomic and physiologic aspects of the central nervous system establish unique interactions between tumor cells and host cells, which we pursue with the intent of opening new treatment approaches to this devastating disease. Three pillars of study dominate the landscape of the BTU’s research: Invasion Biology, Treatment Development, and Correlative Studies to Clinical Trials.
Cancer is fatal due to dissemination of the disease. This invasion disrupts the function of the adjacent tissue and organ, which in the case of primary brain tumors leads to devastating neurological deficits, and in the case of metastatic cancers to the brain leads to treatment challenges inherent to delivery across the blood brain barrier. We (and others) have observed an inverse relationship between cancer cell migration and proliferation. This led to a paradigm dubbed “go versus grow”, where proliferation (growth) is achieved at the expense of invasion (go). Cancer cells are not all the same. Some cancer cells disperse to expand the area of disease, while others are highly committed to numerical expansion in a restricted area. The functional property of “stemness” of cancer cells interdigitates in the invasion biology, as well do fluctuations in vulnerability to therapy associated with invasion.
In collaboration with an interdisciplinary team, we are studying the changes in glioma gene expression that accompany the transition of cell egress from multicellular spheroids and tumor, the adoption of an invasive/migratory phenotype, and the subsequent cessation of invasion that coincides with resumed proliferation. These experiments are designed to discover key genetic regulation of the cancer cell transition from proliferative to migratory behaviors. The findings may indicate strategies by which to control the spread and metastasis of cancer.
The translational applications of our studies include the discovery and validation of markers of glioma invasion, which are explored for value as therapeutic targets. Preclinical validation of these targets fosters maturation of assays by which to test for inhibitors. The lab has developed and employed screening technologies by which to test libraries of small molecules for their migration-arresting properties. Active candidate compounds are being tested for synergistic effects with conventional chemotherapeutic agents or with radiation therapy. Preliminary preclinical in vivo experiments support the potentiation of cytotoxic therapy when tumors are treated with migration arresting compounds. Expression of epitopes on brain tumors suitable for immune targeting is an active and emerging pursuit.
Correlative Studies to Clinical Trials
Signals of tumor response or non-response (resistance or subclonal emergence) offer enormous value to the drug development enterprise. The Brain Tumor Lab develops pharmacokinetic assays indicative of “target-hit” and “efficacy”, which are tailored to targeted therapeutics as well as broadly instructive of early detection of treatment outcome, which accelerate and make-precise the use of new agents.