Funded Grants

Characterization of a glioma precursor lesion

WHEN DO GLIOMAS BECOME INCURABLE?

While breast and colon cancers still remain very difficult to treat if diagnosed in their advanced stages, they both are readily curable if detected and treated at early points in their evolution. This need to diagnose early if cure is to be attained therefore both highlights and justifies the use of routine mammograms and colonoscopies in individuals at risk.

Interestingly, despite being at least as incurable as these two systemic cancers, such an approach has never been considered for gliomas, the most common type of primary brain tumor. Thus, although it is readily acknowledged by experts that these tumors are universally very difficult to cure once diagnosed, research efforts continue to be directed exclusively towards finding a cure for established tumors.

I believe that the major reason for this lack of interest is that it is implicitly believed that a glioma’s prognosis is fixed at the onset of the disease. This naturally leads to a conclusion that there seems little point in early detection, since incurability starts at the time that the first glioma cell is formed. However, I believe that the best chance for a therapeutic breakthrough in this disease is if our implicit assumption is wrong, i.e., that gliomas are not incurable from outset but become so at some later point in their evolution.

To evaluate whether early detection represents a viable strategy, one first needs to establish the sequence of events that occur early during glioma development. This includes not only those events that occur at and subsequent to the point of detection (i.e., by MRI) but also those occurring before. Second, a firm grasp of the cellular and environmental influences on the process are needed to enable the investigator to develop potential preventative therapies. Such a potential therapy then needs to be tested at various points in the course of glioma evolution to address whether it is curative only if administered before a certain point is reached.

My laboratory has been using an established model of neurocarcinogenesis which closely mirrors the clinical picture to address these issues. Our data suggests that gliomas arise from a common precursor lesion. More surprisingly, we found that pathologic changes are noted four to five weeks before MRI imaging abnormalities (which if one extrapolates in terms of the differences in life expectancy translates to over three years for humans) and that gliomas themselves undergo a phenotypic change at the time of MRI detection.

Our preliminary results have therefore laid the foundation from which we can now start to address the heretofore unasked question of whether early treatment can make a difference for our patients. In our application, we present experiments that will help us address the first and second steps in the process. Thus, we propose to develop reagents that can help us better monitor glioma evolution from before the earliest cells are pathologically detected through MRI detection and beyond. Furthermore, we will examine whether a cytokine whose appearance closely correlates with MRI detection (osteopontin) plays a role in driving the process of glioma formation. Having taken care of glioma patients for over two decades, I have participated in or read about countless therapies that have been heralded as potential breakthroughs for this disease, only to watch them fail to significantly improve outcome. However, even my
increasing frustration does not yet allow me to champion expending efforts and resources to take this strategy to the clinic before there is sufficient evidence that justifies moving in this direction. One only has to look at how much of an impact early diagnosis has made in breast and colon cancers in the last few years to realize however that early glioma detection is a question that we need urgently to address.