Robbins Lab Research Interests
Progressive dementia occurs in 20-50% of brain tumor patients who are long-term survivors after treatment with large field or whole brain irradiation (WBI). There are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. The need to both understand and minimize the side effects of brain irradiation is heightened by the ever-increasing use of large field or WBI in the treatment of secondary brain metastases. Approximately 20-40% of the > 1,400,000 new cancer patients diagnosed in 2008 will develop brain metastases, making this the 2nd most common site of metastatic cancer, the most common neurological manifestation of cancer, and a cancer problem more common in incidence than newly diagnosed lung, breast, or prostate cancer. Currently some 200,000-cancer patients/year receive partial or WBI.
Radiation-induced late effects are now viewed in terms of dynamic interactions between multiple cell types within a particular organ that can be modulated. In the brain, these include astrocytes, endothelial cells, oligodendrocytes, microglia and neurons. These cells are viewed now not as passive bystanders, merely dying as they attempt to divide, but as active participants in an orchestrated, yet limited, response to injury.
This new paradigm offers the possibility that radiation-injury can be modulated by the application of therapies directed at altering steps in the cascade of events leading to the clinical expression of normal tissue injury. However, details of the molecular, cellular, and biochemical processes responsible for the expression and progression of radiation-induced brain injury, including cognitive impairment, are currently ill-defined.
We hypothesize that the development and progression of radiation-induced late effects are driven, in part, by a chronic oxidative stress. To test this hypothesis, we are currently evaluating the ability of Peroxisomal Proliferator-Activated Receptor (PPAR) α and PPARg agonists, to modulate the radiation response of the normal brain. Ongoing studies utilize not only tissue culture models including primary rat astrocytes, rat brain microvascular endothelial cells, microglia and oligodendrocytes, but also rat and transgenic mouse models.
We are also investigating the role of the intrinsic brain renin-angiotensin system (RAS) in radiation-induced brain injury (Fig. 1).
Fig. 1 The role of oxidative stress and the renin-angiotensin system in radiation-induced late effects