PROJECT SUMMARY Currently, there are few options for treating diffuse cancers. This is a particular challenge for diffuse cancers that arise in sensitive tissues (i.e., not amenable to resection), in tissues in which drug diffusion is limited, or in patients for whom typical interventions incur unacceptable sequelae (e.g., pediatric patients). Here, we investigate a novel approach: guiding cells with electrical fields (electrotaxis) to consolidate the diffuse cancer cells to one or few locations (making them less diffuse), or alternately, move these cells to a less critical location. As a basis for our approach, we will use one of the most aggressive forms of pediatric brain tumor, Diffuse Intrinsic Pontine Glioma (DIPG), which is emblematic of the challenges inherent in treating diffuse cancers. The need for new treatments for DIPG is particularly critical, as it arises in the pons–a site that hosts critical centers for breathing, chewing, heartbeat and swallowing–and incurs a dismal median survival time of 9 months and is fatal in more than 99% of patients. We propose to quantify, using transcriptomics and pharmacological inhibition, underlying mechanisms of electrotactic tumor cell response. This will reveal electrotactic drug targets and provide controls to manipulate/enhance further electrotaxis. We will investigate in vivo, the effects of various electrode montages to shape and steer infiltrative DIPG cells in both the cortex and pons. To support our approach, we will apply computational methods to iteratively model and design stimulation montages in response to observed patterns of growth after field application. These studies will provide a novel approach to addressing the general problem of a diffuse cancer so that they can become more amenable to standard-of-care therapies.