High-throughput Identification and Validation of Drugs to Target Migrating and Treatment-Resistant Glioblastoma Cells - Diffuse single cancer cell infiltration into normal surrounding brain is a pathological hallmark of Glioblastoma (GBM). Current treatment regimens yield survival rates of 14 months, but patients ultimately die of widely infiltrative tumors that are resistant to all therapies. Infiltrating GBM cells pose the single greatest challenge to improving the prognosis for primary brain tumor patients. Therapies which effectively block single brain cancer cell migration could transform this fatal tumor into a local disease, one that could be effectively treated by surgery and/or high dose focal radiation. To address this important need, our Cancer Working Group members (faculties at UTA, OUHSC and UTSW) have brought their diverse expertise in clinical tumor biology, engineering-enabled cancer treatment and high-throughput (HT) drug screening together to create a powerful, single-cell-level Ex vivo platforms for the quantitative analysis of malignant therapy resistant cancer cells and biophysical properties assessment that can provide unique insights into treatment resistant cancer cells. Ultimately, this system could result in the development of new treatments for eradicating or significantly slowing down the treatment resistant brain cancer cells. In our studies, we have discovered that the microstructure environment under which cells are tested with potential drugs is profoundly important and needs to mimic the in vivo setting. Additionally, we have found that this microchannel technology can reliably produce treatment resistant migrating GBM cells which significantly express the brain cancer stem cell related markers. A similar resistant phenotype was observed when physically confined migrating GBM cells were treated with gamma radiation. We have developed the HT cancer cell migration/viability screening platform that is designed to monitor single cancer cells migrating through spatially restricted channels and how migratory inhibitors affect cancer cell migration/viability. This platform is currently utilized for massive cell migration and viability studies by fully automated HT screening system at the UTSW. In this AREA project, we propose to search for novel GBM therapies by a target identification strategy and by a drug screen strategy. We plan to (i) employ an ex vivo integrated HT platform for the quantitative cellular/molecular analysis of malignant therapy resistant brain cancer cells and biophysical properties assessment; and (ii) establish a pipeline of target and novel drug discovery using this system suitable for identifying molecules for eradicating the treatment resistant cancer cells. These collaborative efforts can i) develop a system that reliably induces/enriches the treatment resistant cancer cells and has the ability for HT screening of drugs could revolutionize drug discovery in many malignant and treatment resistant tumors; and ii) provide a steady flow of highly research-capable undergraduate students for building a diverse biomedical research workforce in the field of HT drug screening.
