Goal: We propose to develop a therapeutic screening platform that rapidly determines the response of intact human tumor samples to many potential therapies in parallel.
The aim i s to identify the subset of therapies of greatest potential value to individual patients, n a timescale rapid enough to guide therapeutic decision- making. Innovation: We have developed a microfluidic perfusion system that maintains intact primary tumor slice tissue in culture and enables the arrayed delivery of large numbers of different drugs, drug combinations or drug regimens to anatomically-defined regions of the tumor. Our system improves upon existing models for screening chemotherapeutic drug activity (e.g. tumor cells in culture, mouse xenografts, or genetically engineered mouse models): it uses intact tumor samples that retain the human tumor microenvironment and allows the generation of response data in a time frame that can guide decision-making for the initial phases of therapy. Focus/Aims: Our proposed research focuses on human brain tumors, specifically the malignant gliomas that comprise the majority (70%) of primary adult brain tumors. These include Grade III malignant gliomas and the more common Grade IV glioblastoma multiforme (GBM). Patients diagnosed with GBM have a median survival of ~1 year and an overall 5-year survival of <5 %, despite decades of effort to improve treated outcomes. In this proposal we argue that an important way to make progress in treating these lethal, refractory tumors is to develop a way to rapidly test many potential therapeutic agents or regimens in parallel on intact GBM specimens from individual patients. Tumor response to drugs will be measured by imaging of markers for cell death and for cell viability. As individual tumor samples are often heterogeneous, it is critical that our microfluidi system enables multiplexed drug testing across different regions of the sample. Positive drug responses should be consistent and specific across the tumor. The multiplexed platform will also enable investigation of specific drug combinations and dosages that might be therapeutically useful. Impact: This work addresses the urgent need to develop approaches and devices to rapidly and reliably assess the response of often heterogeneous, intact primary tumor specimens to a range of possible therapies, with the goal of identifying the most effective subset of therapies for individual tumors and patients.
Pre-clinical assays are sorely needed to complement molecular tumor profiling and to better inform individualized therapy for patients with the lethal brain cancer, Glioblastoma Multiforme (GBM). Here we propose a novel microfluidic platform that utilizes patient-derived tumor slice cultures and enables multiplexed drug testing. Our approach offers a critical advantage over existing cell culture models in that it incorporates the native tumor environment and it also offers a precious alternative to animal tumor models in that it achieves cost-effective chemosensitivity readouts in a time-frame required for real-time therapeutic decision-making.
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