Numerous clinical studies have established the debilitating side effects of cancer therapies on cognition, and the major impact that these cognitive impairments have on quality of life. For those patients afflicted with primary and metastatic brain tumors, radiotherapy in combination with chemotherapy is the frontline treatment and remains the only tenable option for providing a temporary restraint on disease progression. Both radiotherapy and chemotherapy are associated with serious, long-term cognitive side effects, and with major advances in early detection and treatment increasing numbers of patients diagnosed with cancer are surviving long-term. At present, there remain no satisfactory treatments for reducing the progressive adverse effects of radiation- and chemotherapy-induced brain injury. Here, we propose a comprehensive series of studies to investigate the translational potential and mechanistic basis underlying the capability of intracranial transplantation of a good manufacturing produced (GMP) human neural stem cell (hNSC) line to restore cognition in rats treated with clinically relevant doses of radiation and chemotherapy. Using a complementary approach, microvesicles secreted from GMP-derived hNSC will be cranially transplanted to ascertain the extent that this approach can ameliorate neurocognitive sequelae. For this proposal, we have focused on (1) the combined radiation and chemotherapy regimen most commonly used in brain cancer patients, (2) the use of a GMP-derived hNSC line that will hasten the translational applicability of our approach, and (3) a novel approach whereby microvesicles will be substituted for stem cells. Should microvesicles afford similar neurocognitive benefits then their usage would preclude any risks of teratoma formation and limit immunorejection, factors that can complicate certain cellular transplantation strategies. Preliminary data has shown that irradiation and chemotherapy both increase neuroinflammation and compromise the structural integrity of neurons and the microvasculature. Preliminary data has shown that stem cells and microvesicles can reduce each of these adverse effects, and modify the surrounding microenvironment to reduce inflammation, preserve host neuronal morphology and improve microvasculature integrity. These studies will elucidate the neurobiological mechanisms that underlie observed cognitive changes, and determine the capability of transplanted stem cells or microvesicles to protect against these adverse effects. These data will provide critical information necessary to evaluate the translational potential of using such GMP derived stem cell and vesicle based strategies in the clinic to treat a devastating side effect of cancer therapy.
Numerous clinical studies have established the debilitating effects of radiotherapy and chemotherapy on cognition, with severe impairments in cognition persisting long after the cessation of treatment in as many as 75% of cancer survivors. To date, these problems persist, with an ever-growing number of cancer survivors suffering without any long-term satisfactory solutions to this unmet medical need. To directly address this problem, we will implement a series of cranial transplantation strategies using good manufacturing produced human neural stem cells and secreted microvesicles to ameliorate radiation and chemotherapy induced cognitive dysfunction. We posit that engrafted cells in the brain will impart long-lasting cognitive benefits by protecting neuronal structure and the integrity of the vascular bed while reducing neuroinflammation. These studies will deepen our understanding of the neurobiological mechanisms of cognitive decline, while testing a tractable translational strategy for attenuating the adverse neurocognitive side effects of radiation and chemotherapy.
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