The overall hypothesis guiding the OHSU Blood-Brain Barrier (BBB) Program for the past three decades has been that the BBB and blood-tumor barrier, as well as the blood-cerebral spinal fluid (CSF) barrier, limit agent delivery and therefore dose intensity in brain tumors. We have tested the hypothesis that increased dose intensity may be achieved by increasing drug delivery to brain tumor with osmotic BBB disruption (BBBD). Another approach to increasing dose intensity is to deplete glutathione, an endogenous anti-oxidant which inactivates alkylating chemotherapeutics. Since dose intensification can increase chemotherapy toxic side effects, we will use thiols that mimic the activity of glutathione, including sodium thiosulfate and N- acetylcysteine, to reduce chemotherapy toxicities, as we have during the last 8 years of this Javits Award.
In Specific Aim 1 of this revised proposal, we will assess the potential for enhancing chemotherapy dose intensity for intracerebral medulloblastoma as a model of primitive neuroectodermal tumors within brain parenchyma, by using BBBD and by depleting glutathione stores in conjunctions with thiol rescue. Additionally we will evaluate new imaging techniques for assessing efficacy in solid brain tumors. These studies will test the hypothesis that lowering glutathione concentrations will safely improve alkylating chemotherapy efficacy.
Specific Aim 2 will utilize the chemo-enhancement and protection strategies of Aim 1 to improve alkylating chemotherapy efficacy against disseminated medulloblastoma in the leptomeninges and CSF, and will use novel imaging techniques to monitor hydrocephalus and chemotherapy efficacy.
Specific Aim 3 will evaluate thiol chemoprotection for models of platinum-induced ototoxicity. We hypothesize that thiol chemoprotection separated from chemotherapy by timing, route of administration, and utilizing the neurovascular barriers, will allow increased chemotherapy doses while reducing chemotherapy toxicity in normal tissues.
Specific Aim 4 will translate the chemoprotection and enhanced delivery into a Phase I/II clinical trial in CNS embryonal tumors. Our overall hypothesis is that by modulating the timing and route of administration of chemo-enhancers, chemotherapy, and chemoprotection, toxicity at the blood-neural barriers can be decreased while increasing anti-tumor efficacy.

Public Health Relevance

We hypothesize that increased dose intensity in chemotherapy sensitive brain tumors such as primitive neuroectodermal tumors (PNET), may be achieved by increasing drug activity using chemo-enhancers, decreasing non-specific drug cytotoxicity using chemoprotectors that do not cross the blood-brain barrier (BBB), and increasing chemotherapy drug delivery to brain tumor with osmotic BBB disruption. Aims 1-3 are preclinical studies of modulating glutathione, and aim 4 will be clinical trials of thiol chemoprotection with the goal of testing chemo-enhancement in brain tumor subjects.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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Oregon Health and Science University
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Muldoon, Leslie L; Wu, Y Jeffrey; Pagel, Michael A et al. (2015) N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models. J Neurooncol 121:433-40
Doolittle, Nancy D; Muldoon, Leslie L; Culp, Aliana Y et al. (2014) Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances. Adv Pharmacol 71:203-43
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Wu, Ying-Jen Jeffrey; Neuwelt, Alexander J; Muldoon, Leslie L et al. (2013) Acetaminophen enhances cisplatin- and paclitaxel-mediated cytotoxicity to SKOV3 human ovarian carcinoma. Anticancer Res 33:2391-400
Thompson, Eric M; Pishko, Gregory L; Muldoon, Leslie L et al. (2013) Inhibition of SUR1 decreases the vascular permeability of cerebral metastases. Neoplasia 15:535-43
Muldoon, Leslie L; Gahramanov, Seymur; Li, Xin et al. (2011) Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models. Neuro Oncol 13:51-60
Gahramanov, Seymur; Raslan, Ahmed M; Muldoon, Leslie L et al. (2011) Potential for differentiation of pseudoprogression from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol vs. gadoteridol: a pilot study. Int J Radiat Oncol Biol Phys 79:514-23

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