Chemotherapy is a primary therapy in many brain malignancies, but efficacy is limited by the low permeability of the blood-brain barrier (BBB) and blood-tumor barrier. The overall hypothesis guiding the OHSU Blood-Brain Barrier Program for the past three decades has been that increasing chemotherapy delivery across the BBB and dose intensity within the cancer cells will improve anti-tumor efficacy. However, in addition to tumor cell toxicity, chemotherapy agents also induce oxidative stress in normal tissues causing toxic side effects such as ototoxicity and nephrotoxicity that can lead to dose reductions and decreased quality of life. The platinum-based chemotherapeutic cisplatin, commonly used for brain tumor therapy in pediatric patients, causes progressive hearing loss in over 80% of patients with medulloblastoma. We have investigated the use of thiols that mimic the activity of the endogenous antioxidant glutathione to protect against oxidative stress and to reduce chemotherapy toxicities. Our preclinical and clinical NIH-funded studies of chemoprotection with sodium thiosulfate (STS) have led to two Phase III cooperative group trials. The Children's Oncology Group (COG) trial ACCL0431 clearly showed that delayed STS protected against hearing loss in children receiving cisplatin, but also showed the need for further improvement in hearing protection.
In Specific Aim 1 we will investigate strategies to improve chemoprotection using both STS and N-acetylcysteine (NAC) against the toxicities of cisplatin and other alkylating chemotherapy. The COG trial and a trial conducted by the International Society of Pediatric Oncology both showed no impact of delayed STS on cisplatin efficacy in localized standard risk cancers; however, a small post hoc analysis of the COG trial did show tumor protection in patients with disseminated disease. We hypothesize that disseminated medulloblastoma will require further dose intensification and therefore additional chemoprotection strategies.
Specific Aim 2 will assess the impact of chemoprotection on chemotherapy efficacy in rat models of disseminated medulloblastoma and investigate mechanisms by which disseminated disease differs from localized tumors. We will investigate new approaches to improve chemotherapy efficacy by dose escalation, enhancing delivery with BBB disruption or increasing chemotherapy toxicity by depleting glutathione concentrations.
Specific Aim 3 will further translate our chemoprotection strategies to the clinic. We will conduct a phase I dose escalation study to determine the NAC dose that can safely be given in combination with STS to achieve plasma levels needed for chemoprotection, in children with localized disease who undergo treatment with cisplatin-based chemotherapy. In addition, we will determine the association between hearing and quality of life in a unique large cohort (n = 160) of childhood cancer survivors who were treated at a young age with cisplatin at OHSU. We hypothesize that by modulating the timing and route of administration of chemo-enhancers, chemotherapy, and chemoprotection, toxicity can be decreased while maintaining or increasing anti-tumor efficacy.
Chemoprotection with the thiols sodium thiosulfate and/or N-acetylcysteine may decrease the toxic side effects of chemotherapy. Conversely, chemotherapy efficacy may be improved by depleting the endogenous thiol glutathione. We will perform preclinical and clinical studies to assess the impact of modulating thiols in pediatric cancers inside and outside the brain, with a focus on medulloblastoma.
|Horváth, Andrea; Varallyay, Csanad G; Schwartz, Daniel et al. (2018) Quantitative comparison of delayed ferumoxytol T1 enhancement with immediate gadoteridol enhancement in high grade gliomas. Magn Reson Med 80:224-230|
|Brock, Penelope R; Maibach, Rudolf; Childs, Margaret et al. (2018) Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. N Engl J Med 378:2376-2385|
|Varallyay, Csanad G; Nesbit, Eric; Horvath, Andrea et al. (2018) Cerebral blood volume mapping with ferumoxytol in dynamic susceptibility contrast perfusion MRI: Comparison to standard of care. J Magn Reson Imaging 48:441-448|
|Ambady, P; Wu, Y J; Walker, J M et al. (2017) Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors. Cancer Gene Ther 24:348-357|
|McConnell, Heather L; Kersch, Cymon N; Woltjer, Randall L et al. (2017) The Translational Significance of the Neurovascular Unit. J Biol Chem 292:762-770|
|Varallyay, C G; Toth, G B; Fu, R et al. (2017) What Does the Boxed Warning Tell Us? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent. AJNR Am J Neuroradiol 38:1297-1302|
|Dósa, Edit; Heltai, Krisztina; Radovits, Tamás et al. (2017) Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency. Fluids Barriers CNS 14:26|
|Wu, Yingjen Jeffrey; Pagel, Michael A; Muldoon, Leslie L et al. (2017) High ?v Integrin Level of Cancer Cells Is Associated with Development of Brain Metastasis in Athymic Rats. Anticancer Res 37:4029-4040|
|Neuwelt, Alexander J; Nguyen, Tam; Wu, Y Jeffrey et al. (2014) Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors. Pediatr Blood Cancer 61:120-7|
|Thompson, Eric M; Dosa, Edit; Kraemer, Dale F et al. (2010) Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery 67:87-93|