Therapy for brain tumors is complicated by the blood-brain barrier (BBB), which impedes delivery of chemotherapeutic agents to the central nervous system (CNS). Osmotic BBB disruption (BBBD) is a method to deliver agents across the BBB to infiltrating tumor cells. The Brain Tumor Program Review Group (PRG) recently identified the areas of drug delivery,targeted chemotherapy, imaging, and the BBB as priorities forresearch in CNS metastases. During the previous funding period, we addressed the PRG points by showing that route of delivery of a tumor-specific immunoconjugate(BR96-DOX) is directly related to survival in an implanted metastasis model, and combination protocols with radiotherapy further improved survival. The current question is how to further extend this paradigm in the laboratory and the clinic by focusing on the BBB, ~to examine issues in delivery of antitumor agents to brain tumors and to evaluate the efficacy of therapeutic approaches.
In Aim 1, we plan to expand our current implanted CNS metastatic tumor model in nude rats to a hematogenous CNS metastatic model. We propose to assess tumor growth by using a novel magnetic resonance (MR) imaging approach using super- paramagnetic iron particles to detect CNS tumors prior to conventionalimaging.
Aim 2 will investigatetherapeutic approaches for CNS metastases. We will determine if protein bindingimpactsCNS chemotherapeutic delivery and efficacy. Additionally, we will assess targeted delivery of the BR96-DOX immunoconjugate used in conjunction with standard chemotherapy and external beam radiotherapy.
In Aim 3 we will test the hypothesis that the thiol N- acetylcysteine (NAC) with or without sodium thiosulfate (STS), may ameliorate the bone marrow toxicity of combination chemotherapy/radiation protocols without compromising CNS chemotherapyefficacy. Finally,in Aim 4 a clinical phase 1trial of NAC is proposed. We hypothesize that NAC administered i.a. caudallyin the aorta will be safe in patients and prevent myelosuppresion in combination with high dose chemotherapy given into the vertebral and carotid arteries cephalad. Our overall hypothesis is that CNS enhanced delivery and combination therapies in models of CNS metastasis will increase anti-tumor efficacy as assessed by serial MR imaging, tumor volumetrics, and survival, whileminimizingtoxicity withchemoprotection. Laboratory studies of BBBD-enhanced chemotherapy have been translated intoclinical trials, and excitingefficacy has been demonstrated in primary CNS lymphoma. This revised competitive renewal is the continuation of the original 1978 surgical CREG, and is responsive to the priorities established in July 2000 by the joint NINDS and NCI Brain Tumor PRG.
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