As with most solid tumors, clinical efficacy with cytotoxic chemotherapy compounds has been discouraging for malignant gliomas, mostly because of systemic drug toxicities and delivery limitations. Because they are locally invasive and rarely metastasize, malignant gliomas have features of a local-regional disease that make them uniquely amenable to new strategies of regional drug delivery. Intracerebral clysis (ICC) is a novel drug delivery strategy that utilizes a microinfusion pump to establish a positive pressure gradient in the brain via an implanted catheter. The pressure gradient produces convective forces that distribute a therapeutic agent throughout the tumor and surrounding interstitial space in the brain. Our preliminary data has shown that glioma cells are sensitive to topoisomerase I inhibitors including topotecan at levels that can be achieved in vivo with ICC. Additionally, topotecan by ICC is expected to have reduced toxicity by virtue of reduced topoisomerase I levels in normal brain compared to gliomas. Although ineffective in clinical trials due to systemic toxicity, topotecan has been safe and effective in our rat glioma model using ICC. The safe use of ICC as a delivery method has already been validated in early human trials. These findings lead us to hypothesize that topotecan delivered by ICC will increase survival in patients with primary malignant brain tumors. Furthermore, non- invasive radiographic methods of monitoring drug distribution and treatment response have been developed which will maximize its clinical application. These data lead to the Specific Aims which are: (1) to evaluate the safety and efficacy of ICC therapy with topotecan in patients with refractory and progressive primary malignant brain tumors; (2) to apply advanced MR imaging as a non-invasive means of optimizing treatment parameters and determining volume of drug distribution with ICC; and (3) determine whether the expression of the topoisomerase target in the tumor influences its response to topotecan by analyzing tumor histopathology, topoisomerase I expression, and in vitro drug sensitivity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089395-05
Application #
7030906
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Wu, Roy S
Project Start
2002-05-01
Project End
2010-03-31
Budget Start
2006-05-03
Budget End
2010-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$469,759
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Surapaneni, Krishna; Kennedy, Benjamin C; Yanagihara, Ted K et al. (2015) Early Cerebral Blood Volume Changes Predict Progression After Convection-Enhanced Delivery of Topotecan for Recurrent Malignant Glioma. World Neurosurg 84:163-72
Anderson, Richard C E; Kennedy, Benjamin; Yanes, Candix L et al. (2013) Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children. J Neurosurg Pediatr 11:289-95
Lopez, Kim A; Tannenbaum, Aaron M; Assanah, Marcela C et al. (2011) Convection-enhanced delivery of topotecan into a PDGF-driven model of glioblastoma prolongs survival and ablates both tumor-initiating cells and recruited glial progenitors. Cancer Res 71:3963-71
Bruce, Jeffrey N; Fine, Robert L; Canoll, Peter et al. (2011) Regression of recurrent malignant gliomas with convection-enhanced delivery of topotecan. Neurosurgery 69:1272-9; discussion 1279-80
Sonabend, Adam M; Stuart, R Morgan; Yun, Jonathan et al. (2011) Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump. Neuro Oncol 13:886-93
Bohman, Leif-Erik; Swanson, Kristin R; Moore, Julia L et al. (2010) Magnetic resonance imaging characteristics of glioblastoma multiforme: implications for understanding glioma ontogeny. Neurosurgery 67:1319-27; discussion 1327-8
Joshi, Shailendra; Ornstein, Eugene; Bruce, Jeffrey N (2007) Targeting the brain: rationalizing the novel methods of drug delivery to the central nervous system. Neurocrit Care 6:200-12
Senatus, Patrick B; Li, Yin; Mandigo, Christopher et al. (2006) Restoration of p53 function for selective Fas-mediated apoptosis in human and rat glioma cells in vitro and in vivo by a p53 COOH-terminal peptide. Mol Cancer Ther 5:20-8
Chen, Johnson; Balmaceda, Casilda; Bruce, Jeffrey N et al. (2006) Tamoxifen paradoxically decreases paclitaxel deposition into cerebrospinal fluid of brain tumor patients. J Neurooncol 76:85-92
Lopez, Kim A; Waziri, Allen E; Canoll, Peter D et al. (2006) Convection-enhanced delivery in the treatment of malignant glioma. Neurol Res 28:542-8

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