We are proposing a new approach to treating brain tumors utilizing local controlled delivery via biodegradable polymers of effective agents directly to the site of the tumor. During the prior granting period we tested the hypothesis that local sustained treatment by delivery of such agents directly at the tumor site via biodegradable controlled release polymers would be more effective than systemic therapy. We developed polymer/drug complexes; and, after extensive preclinical studies in animal models that established their biocompatibility, safety, and effectiveness, we conducted Phase l - 3 clinical trials with a BCNU-polymer implant devised through the collaborative efforts of this NCDDG. We have, in collaboration with the other programs of this NCDDG, developed new polymers with new effective agents and demonstrated their safety and improved efficacy for treating brain tumors. We are now in a position to build on the gains made in the past 4 years to test our hypotheses that the optimal direct tumor delivery of an effective agent will improve outcome without the side effects of systemic therapy and that combinations of agents and/or biological approaches will be more effective than single agents.
Our specific aims are:
Aim l: To test the effectiveness of new biodegradable polymers by (a) evaluating their safety in the brain; and (b) assessing their effectiveness when utilized with established drugs against rat brain tumors.
Aim 2 : To test the effectiveness of newly developed antitumor drugs by (a) determining their release kinetics from various polymers and their efficacy in vitro; (b) evaluating the new drug polymer combination for neurotoxicity and establishing the maximum tolerated dose; (c) evaluating the effectiveness in the rat 9L glioma model; and (d) efficacy against human xenografts in the nude rat.
Aim 3 : To explore combinations of drugs and other treatments, including (a) investigating radiosensitizers in combination with external radiation; (b) utilizing antiangiogenic agents, immunotoxins, and cytokines, with chemotherapeutic and other biological agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
3U19CA052857-10S1
Application #
6396796
Study Section
Project Start
1999-07-26
Project End
2000-09-30
Budget Start
Budget End
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Gabikian, Patrik; Tyler, Betty M; Zhang, Irma et al. (2014) Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres. J Neurosurg 120:1078-85
Tyler, Betty; Wadsworth, Scott; Recinos, Violette et al. (2011) Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats. Neuro Oncol 13:700-9
Slager, Joram; Tyler, Betty; Shikanov, Ariella et al. (2009) Local controlled delivery of anti-neoplastic RNAse to the brain. Pharm Res 26:1838-46
Pradilla, Gustavo; Wang, Paul P; Gabikian, Patrik et al. (2006) Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model. J Neurooncol 76:131-8
Sampath, Prakash; Rhines, Laurence D; DiMeco, Francesco et al. (2006) Interstitial docetaxel (taxotere), carmustine and combined interstitial therapy: a novel treatment for experimental malignant glioma. J Neurooncol 80:9-17
Legnani, Federico G; Pradilla, Gustavo; Thai, Quoc-Anh et al. (2006) Lactacystin exhibits potent anti-tumor activity in an animal model of malignant glioma when administered via controlled-release polymers. J Neurooncol 77:225-32
Li, Yawen; Ho Duc, Hong Linh; Tyler, Betty et al. (2005) In vivo delivery of BCNU from a MEMS device to a tumor model. J Control Release 106:138-45
Sorg, Brian S; Peltz, Cathryn D; Klitzman, Bruce et al. (2005) Method for improved accuracy in endogenous urea recovery marker calibrations for microdialysis in tumors. J Pharmacol Toxicol Methods 52:341-9
Li, Yawen; Shawgo, Rebecca S; Tyler, Betty et al. (2004) In vivo release from a drug delivery MEMS device. J Control Release 100:211-9
Li, Khan W; Dang, Wenbin; Tyler, Betty M et al. (2003) Polilactofate microspheres for Paclitaxel delivery to central nervous system malignancies. Clin Cancer Res 9:3441-7

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