We are proposing a fundamentally new approach for the treatment of malignant brain tumors. The discovery and development, by members of this NCDDG, of biodegradable and biocompatible controlled release polymers has enabled us to bypass the limitations of the blood-brain barrier and expose the growing brain tumor to high drug concentrations for extended intervals. This approach is not limited to the local, controlled administration of standard drugs, such as lipid-soluble carmustine (BCNU), but can effectively administer other chemotherapeutic agents as well as rationally designed new drugs. The local, prolonged release of drugs at the site of tumor growth exposes the tumor to high levels of the drug while minimizing systemic exposure and toxicity. Program I, headed by Dr. Henry Brem, will investigate the effectiveness and safety of new formulations of controlled-release drug delivery for the treatment of brain tumors. Program Ii, headed by Dr. Robert Langer, will provide new biodegradable polymers with better release kinetics as well as microencapsulated polymer formulations. Program II, headed by Dr. Robert Langer, will provide new biodegradable polymers with better release kinetics as well as microencapsulated polymer formulations. Program III, headed by Dr. W. Mark Saltzman, will construct mathematical models for predicting drug distribution and clearance in the brain. Program IV, headed by Dr. Mark Chasin, will develop new methods of preparation, scale up, and purification of the polymer and investigate in vitro drug release and polymer degradation. The five sections of this NCDDG have been working together as a cohesive, collaborative group over the past four years. This cooperative effort has allowed us to design and carry out a series of pre-clinical studies to evaluate this new, potentially curative, cancer treatment. Our effort has led to the initiation of two multi-institutional, Food and Drug Administration-approved clinical trials of BCNU_impregnated polymers for the treatment of recurrent malignant gliomas. We are hopeful that with the NCI support and participation we can continue to interact synergistically and develop fully the promise of this new approach.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (SRC (40))
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Johns Hopkins University
Schools of Medicine
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Tyler, Betty M; Hdeib, Alia; Caplan, Justin et al. (2012) Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel. J Neurosurg Spine 16:93-101
Tyler, Betty; Fowers, Kirk D; Li, Khan W et al. (2010) A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats. J Neurosurg 113:210-7
Slager, Joram; Tyler, Betty; Shikanov, Ariella et al. (2009) Local controlled delivery of anti-neoplastic RNAse to the brain. Pharm Res 26:1838-46
Brem, Sarah; Tyler, Betty; Li, Khan et al. (2007) Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model. Cancer Chemother Pharmacol 60:643-50
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
Hsu, Wesley; Lesniak, Maciej S; Tyler, Betty et al. (2005) Local delivery of interleukin-2 and adriamycin is synergistic in the treatment of experimental malignant glioma. J Neurooncol 74:135-40
Lesniak, Maciej S; Upadhyay, Urvashi; Goodwin, Rory et al. (2005) Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. Anticancer Res 25:3825-31
Lesniak, Maciej S; Gabikian, Patrick; Tyler, Betty M et al. (2004) Dexamethasone mediated inhibition of local IL-2 immunotherapy is dose dependent in experimental brain tumors. J Neurooncol 70:23-8
Sampath, Prakash; Amundson, Eric; Wall, Monroe E et al. (2003) Camptothecin analogs in malignant gliomas: comparative analysis and characterization. J Neurosurg 98:570-7
Lesniak, Maciej S; Tyler, Betty M; Pardoll, Drew M et al. (2003) Gene therapy for experimental brain tumors using a xenogenic cell line engineered to secrete hIL-2. J Neurooncol 64:155-60

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