Major Scientific Accomplishments
- Isolation and characterization of a novel gene, PTEN, which is mutated or deleted in up to 60% of malignant gliomas, but is not involved in low-grade gliomas. (Drs. S. Bigner, R. Parsons, A. Rasheed, D. Bigner)
- Definition of the major cytogenetic abnormalities in malignant human gliomas; i.e., gains of chromosome 7, losses of chromosome 10, structural abnormalities of 9p and the presence of double-minute chromosomes in 40% of cases. (Drs. S. Bigner, H. Friedman, A. Friedman, D. Bigner)
- Discovery in human gliomas of an amplified new gene, gli, an oncogene that encodes a nuclear protein. Preparation of specific monoclonal and polyclonal antibodies to the gli gene product. (Drs. S. Bigner, B. Vogelstein, D. Bigner)
- Demonstration that c-myc is the most common, amplified oncogene in medulloblastoma and is likely to be associated with adverse prognosis. (Drs. S. Bigner, H. Friedman, D. Bigner)
- Confirmation of amplification and rearrangement of the c-erb oncogene in 40% of patients with malignant gliomas, and characterization of abnormal gene products of this epidermal growth factor receptor (EGFR) gene, including an example of a truncated, potentially self-firing EGFR. Identification and sequencing of rearranged EGFR genes, their deletion-mutant gene products, and preparation of highly specific monoclonal antibodies to the unique tumor-specific sequences of EGFRvIII. (Drs. D. Bigner, S. Bigner, B. Vogelstein, A. Wong)
- Demonstration that 50% of biopsy samples of human gliomas expressed the tumor-associated variant of EGFRvIII on the cell surface; receptor densities in excess of 2.5 x 105/cell, consistent with immunotargeting approaches, were identified. (Drs. C.J. Wikstrand, D. Bigner)
- Preparation and characterization of a single-chain Fv fragment (MR1) specific for a mutant epidermal growth factor receptor (mutant EGFRvIII); generation and characterization of MR1(scdsFv); generation of divalent form of MRI(scFv')2; generation of MR1(scFv) diabody. (Drs. D. Bigner, C.-T. Kuan, I. Pastan)
- Continuing development and characterization of one of the largest libraries of human glioma and medulloblastoma cell lines (>35) and of transplantable human xenografts of gliomas and medulloblastomas in the world (>45).
- Development of human xenograft models of carcinomatous meningitis from primary CNS tumors and other systemic carcinomas for preclinical evaluation of MAb and drug therapy.
- Demonstrated that CPT-11 plus BCNU produces marked synergistic activity against GBM xenografts. (Drs. H. Friedman, D. Bigner)
- Demonstrated that Intrathecal temozolomide and busulfan are active agents against human neoplastic meningitis. (Drs. H. Friedman, H. Fuchs)
- Discovery that the enzyme 06 alkyltransferase repairs a component of cyclophosphamide damage in tumors. (Drs. O. M. Colvin, H. Friedman)
- Established that the 10, 11-methyldioxycamptothecins are more potent against glioma cell lines than previous generations of camptothecins. (Drs. O.M. Colvin, H. Friedman)
- Demonstrated that 4-hydroxycyclophosphamide produces markedly synergistic toxicity with camptothecins against glioma cell lines. (Drs. O.M. Colvin, H. Friedman)
- Demonstrated that Navelbine is active against both cyclophosphamide-sensitive and -resistant medulloblastoma xenografts. (Drs. H. Friedman, O.M. Colvin, D. Bigner)
- Demonstrated that CPT-11 is active against recurrent and newly diagnosed GBM. (Drs. H. Friedman, A. Friedman)
- Demonstrated that O6-BG (IV) can deplete the AGT activity of intracranial tumors—specifically GBM. (Drs. H. Friedman, O.M. Colvin)
- Synthesis of the thymidine analogue 5-[211At]astato-2'-deoxyuridine and demonstration of its high cytotoxicity for human glioma cells. (Drs. M. Zalutsky, G. Akabani, D. Bigner)
- Demonstration that use of the positively charged labeling compound N-succinimidyl 5-iodo-3 pyridine carboxylate (SIPC) for iodination of anti-EGFRvIII MAbs resulted in increased intracellular retention of radiolabel as compared to iodination using Iodogen or N’-succinimidyl 3-iodobenzoate (SIB)
- Development of radiohalogenated biotin conjugates resistant to degradation by biotinidase for use in pretargeted radioimmunotherapy. (Dr. M. Zalutsky)
- Demonstration that use of hyperthermia increases uptake of an intact monoclonal antibody to tenascin in a human brain tumor xenograft model. The mechanisms underlying the increase in uptake have been shown not to be related to changes in antigen antibody binding or interstitial fluid pressure. (Drs. M. Dewhirst, M. Zalutsky, D. Bigner)
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- Development of a method for quantifying I-131 activity and activity concentrations in brain tumors using ultra-high resolution pinhole SPECT with validation using a phantom study. (Drs. R. Jaszczak, R. E. Coleman)
- Demonstration that SPECT can be used with 123I-labeled human albumin for determining volume of distribution following convection-enhanced delivery administration of radiolabeled monoclonal antibody into gliomas. (Drs. R. E. Coleman, R. Jaszczak)
- Demonstrated that Patient-specific dosimetry of 131I-labeled 81C6 is effective for? for the treatment of brain tumors (Drs. G. Akabani, D. Bigner, M. Zalutsky)
- Dosimetry of bone marrow for 211At-labeled antibodies and compounds (Drs. G. Akabani, M. Zalutsky)
- Successful conduct of Phase I and Phase II trials for both newly diagnosed and recurrent intracranial gliomas and metastases with 131I-labeled anti-tenascin 81C6 after intrathecal, intracystic, or surgically created cystic resection cavity administration.
- Successful conduct of a Phase I dose-escalation trial of 131I Mel-14 F(ab')2 for the treatment of neoplastic meningitis; one patient completely responded with no evidence of disease for more than five years after treatment.
- Successful conduct of a Phase I trial of intrathecal Melphalan for the treatment of neoplastic meningitis and demonstration of its activity.
- Successful conduct of a Phase I trial of CPT-11 Irinotecan (in recurrent malignant glioma patients) and demonstration of its activity.
- Successful conduct of a Phase I trial of Topotecan in newly diagnosed and recurrent glioma patients and demonstration of its activity.
- Discovery that the intra-arterial delivery of the alkylating agents 4 hydroperoxycyclophosphamide and melphalan was more effective in treatment of experimental tumors than intravenous administration.
- Immunologic characterization of the epidermal growth factor receptor variant III (EGFRvIII) with polyvalent sera raised in rabbits and goats to the 14 mer synthetic peptide spanning the fusion junction of the in-frame deletion mutant. Demonstration that peptide immunization alone was not optimal for the production of EGFRvIII protein reactive antibodies in mice, rats, and macaques.
- Generation of monoclonal antibodies to EGFRvIII, which required immunization with the variant receptor as well as linear peptide. Specificity of these MAbs was established by recognition of variant receptor and lack of recognition of wild-type receptor by immunoprecipitation, immunoblot analysis, and immunohistochemical reactivity with antigen-defined tumor tissue. Definition of the epitope recognized by each of five anti-EGFRvIII MAbs in the 14 mer linear peptide used in immunization protocols.
- Demonstration of the rapid (within 20 minutes) internalization of the anti-EGFRvIII MAbs bound to surface antigen via the lysosomal pathway.
- Demonstration of EGFRvIII protein in biopsy tissue of glioblastoma multiforme patients by flow cytometry of freshly disaggregated tissue and immunohistochemical analysis of freshly frozen and formalin-fixed biopsy samples. Demonstration of EGFRvIII mRNA was demonstrated by RT-PCR; amplification of DNA was demonstrated by slot blot.
- Specific tumor localization of anti-EGFRvIII MAbs in athymic mouse xenograft models.
- Demonstration of the role of DNA mismatch deficiency in mediating procarbazine and other methylator resistance in GBM.
- Demonstration of the role of intrathecal busulfan in the treatment of human neoplastic in nude athymic rats.
- Initiation of Phase I studies of intrathecal busulfan for patients with neoplastic meningitis under an FDA IND permit.
- Demonstration of the lack of a role for nucleotide excision repair in mediating repair of phosphoramide mustard-induced DNA interstrand crosslinks.
- Demonstration of the enhanced activity of the combination of CPT-11 with BCNU or temozolomide in the treatment of malignant glioma xenografts in athymic nude mice.
- Demonstration of the role of O6-BG in restoring temozolomide sensitivity in patients with temozolomide-resistant malignant glioma.
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- Established carboplatin as an effective salvage therapy for pediatric patients with progressive low-grade glioma (Drs. D. Reardon, S. Gururangan and Friedman).
- Established temozolomide as an effective therapy for patients with progressive low-grade glioma.
- Established maximum tolerated dose and dose-limiting toxicity of temozolomide administered with 0-6 benzylguanine for patients with recurrent malignant glioma (Drs. D. Reardon, J. Quinn and Friedman).
- Generation of specific polyclonal sera and MAbs to GPNMB for quantitative and qualitative antigenic analysis of human biopsy samples; demonstration of GPNMB positivity in 56% of GBM and 75% of AA (73-case study) (Drs. D. Bigner, C.J. Wikstrand, and C-T Kuan).
- Generation of specific polyclonal sera and MAbs to MRP3 for quantitative and qualitative antigenic analysis of human biopsy samples; demonstration of MRP3 positivity in 89% of GBM and 83% of AA (34-case study) (Drs. D. Bigner, C. J. Wikstrand, and C-T Kuan).
- Generation of specific MAbs to the extracellular domain of somatostatin receptor 2A for quantitative and qualitative antigenic analysis of medulloblastoma ) (Drs. D. Bigner, C. J. Wikstrand, and C-T Kuan).
- Generation of anti-EGFRvIII MR1-1 scFv-CH3 minibody with superior affinity to the parental MR1-1 scFv (Drs. C-T Kuan, C. J.Wikstrand, and D. Bigner).
- Demonstration of a viral pathogenic mechanism at the level of translation control, construction and characterization of a novel oncolytic virus based on poliovirus, elucidation of the pathogenetic mechanism of provocation poliomyelitis, unraveling of the role of the poliovirus receptor (CD155) in poliopathogenesis and neuro-oncogenesis, discovery of a novel mechanism of translation control via internal ribosomal entry and its cell type specific restrictions in the human brain (Dr. M. Gromeier).
- 131I-labeled anti-tenascin monoclonal antibody 81C6 administered into the resection cavity of patients with newly diagnosed malignant glioma prolongs survival and is associated with a significantly lower rate debulking surgery for radionecrosis than other brachytherapy approaches (Drs. D. Reardon and D. Bigner).
- Demonstrated that TP-38, a recombinant protein composed of the EGFR ligand TGF-a and the Pseudomonas exotoxin PE-38, infused directly around the tumor bed of patients with recurrent malignant brain tumors via convection enhanced delivery, resulted in striking antitumor responses in some patients accompanied by minimal CNS impairment and no systemic toxicity (Drs. D. Reardon, D. Bigner, J. Sampson and I. Pastan).
- Demonstrated that Radiation boost dose of 44 Gy to the resection cavity perimeter by 131I-labeled anti-tenascin monoclonal antibody 81C6 optimizes tumor control while minimizing the risk of radionecrosis for patients with malignant glioma (Drs. D. Reardon, D. Bigner and G. Akabani).
- Established maximum tolerated dose and dose-limiting toxicity of 131I-labeled human/mouse chimeric anti-tenascin monoclonal antibody 81C6 administered into the resection cavity of patients with newly diagnosed and recurrent malignant glioma (Drs. D. Reardon and D. Bigner).
- Discovery that the locus of the human GSTP1 gene is polymorphic, molecular cloning of full-length cDNAs of three of the most common alleles from human glioma cells. the cloning of three allelic GSTP1 cDNAs and demonstration that the encoded allelic proteins to differ in their metabolic function. These findings have helped develop new research paradigms in molecular epidemiology, pharmacogenetics and toxicology.
- Demonstrated that aberrant over-expression and nuclear localization of the GSTP1 protein is a significant prognostic indicator in human gliomas and a predictor of poor patient survival.
- Discovery and characterized multiple cis- and trans- regulatory elements involved in GSTP1 gene regulation, including, p53, cAMP (CRE) and retinoic acid response elements (RAREs).
- Discovery of phosphorylation and metabolic activation of the GSTP1 protein by activated the ser/thr kinases, PKA and PKC as a novel mechanism of tumor drug resistance.
- Completed Rational design and development of first-generation lead GSTP1-targeted small molecule with potential as brain tumor therapeutics.
- Demonstration of GSTP1 and GSTT1 polymorphisms as negative prognostic indicators in human malignant astrocytomas.
- Demonstrated that deletions and rearrangements inactivate the p16INK4 gene in human glioma cells and are important structural/genetic alterations that play an important part in cell cycle arrest following treatment of the tumor cells with DNA damaging antiglioma agents, such as BCNU and cisplatin.
- Provided the first evidence that phosphorylation at specific tyrosines is a regulatory mechanism for O6-methylguanine-DNA methyltransferase in human glioma cells, providing for a direct link between protein kinases and MGMT as a novel mechanism of drug resistance and carcinogenesis mediated by MGMT.
- Demonstration that the DNA repair protein, O6-methylguanine-DNA methyltransferase, is a proteolytic target for the E6 human papillomavirus oncoprotein and that this may be a molecular basis of papillomavirus-associated oncogenesis.
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