Abstract

The role of Core 2 is threefold: 1) the preclinical evaluation and analysis of drugs, peptides, MAbs and derived constructs, and activated immune cells for clinical application in terms of toxicity, stability, in vivo localization and therapeutic effect, generated in Projects 1, 2, and 3 of this SPORE and implemented clinically in Core 3; 2) the production of clinical grade MAb reagents; and 3) the preparation and submission of Investigational New Drug (IND) permit applications for all reagents of potential clinical utility. This Core provides a continuum from bench to clinical administration and assures the orderly progression and quality control of reagents in development that have characterized the development and implementation of our currently successful MAb reagents in Phase I and II clinical trials. The Functions/Specific Aims of Core 2 are as follows:
Specific Aim 1. Pro-clinical evaluation of intact, engineered, conjugated, and modified constructs of MAbs and immunoreagent batches currently under investigation in Core 3 of this SPORE in terms of in vivo stability, localization, and therapeutic effect in immunocompetent and athymic rodent tumor xenograft models, including subcutaneous and intracranial models.
Specific Aim 2. Pro-clinical analysis of derived peptides, drugs, and other moieties in terms of in vivo stabality, localization, and therapeutic effect in animal models as described in Aim 1 for any reagents of promise identified in Projects 1, 2, and 3.
Specific Aim 3. Pro-clinical evaluation and quality certification of all reagents (drug, peptide, MAb, and derived constructs) generated in Projects 1, 2, and 3 and under investigation in Core 3 of this SPORE. a. Quality control by performance of, or contract for, all assays for bacterial, fungal, viral, pyrogen, and DNA contamination, and general safety tests in vivo (Core 3 immunoreagents), b. Toxicity testing and analysis of drug, peptide, MAb-toxin conjugates, nuclide-MAb conjugates and their derivatives, and effector cells in animal models (normal and athymlc rodents; Projects 1, 2 and 3; Core 3). c Determination of the maximum tolerated doses (MTD) for all substances showing no toxicity and maximal stability and therapeutic effect in athymic and normal rat and mouse model systems (subcutaneous, intracranial, CNS tumor xenografts: Projects 1 and 2).
Specific Aim 4. Production of clinical grade reagents: Production of clinical grade MAb, antibody fragments, constructs, and conjugates in sufficient quantity for clinical trials conducted m Core 3. Small molecule inhibitors from Project 1 will be contracted out to GMP producers or the NCI RAID Program.
Specific Aim 5. Preparation and submission of IND permit applications for all proposed therapies developed in Projects 1, 2, and 3. As the pre-clinical development Core, Core 2 has fundamental support functions for Projects 1, 2, and 3, and Cores 1 and 3.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA108786-03
Application #
7286332
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$172,283
Indirect Cost

  Institution

Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Kurmasheva, Raushan T; Kurmashev, Dias; Reynolds, C Patrick et al. (2018) Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 65:
Lock, Richard; Carol, Hernan; Maris, John M et al. (2017) Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program. Pediatr Blood Cancer 64:
Kurmasheva, Raushan T; Sammons, Melissa; Favours, Edward et al. (2017) Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 64:
Kurmasheva, Raushan T; Gorlick, Richard; Kolb, E Anders et al. (2017) Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 64:
Attiyeh, Edward F; Maris, John M; Lock, Richard et al. (2016) Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program. Pediatr Blood Cancer 63:276-86
Gorlick, Richard; Kolb, E Anders; Keir, Stephen T et al. (2016) Initial Testing of NSC 750854, a Novel Purine Analog, Against Pediatric Tumor Models by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 63:443-50
Kang, Min H; Reynolds, C Patrick; Kolb, E Anders et al. (2016) Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 63:1744-52
Smith, Malcolm A; Hampton, Oliver A; Reynolds, C Patrick et al. (2015) Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673. Pediatr Blood Cancer 62:91-8
Krishnamachari, Bhuma; Il'yasova, Dora; Scheurer, Michael E et al. (2015) A pooled multisite analysis of the effects of atopic medical conditions in glioma risk in different ethnic groups. Ann Epidemiol 25:270-4
Sayour, Elias J; McLendon, Pat; McLendon, Roger et al. (2015) Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma. Cancer Immunol Immunother 64:419-27

Showing the most recent 10 out of 178 publications