A restrictive receptor (R) for interleukin 13 (IL13) was found in a vast majority of human high-grade (grade Ill and IV) astrocytoma (HGA) specimens in situ, but not in low-grade (grade I and II) astrocytomas or brain tumors of non-glial origin. The HGA-associated restrictive receptor for IL 13 was identified molecularly to be IL13Ra2, a 45-kDa plasma membrane protein most of which is its extracellular domain. IL13Ra2 was also found to be a cancer/testis tumor antigen (CTA). By definition, CTAs provide extremely high specificity for molecular targeting/recognition of cancer. Moreover, IL13-based bacterial toxin-containing cytotoxins were shown to be arguably most potent anti-glioma agents in pre-clinical evaluation and they have entered or are being developed for clinical trials. Furthermore, IL13's structure-function relationship analysis revealed several macro-regions important for its interaction with respective receptors that are present in transformed cells or normal organs. It is proposed to continue the mutational analysis of ILl 3 to identify precisely the molecular requirements to bind its respective receptors, and to an HGA-associated receptor in particular. One region of IL13, a ct-helix D, appears to be pivotal for the 1113 binding to an HGA-associated receptor and will be the subject of detailed structural analysis. Guided with the results of such experiments, the minimization of the size of the ligand with an ability to bind IL13Ra2 will be attempted. Furthermore, the search will begin for small molecules that are interactive with the HGA-associated receptor. The next generation(s) of cytotoxins are expected to be developed in the course of experiments on IL13 structure-function relationship. Several members of the now third generation of IL 13 cytotoxins, based on multiply-mutated cytokine, will be. thoroughly evaluated in vivo, since they exhibit the preservation of potent cytotoxicity on HGA cells while being much less toxic than cytotoxins based on wild type or singly-mutated IL13. The whole IL13 system be it ligand or receptor is of highest interest from the experimental therapeutic point of view, since the target (ILl 3Rcx2) is very specific to HGA and the ligand (IL13) is amenable to a variety of modifications for the purpose of specific molecular targeting of this incurable malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074145-05
Application #
6624298
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Hecht, Toby T
Project Start
1998-07-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$245,875
Indirect Cost
Name
Pennsylvania State University
Department
Surgery
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Sattiraju, Anirudh; Solingapuram Sai, Kiran Kumar; Xuan, Ang et al. (2017) IL13RA2 targeted alpha particle therapy against glioblastomas. Oncotarget 8:42997-43007
Sonawane, Poonam; Choi, Young A; Pandya, Hetal et al. (2017) Novel Molecular Multilevel Targeted Antitumor Agents. Cancer Transl Med 3:69-79
Sai, Kiran Kumar Solingapuram; Sattiraju, Anirudh; Almaguel, Frankis G et al. (2017) Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker. Oncotarget 8:50997-51007
Ferluga, Sara; Tomé, Carla Maria Lema; Herpai, Denise Mazess et al. (2016) Simultaneous targeting of Eph receptors in glioblastoma. Oncotarget 7:59860-59876
Ferluga, Sara; Hantgan, Roy; Goldgur, Yehuda et al. (2013) Biological and structural characterization of glycosylation on ephrin-A1, a preferred ligand for EphA2 receptor tyrosine kinase. J Biol Chem 288:18448-57
Debinski, Waldemar; Dickinson, Peter; Rossmeisl, John H et al. (2013) New agents for targeting of IL-13RA2 expressed in primary human and canine brain tumors. PLoS One 8:e77719
Beauchamp, Amanda; Lively, Mark O; Mintz, Akiva et al. (2012) EphrinA1 is released in three forms from cancer cells by matrix metalloproteases. Mol Cell Biol 32:3253-64
Lema Tomé, Carla M; Palma, Enzo; Ferluga, Sara et al. (2012) Structural and functional characterization of monomeric EphrinA1 binding site to EphA2 receptor. J Biol Chem 287:14012-22
Pandya, Hetal; Debinski, Waldemar (2012) Toward intracellular targeted delivery of cancer therapeutics: progress and clinical outlook for brain tumor therapy. BioDrugs 26:235-44
Pandya, Hetal; Gibo, Denise M; Garg, Shivank et al. (2012) An interleukin 13 receptor ? 2-specific peptide homes to human Glioblastoma multiforme xenografts. Neuro Oncol 14:6-18

Showing the most recent 10 out of 31 publications