High Grade Astrocytoma Specific Molecular Targeting

Pennsylvania State Univ Hershey Med Ctr, Hershey PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): 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.