Patients with glioblastoma (GBM) have dismal prognosis and GBM represents an unmet need in medicine. In our search for molecular targets in GBM, we discovered a plasma membrane receptor, interleukin 13 receptor alpha 2 (IL-13RA2), which is over-expressed in vast majority of patients (protein: >70%; gene: 58%), but not in normal brain. The receptor is over-expressed preferentially in a mesenchymal subgroup of GBM and may be also important for glioma stem-like cells pathobiology. Thus far, this receptor has served clinical development of several therapeutic approaches, because it is a very specific and attractive target for diagnosing, imaging and treatment of IL-13RA2 expressing malignancies, including melanoma and other aggressive peripheral tumors. With the help of this currently held grant, we have generated novel agents that recognize IL-13RA2 and they are amenable to translational efforts in order to better manage cancer. Firstly, in proof-of-concept study, a double-level targeted agent, which is composed of IL-13RA2 receptor-recognition unit (IL-13.E13K, a mutated form of native ligand), a portion of a bacterial toxin that enables cytosolic transport (D2) and a nuclear localization signal (NLS) IL-13.E13K-D2-NLS-Cys, was conjugated to a modified Doxorubicin (WP936). IL- 13.E13K-D2-NLS-Cys[WP936] conjugate showed distinct advantages over the treatment with WP936 alone on GBM cells. This opens a novel way of delivering drugs/labels not only to a targeted subpopulation of cells, but also directly to their intracellular site of action. Secondly, we have isolated a small peptide, Pep-1-L which binds specifically IL-13RA2, induces its internalization and the binding is not competed for by either native ligand or anti-IL-13RA2 antibody. We have also demonstrated that the peptide home to peripheral and intracranial tumors in mice when injected systemically. Thirdly, we have raised monoclonal antibody 1E10B9, which recognizes specifically IL-13RA2 in various immunoreactivity assays in tissue specimens and live cells. We plan on taking a full advantage of these novel agents for the purpose of monitored effective treatment of malignancies over-expressing IL-13RA2 by executing three Specific Aims.
In Aim 1, we will continue developing drug conjugates with intrinsic property of delivering drugs to their site of action in cancer cells We will use a blood-brain barrier-penetrating anthracyclin, Berubicin, for conjugation to our novel drug delivery vectors.
In Aim 2, we will exploit small peptides binding to IL-13RA2 for double-load combinatorial targeted therapy and monitoring of responses to therapy.
In Aim 3, we will generate recombinant fragments of antibody 1E10B9, optimize its binding, and equip with ADCC/CDC and CTLA4 or PD1 immune checkpoints blocking activity. We will also study the structural basis of Pep-1-L and 1E10B9 binding to IL-13RA2. The pre-clinical evaluation of these candidate drugs/imaging agent will be conducted in models of GBM and melanoma. We expect to generate novel, specific and potent therapeutics with a possibility to monitor their effectiveness against some of the most dreadful human malignancies, to be examined in patients in a foreseeable future.

Public Health Relevance

Glioblastoma (GBM) remains an incurable primary brain tumor. We identified a unique molecular target that is present in vast majority of patients with GBM, but not normal brain, and in some aggressive peripheral cancer metastasizing to brain. We have developed several novel therapeutic and imaging strategies based on new tools and drugs generated by us that have potential to change the management of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074145-20
Application #
9302682
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Salomon, Rachelle
Project Start
1998-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
20
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Surgery
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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

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