Physicians need rapid and specific histopathologic diagnoses for their cancer patients. For example, open surgical biopsies may contain diagnostic information bearing on intraoperative decisions such as surgical resection vs conservative treatment. But standard rapid diagnosis by frozen section may not discriminate between relevant pathologies. Standard specific diagnosis by immunohistochemistry (IHC) can take days to provide these data. This situation may deny information critical for good decision making at open biopsy. For example, small cell astrocytomas and central nervous system lymphomas are difficult to distinguish on frozen section. Astrocytomas require aggressive resection, but lymphomas are best left unresected. Misdiagnosis could lead to unnecessary resection of eloquent brain or missed aggressive resection of an invasive malignant tumor. A method that rapidly provides relevant diagnostic information will improve clinical care. This project develops nanoprobes that rapidly provide diagnostic histopathologic information from fresh tumor biopsies. Aptamers are an emerging class of polynucleotides easily engineered to identify specific molecular targets. Recent methods let aptamers switch conformation when they bind a target, and this change can provide imaging contrast. Our project aims to generate switchable aptamer contrast agents that detect clinically relevant extracellular and intracellular IHC targets Aim 1 develops a switchable aptamer that rapidly detects the extracellular marker for human central nervous system lymphoma in fresh xenograft tissue biopsies.
Aim 2 develops a switchable aptamer against the intracellular astrocytoma marker glial fibrillary acid protein (GFAP). We plan to rapidly deliver the GFAP-specific aptamer to intracellular space using a DNA tetrahedron nanostructure.
Both aims optimize rapid aptamer-based labeling of xenograft biopsies. This project develops switchable aptamers as contrast agents for rapid IHC-quality labeling. Our future plan is to develop a clinical trial evaluating aptamer-based diagnostics on intraoperative decision-making during initial craniotomy for brain diagnosis and/or resection. This proposal brings together physicians and scientists from the Barrow Neurological Institute (BNI) and Arizona State University's (ASU) Biodesign Institute. BNI is the largest Neurosurgery residency program in North America and cares for one of the largest volumes of brain tumor patients in the United States. BNI has been a leader in advancing fluorescence imaging tools for brain tumor imaging, and is the only North American center with an advanced Zeiss LSM710/5LiveDUO confocal microscope situated in the pathology department. The Biodesign Institute has been a leader in developing DNA nanotechnology, and its Center for Molecular Design and Biomimetics is innovating the use of DNA as structural material. This collaboration between BNI and the Biodesign Institute will develop an innovative class of nanomolecules for the rapid diagnosis, and improved care of cancer patients.

Public Health Relevance

Treatment for cancer patients often relies on definitive histopathological diagnosis from biopsies; however, time-consuming specific stains utilized to make these diagnoses can increase patient morbidity and health care costs by delaying implementation of treatment plans. Aptamers are a newer class of nanomolecules that quickly bind molecular targets to produce labeling similar to specific clinical stains. This project develops novel switchable fluorescent aptamer-based molecular nanoprobes for rapid histopathological detection of cancer- specific cellular markers in biopsies, thereby developing an innovative tool for improving patient care.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB020237-02
Application #
9222010
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Krosnick, Steven
Project Start
2016-03-01
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$159,773
Indirect Cost
$20,174
Name
Arizona State University-Tempe Campus
Department
Miscellaneous
Type
Organized Research Units
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Joy, Anna; Kapoor, Manisha; Georges, Joseph et al. (2016) The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression. J Neurooncol 130:43-52