All ETDs from UAB

Advisory Committee Chair

Suzanne E Lapi

Advisory Committee Members

Douglas Hurst

Douglas Hurst

William J Placzek

Anna Sorace

Jason Warram

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Breast cancer is one of the most common and deadly cancers diagnosed in women each year. The HER2-positive subtype of breast cancer is associated with poor prognosis and lower progression-free survival. Early identification of HER2 expression is extremely important for the effective treatment of the disease. Current methods to diagnose HER2-positive breast cancer involve invasive biopsies to semi-quantitatively determine the amount of HER2 expression. However, many lesions are often unavailable for biopsy due to their location and there may be variable HER2 expression between the primary tumor and metastasis. Positron emission tomography (PET) can give a full-body, non-invasive evaluation of HER2 expression in patients with breast cancer. Current clinical trials for PET imaging of HER2 use one of two antibodies, [89Zr]trastuzumab and [89Zr]pertuzumab, to evaluate potential HER2-positive lesions. While both antibodies show high affinity for HER2, there are challenges associated with antibody-based PET imaging including a 4-7 day post-injection wait period before clear image acquisition can occur which creates logistic challenges for both patients and clinics. Expanding the PET imaging capabilities by developing other radiotracer strategies can results in faster injection-to-image time, decreased dose to the patient, and quicker choices for optimal therapy. This project evaluated three different radiotracer strategies for HER2 imaging capabilities including the DOTA-PEG2-GSGKCCYSL and DOTA-PEG2-DTFPYL GWWNPNEYRY peptides, the 2Rs15d nanobody, and trastuzumab-coated polymersomes. All radiotracers evaluated were developed for high radiolabeling efficiency and ability to target HER2 in vitro. The peptides and nanobody also showed the ability to target HER2-positive tumors in vivo. The peptides had rapid injection-to-image acquisition and were able to utilize the short-lived radioisotope 68Ga. 2Rs15d showed the highest in vivo binding to HER2-positive tumors at 48 hours post-injection. Lastly, the trastuzumab-coated polymersomes showed the highest in vitro binding to HER2-positive cells, paving the way for future development for HER2 PET imaging. The expansion of new radiotracers for targeted HER2-positive PET imaging improves diagnostic capabilities while paving the way for potential future development of radiotherapeutics utilizing these same imaging agents.

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