Theranostic Approaches to Breast Cancer Using Image Guided Surgery and Adjuvant PTT

Breast cancer (BCa) remains a leading cause of mortality among women globally, and current therapeutic paradigms often fail to prevent tumor recurrence and metastasis. Despite surgical resection being a cornerstone of treatment, residual tumor cells after surgery and the immune suppressive tumor microenvironment pose significant barriers to long-term survival and remission. Our research aims to address these unmet needs by leveraging combined theranostic efficacies of AKRO-6qc. The AKRO-6qc was designed for the highly specific binding followed by activation by cysteine proteases, which are highly overexpressed virtually in all human solid tumors. In this application we demonstrate that AKRO-6qc not only is useful as a targeted Fluorescence Image- Guided Surgery (FIGS) agent but also has significant Photothermal Therapy (PTT) characteristics that when combined, i.e. FIGS/PTT, synergize to eradicate BCa in mouse models of BCa. Using an immunocompetent syngeneic mouse model of BCa this innovative approach is designed to enhance the precision of tumor removal, induce a robust immune response, and prevent metastasis. Our plan is supported by three specific aims the first two aims optimizing use of AKRO-6qc for this approach and then culminating with Aim 3, which demonstrates utility. Aim 3.1 involves assessing the efficacy of AKRO-6qc-targeted FIGS/PTT in extending animal survival, delaying tumor recurrence, and preventing local and distant metastasis. Using the 4T1/luc transfected BCa cell line, we will perform tumor excision followed by PTT on female BALB/c mice. The study will measure the impact on primary tumor removal, survival, and distant metastasis. Aim 3.2 focuses on elucidating the relationship between AKRO-6qc-targeted FIGS/PTT and immune response. We will investigate the impact of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) on the immunologic response to FIGS/PTT. Strategies to enhance the immune response through depletion of MDSCs and co-administration of immune checkpoint inhibitors will be explored. We expect that FIGS/PTT will significantly reduce tumor recurrence and metastasis, leading to extended survival. By modulating the immune response, we aim to achieve a durable clinical response, potentially transforming the therapeutic landscape for BCa. Our comprehensive approach combining advanced imaging, targeted therapy, and immune modulation holds promise for overcoming the current limitations in BCa treatment and may ultimately improve outcomes for female patients with BCa and potentially for all patients with solid cancers. Project Number: 1R01CA306944-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: James Basilion | Institution: CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OH | Award Amount: $630,108 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CTH-E (57)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11274960