Wednesday, April 2, 2025
4/2/2025
Novel MUC1 Theranostic Peptides for Imaging and Treatment of Triple-Negative Breast Cancer - ABSTRACT. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by a poor overall prognosis, aggressive and early pattern of metastases, and a lack of treatments that lead to sustained disease control. There is a critical need for molecular targeted treatments for patients with TNBC that are more effective, have reduced side effects, and decrease the mortality associated with TNBC. Mucin-1 (MUC1) is overexpressed and underglycosylated in 94% of TNBC and the receptor density is extremely high. The combination of the modification of the glycosylation and overexpression allow tumor associated MUC1 distinguishable and targetable from normal tissue. Targeted radionuclide therapy (TRT) is a molecular targeted treatment that specifically uses radiolabeled moieties as biological targeting vectors intended to deliver localized cytotoxic radiation to cancer cells that overexpress specific receptors, without harming normal cells. We propose to combine the suitability of MUC1 as a therapeutic target in TNBC with the promising technique of TRT to develop a novel theranostic peptide for diagnostic imaging and TRT of TNBC. The aims of this proposal are to develop MUC1 targeted peptides that can successfully be applied for TRT, exhibiting properties suitable for clinical translation. The advantages of peptides over previously studied antibody radioisotope complexes include the superior pharmacokinetics, low immunogenicity, and ease of synthesis for widespread application. In Aim 1 we will determine the mechanism and specificity of peptide binding, optimize the incorporation of a metal chelator through various spacer moieties, and employ different cyclization strategies to improve peptide affinity and stability. In Aim 2 we will radiolabel three peptide sequences with promising binding affinities with gallium-68 and lutetium-177. We will complete a comprehensive analysis of binding and internalization in TNBC cells, and determine in vivo tumor targeting properties and biodsitribution in mouse models of TNBC. In Aim 3, we will advance the most promising peptide sequence, identified through quantitative metrics, to therapeutic studies and determine the ability of MUC1 TRT to treat TNBC in mouse models. We will additionally complete a preliminary safety assessment. Through these studies we will also understand any issues related to proceeding with clinical translation of the MUC1 theranostic peptide for application in TNBC. Given the morbidity and mortality associated with TNBC and the critical need for targeted treatments, this MUC1 TRT will have high impact for the treatment and management of TNBC. We will provide proof of concept that MUC1 is a valid therapeutic target and that TRT can effectively treat TNBC. We intend for our results to lay the foundation for subsequent development of randomized, controlled clinical trials that test this promising treatment in patients with TNBC. If successful, this will be a significant step forward for reducing the mortality associated with TNBC.
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