HARNESSING CXCR4-TARGETING PEPTIDES FOR PRECISION ONCOLOGY: NEW AVENUES IN CANCER THERAPY AND DIAGNOSIS

Peptides are emerging as highly promising therapeutic agents, offering a combination of high specificity, low toxicity, and substantial structural versatility. These features render them ideal candidates for both diagnostic and therapeutic applications, particularly in the field of cancer research. In the context of clinical oncology, diagnostic techniques such as Positron Emission Tomography (PET) imaging and Liquid Biopsy enable precise tumor localization and real-time monitoring of disease progression. These strategies rely on the identification of suitable molecular targets. Among these, the C-X-C chemokine receptor 4 (CXCR4) is emerging as a particularly relevant target, given its overexpression in more than 30 types of solid and hematological tumors. In this perspective, our research group has developed a family of cyclic peptides that, inspired by the endogenous ligand CXCL12, function as potent, selective, and stable CXCR4 antagonists. The lead peptide, R54, was optimized during this doctoral work by replacing the native disulfide bond with more stable lactam linkages. Two parallel cyclization strategies were explored: a side chain-to-tail macrolactam approach led to the identification of promising candidates that retained high binding affinity and biological activity, while showing markedly improved stability under reductive conditions. A second strategy based on side chain-to-side chain lactam formation yielded peptide L10, which preserved the pharmacological profile of the parent compound and demonstrated enhanced resistance to reduction as well. Given their favorable properties, these peptides were employed in innovative diagnostic platforms. R54 was successfully used to decorate self-assembling amphiphilic dendrimers for PET imaging of CXCR4-overexpressing tumors, showing promising in vivo results in mice bearing CHO- CXCR4 xenografts. In parallel, L10 was incorporated into gold-coated photonic biosensors for the detection of CXCR4-overexpressing circulating tumor cells (CXCR4-CTCs), demonstrating selective recognition of CXCR4-positive tumor cells and providing a proof of concept for their potential clinical application. Together, these approaches lay the groundwork for innovative diagnostic tools with potential applications in precision oncology and real-time disease monitoring. Overall, this work contributes to the development of structurally optimized, high-affinity CXCR4-targeting peptides, opening new avenues for their application in cancer diagnostics and therapy within the context of precision oncology.