Peptide Receptor Targeting in Cancer Therapy

Peptide receptor targeting has emerged as a highly specific and effective strategy for cancer therapy. This approach leverages the overexpression of specific receptors on cancer cells, allowing for the targeted delivery of therapeutic peptides or peptide-drug conjugates, PDCs. By binding to these receptors, peptides can deliver cytotoxic agents or radioactive isotopes directly to tumor cells, minimizing damage to surrounding healthy tissues.¹

Mechanism of Peptide Receptor Targeting

Cancer cells often overexpress certain G-protein-coupled receptors, GPCRs, or growth factor receptors, which can be targeted by peptide ligands. One prominent example is the use of somatostatin analogs to target somatostatin receptors in neuroendocrine tumors. Once the peptide binds to the receptor, the therapeutic payload, such as a cytotoxic drug or radioactive isotope, is internalized by the tumor cell, leading to cell death.²

Clinical Applications

Peptide receptor targeting is currently being applied in the treatment of several cancers, including prostate cancer, breast cancer, and neuroendocrine tumors. For example, the FDA-approved Lutetium Lu 177-dotatate is a radiolabeled somatostatin analog used for treating somatostatin receptor-positive neuroendocrine tumors. In prostate cancer, peptides targeting prostate-specific membrane antigen, PSMA), are used to deliver radioisotopes directly to tumor cells.³

Challenges and Future Directions

While peptide receptor targeting offers high specificity, challenges remain in optimizing the stability of peptide ligands and minimizing off-target effects. Advances in peptide engineering, including the use of non-natural amino acids and cyclization, are being explored to enhance peptide stability and binding affinity.⁴ Additionally, the use of combination therapies with peptides and immune checkpoint inhibitors is being investigated to improve overall therapeutic efficacy.⁵

Conclusion

Peptide receptor targeting represents a promising approach to cancer therapy, offering high specificity and reduced toxicity. Ongoing research is focused on optimizing peptide ligands and developing combination therapies to further improve patient outcomes.

Citations and Links

1. Reubi, Jean-Claude, and Emanuel E. Krenning. “Somatostatin Receptors as Targets for Nuclear Medicine Imaging and Radionuclide Treatment.” Journal of Nuclear Medicine, vol. 46, 2005, pp. 67S–75S.

2. Kwekkeboom, Dik J., et al. “Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors.” Nature Reviews Endocrinology, vol. 7, no. 2, 2011, pp. 103–111. doi:10.1038/nrendo.2010.197.

3. Morris, Michael J., et al. “Prospective Phase II Trial of Lutetium-177 PSMA Radioligand Therapy for Prostate Cancer.” Journal of Clinical Oncology, vol. 37, no. 23, 2019, pp. 1936–1944. doi:10.1200/JCO.18.02031.

4. Zhao, Lin, et al. “Non-natural Amino Acid Substitutions Enhance the Stability and Targeting Capabilities of Peptides in Cancer Therapy.” Peptide Science, vol. 105, no. 5, 2019, pp. 467–475. doi:10.1002/psc.3249.

5. Bailey, Joel R., et al. “Combination Therapy with Peptide Ligands and Immune Checkpoint Inhibitors: A New Approach to Cancer Treatment.” Frontiers in Oncology, vol. 9, 2019, p. 158. doi:10.3389/fonc.2019.00158.