Putting cancer in our sights

Over the past few decades, how we diagnose and treat cancer has completely transformed. Technology now enables us to probe, at a molecular level, the mechanisms that drive cancer cell growth, and design treatment strategies to specifically target those mechanisms. One approach that brings together these developments is theranostics. “Therapeutics” and “diagnostics” – theranostics  – uses targeted, non-toxic radioactive imaging agents to identify and characterize the disease, along with targeted but toxic radioactive drugs to treat the disease.¹

If You Can See Disease, You Can Treat Disease

The principle behind theranostics is simple: if you can see disease, you can treat disease. Theranostics was first developed in the 1940s, when radioactive iodine was used for both the imaging and treatment of hyperthyroidism and thyroid cancer. Four decades later, another breakthrough was made for the treatment of neuroendocrine tumors, which form in the body’s hormone-producing cells that help regulate growth, reproduction, and metabolism and occur, most commonly, in the small intestine, the pancreas, or the lungs. Researchers initially developed a single agent called indium-111 (¹¹¹In)-pentetreotide that was used for both imaging and treatment. Over the next several years, the approach was refined so that the agents used for imaging contained only one type of radioactive molecule, while the agents used for treatment contained a different radioactive molecule that was better at penetrating and killing the cancer cells. In 2018, the FDA approved LUTATHERA, the most advanced of these treatments, for neuroendocrine tumors.^2,3

More recently, this approach has been applied to prostate cancer [RD1], as most prostate tumors have high levels of a protein called prostate-specific membrane antigen (PSMA).^4,5 Scientists developed radioactive imaging agents and their therapeutic counterparts that are able to stick specifically to PSMA. These agents have been remarkably effective in patients with metastatic prostate cancer.⁶ Currently, both PSMA-targeted imaging and therapy are available to patients in Europe and Australia. In the US, two different PSMA imaging agents were recently approved by the FDA, and approval of the first therapeutic agent, called lutetium-177 (¹⁷⁷Lu)–PSMA-617, was just announced by the FDA on March 23, 2022.

One of the newest frontiers in this field is the development of theranostics that target a protein called fibroblast activation protein, or FAP.⁷ FAP is present in high amounts in the area that surrounds tumors, called the tumor microenvironment, and is known to help cancer cells thrive. Emerging data suggest that FAP-targeting theranostics could be a powerful tool for imaging and treating a wide variety of cancers, including pancreatic, esophageal, gastric, colorectal, breast, cervical, ovarian, and even some types of lymphoma and sarcoma.^8,9

The progress that has been made in theranostics since its inception nearly a century ago has accelerated over the last decade, ushering in a new era of cancer care based on targeted imaging and treatments. Thanks to these advances and the continued efforts of scientists and physicians, patients will continue to benefit from this exciting field for years to come.

References

1. Levine, R. & Krenning, E. P. Clinical History of the Theranostic Radionuclide Approach to Neuroendocrine Tumors and Other Types of Cancer: Historical Review Based on an Interview of Eric P. Krenning by Rachel Levine. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 58, 3s-9s, doi:10.2967/jnumed.116.186502 (2017).
2. Strosberg, J. R. et al. Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors. Journal of Clinical Oncology 39, 4112-4112, doi:10.1200/JCO.2021.39.15_suppl.4112 (2021).
3. Strosberg, J. et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. New England Journal of Medicine 376, 125-135, doi:10.1056/NEJMoa1607427 (2017).
4. Debnath, S. et al. PSMA-Targeting Imaging and Theranostic Agents-Current Status and Future Perspective. Int J Mol Sci 23, doi:10.3390/ijms23031158 (2022).
5. Brenner, W., Strobel, J. & Prasad, V. PSMA Theranostics: Is the Time Ripe to Pave the Way to Further Tumor Entities? Journal of nuclear medicine : official publication, Society of Nuclear Medicine 62, 1242-1243, doi:10.2967/jnumed.121.262737 (2021).
6. Sartor, O. et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. New England Journal of Medicine 385, 1091-1103, doi:10.1056/NEJMoa2107322 (2021).
7. Roustaei, H. et al. Could Fibroblast Activation Protein (FAP)-Specific Radioligands Be Considered as Pan-Tumor Agents? Contrast Media Mol Imaging 2022, 3948873, doi:10.1155/2022/3948873 (2022).
8. Meyer, C. et al. Radiation Dosimetry and Biodistribution of (68)Ga-FAPI-46 PET Imaging in Cancer Patients. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 61, 1171-1177, doi:10.2967/jnumed.119.236786 (2020).
9. Kuyumcu, S. et al. Safety of Fibroblast Activation Protein-Targeted Radionuclide Therapy by a Low-Dose Dosimetric Approach Using 177Lu-FAPI04. Clin Nucl Med 46, 641-646, doi:10.1097/rlu.0000000000003667 (2021).