Molecular therapy (also called targeted radionuclide therapy or molecular radiotherapy) involves a radioactive drug compound called a radiopharmaceutical that seeks and destroys cancer cells.
Most radiopharmaceuticals consist of a small amount of radioactive material — called a radionuclide — combined with a cell-targeting molecule. Some radionuclides have a natural ability to hone in on specific cells or biological processes and do not need to be combined or modified.
When injected into the patient’s bloodstream, the radiopharmaceutical travels to and delivers radiation directly to disease sites. Because it is highly selective in its ability to damage cancerous cells while limiting radiation exposure to healthy tissue, molecular therapy is known as a targeted therapy.
Molecular therapies offer promise as a vehicle for personalized treatment of cancer, because radiopharmaceuticals may potentially be tailored to the unique biologic characteristics of the patient and the molecular properties of the tumor.
In addition to the radiopharmaceuticals being used today to treat a variety of cancers — including advanced prostate cancer — researchers are working on developing and testing new radiopharmaceuticals.
Iodine-131 (I-131) is a radioactive material produced in a nuclear reactor that supplies medical isotopes for nuclear medicine procedures. At high, therapeutic doses the radioisotope can be injected intravenously to effectively penetrate and destroy tumor tissues with localized radiation. Your health care provider will take steps to protect your thyroid gland from being medicated. The radioisotope also gives off gamma particles that can be picked up by a specialized gamma camera in a molecular imaging procedure called scintigraphy. I-131 can be combined with a molecular compound that further personalizes therapy and isolates the radiotherapy to specific cells and their physiological functions.
Iodine-131 Meta-iodobenzylguanidine (I-131 MIBG) can also be used for both imaging and an anti-cancer radiotherapy. This radiopharmaceutical is specifically designed to treat neuroendocrine tumors with nerve cells that interact with the neurotransmitters of the sympathetic nervous system, such as adrenaline and noradrenaline, otherwise known as epinephrine and norepinephrine. The targeted therapy is able to find these tumors because the compound MIBG is very similar to noradrenaline and is transported into the nerve cells. I-131 MIBG can be administered by a nuclear medicine specialist to target and kill a range of neuroendocrine tumors, including neuroblastomas and phaeochromocytomas, located anywhere that these nerve cells reside. As a therapeutic dose of I-131 MIBG is injected into the body and localized in active tumors, the potent radioactive material destroys the affected tumors while sparing healthy surrounding tissues.
Peptide Receptor Radionuclide Therapy (PRRT)
Radiotherapies using peptide-receptor targeting radionuclides function in much the same way as other personalized therapies by pinpointing a particular physiological function that is overactive in tumor cells. Radiopeptides are analogs of natural hormones called somatostatins. Synthetic somatostatins like the man-made octreotide bind to somatostatin receptors in tumors and particularly neuroendocrine tumors of the bowel, stomach, lung, pancreas and other organs of the neuroendocrine system. PRRT combines a therapeutic dose of a radioactive source, such as Yttrium-90, Indium-111 and lutetium 177 and octreotide to kill different kinds of tumors depending on their stage, structure and depth.
Radioimmunotherapy (RIT) is another type of targeted radiotherapy comprised of a radionuclide bound with antibodies that mimic our immune systems to fight a range of cancers and viruses such as HIV. These compounds home in on antigens and cell receptors that are often overexpressed in cancerous tumors. Like other targeted radiotherapies, RIT is injected into a vein and the radioactive material is carried by the antibodies to the tumor, where a lethal dose of radiation from an isotope such as Yttrium-90 (Y-90) selectively destroys the malignant tissues while surrounding healthy tissues remain unharmed.
The following molecular radiotherapies are currently used to relieve pain and/or treat castration-resistant prostate cancer that has spread to the bone:
Both strontium-89 and radium-223 are radionuclides that target areas of increased bone turnover, and are directly injected into the bloodstream. Samarium-153 must be combined with a molecule that targets bone prior to injection into the bloodstream. Often men receiving a course of targeted radionuclide radiotherapy therapy receive several injections, each one separated from the others by a period of weeks. Research has shown that this is effective in relieving pain. Side effects of the therapy include myelosuppression, or a decrease in the production of red blood cells, white blood cells and platelets. Radionuclide treatment is sometimes combined with chemotherapy. Radium-223 (Xofigo), the newest radiopharmaceutical to be approved by the United States Food and Drug Administration, is unique because of the type of radiation it emits. Unlike strontium-89 and samarium-153 that emit beta particles, radium-223 emits alpha particles. Alpha particles deposit a higher amount of energy over a shorter distance than beta particles. Xofigo is especially promising because in addition to providing pain palliation, studies of Xofigo have shown that it can also extend overall survival in patients.
Y-90 Microsphere Therapy
Microsphere therapy is another means of protecting healthy organs and tissues by delivering tiny spherical structures made of glass or plastic directly to the tumor through the blood vessels, such as the hepatic artery or portal vein, the two major blood vessels of the liver. This form of radiotherapy uses Yttrium-90, a radionuclide, which is carried by the spheres and isolated to the affected organ. The microspheres pack a powerful dose of radioactivity that destroys the malignant tissues while protecting nearby organs. Prior to therapy, molecular imaging can be used to map the likely path of these microspheres in order to predict the success of treatment and to help select the best candidates for therapy.
What new molecular radiotherapies are being developed?
As the fields of molecular biology and genomics advance, tumor properties and pathways are being revealed, providing new cancer-specific targets for molecular therapies. For example, scientists have identified a molecular mechanism involved in prostate cancer cell migration and invasion called CXCR4 and are working on developing anti-CXCR4 antibodies that can impair these mechanisms. Because prostate tumors express increased levels of the gastrin-releasing peptide receptor (GRP-R), the receptor is also potential target for molecular therapy.
Scientists are also working on new molecular therapies that will further personalize treatment plans based on specific biochemical markers found in the patient and the characteristics of his or her disease. New studies are also evaluating combination therapies, such as the use of molecular therapy together with the immunotherapy known as sipuleucel-T Provenge® to more effectively treat prostate cancer.
Finally, molecular radiotherapies are playing a role in the emerging field of theranostics. Research has revealed markers for prostate cancer, including cell surface proteins, cell receptors, enzymes, and peptides that are helpful both in imaging the disease and as targets for therapy. In theranostics, imaging probes such as the radiotracers used in PET scanning are paired with cancer-destroying agents. Following delivery of these therapeutic agents, imaging can be performed to study and measure the effectiveness of the therapy.
The expression of the protein prostate specific membrane antigen (PSMA) is a biomarker for prostate cancer because it is expressed by virtually all forms of the disease, especially metastatic and castrate-resistant cancers. Researchers are studying the use of a PSMA-targeting molecule labeled with radionuclide as a means of both imaging and treating prostate cancer treatment.