Targeted radioligand therapy for cancers of the prostate and others

Good day everyone. My name is Frank Lin. I'm the Chief of the Targeted Radionuclide Therapy Section or the Molecular Imaging Program at the National Cancer Institute of the United States. Today, I'll be speaking to you about the current status and future promise of targeted radioligand therapy, or TRT for short, for the treatment of cancers of the prostate and others.

To give a brief overview of my talk, I will first go over the basic concepts important for our understanding of using TRT as a cancer therapeutic. Then, I will move into some background information on prostate cancer and how TRTs are already being used in this space. Next, I will have a more expanded discussion on one particular type of TRT that is showing a lot of promise and is generating a lot of interest and excitement in the prostate medical oncology community. Namely, TRT is based on PSMA or prostate-specific membrane antigen. After the prostate cancer discussion, I will talk about other TRTs, which have already demonstrated good efficacy and are in clinical practice already today. Then, I will finish up with a brief discussion about some promising future directions the field of TRT is moving towards.

First, let's talk about the basics of targeted radionuclide therapy. In today's modern age of cancer treatment, the idea of having a very targeted treatment that is specific for a particular type of tumor cells is very important. While there are many mechanisms that provide the specificity of treatment, one of the cornerstone concepts of targeted therapy is the idea that cancer cells have a pattern or surface receptors that are characteristically over-expressed for that particular tumor type. For example, many lung cancer cells overexpress EGFR, which stands for epidermal growth factor receptor. Many cancers of neuroendocrine origin in the gut overexpress on their surface a receptor for somatostatin or SSTR. Physiologically, all of these surface receptors have something that binds to them naturally, such as the hormonal somatostatin binding to the SSTR. By chemically creating a molecule that mimics these receptors' natural ligands, you can create a drug that has a binding property of the original ligand. You create a scenario where you can achieve very high specific binding of your drug to the tumor cell of interest that expresses a receptor that you're targeting. This concept of having a binding ligand that can target and specifically bind to the matching surface receptor on the tumor cell, is one of the fundamental frameworks of how TRT agents work as a cancer therapeutic. By attaching a radioactive molecule, which is sometimes referred to as the payload of the drug to this binding ligand. You now have a way to bring something that is constantly emitting radiation right up to and sometimes internalizing into the tumor cell that you want to kill. The strength of the drug will be determined by the amount and type of radioactive payload that is attached. For instance, an isotope such as Lutetium 177 emits a lot of beta particles, which can effectively kill tumor cells when in close proximity. However, you can also attach something like Actinium 225, which emits a more powerful alpha particle and can kill a lot more tumor cells per unit of radioactivity administered. Now, there's clinical consensus that the effectiveness of radiation at killing cells correlates strongly with a dose of radiation that is given or delivered to the cell. That dose is determined primarily by how close and for how long you get the source to the target. An effective TRT drug does both of these things well. It can get the radioactive payload close to the tumor target via matching receptor-like impairing and have a stay at the tumor for a long time via receptor internalization after ligand binding. One bonus feature of TRT agents is that you can switch up the kind of radioactive payload so that instead of something that gives therapeutic radiation, you can then pass something that gives off other emissions such as positrons, which can then be picked up by cameras like a PET scanner. This will then allow you to see in the body where the TRT agents have gone and this imaging drug can then be used as a predictive marker of whether your therapeutic drug is going to get to the tumor cells of interest and therefore be effective. This is why sometimes we refer to TRT drugs as Theranostic, which is a combination of the words therapy and diagnostic agent.