Hi, this is Ken Pienta, welcome back to the Introduction to Cancer Biology course. The treatment of cancer. At the end of this module, you will be able to list the most common types of cancer treatment. Understand what chemotherapy is. Understand what immunotherapy is, and understand what a clinical trial is. Before we get started, I want to put in a major disclaimer here. This presentation is for education only. In no way does it take the place of a visit to a doctor. In no way should it be used for treatment decisions. So let's talk about the various types of treatments here in section A. There are many treatment types for cancer, overall these include surgery, radiation, hormonal therapy, chemotherapy, targeted therapy, and immunotherapy. And we will look at each one of these types of treatment and how they apply to the major cancers that we've been talking about throughout this course. Let's first turn towards surgery and radiation. It's very important to realize that approximately 50% of all people diagnosed with cancer in the Untied States are cured by surgery or radiation. Because the cancer is removed or killed by that radiation before it has spread. This means that being diagnosed with cancer, does not mean somebody is automatically dead. Half the people in the United States are cured once they are diagnosed with cancer. So surgery and radiation provide the backbone for all cancer therapy. If it's possible, we want to do surgery to remove the tumor or to kill that tumor with radiation using external beam radiation or by implanting radioactive seeds in the surgery. So let's look at external beam radiation therapy, which is radiation that's delivered by a big machine. It's usually given in several doses or fractions over time. It's important to note that it can be equally as curative as surgery. And in many cases, when you have a small primary cancer, physicians give the patient the option of being treated with surgery or radiation for definitive cure. Radiation can also be used for palliation, to simply shrink a tumor that is causing pain or some other problem in the body. And, when it's not given as curative intent, it's called palliative radiation. How does radiation work? It works by killing dividing cells through DNA damage which leads to cell death. So when the radiation hits your DNA, the DNA is damaged, that is recognized by the cell is not normal and the cell undergoes a programmed cell death. Something you've heard about in earlier lectures. When surgery or radiation are used as the primary therapy to try and cure a cancer, sometimes other therapies, like chemotherapy, are given around the time of the surgery or radiation. If that therapy is given before surgery or radiation, it's called neoadjuvant therapy. If the therapy is given afterwards it's called adjuvant therapy, or adjuvant treatment. And you'll hear these terms as applied to therapy often and it doesn't really matter what cancer you're talking about. Many folks are treated with neoadjuvant or adjuvant therapy after the surgery or radiation. So, when you talk about neoadjuvant therapy, or adjuvant therapy, or treatment of metastatic cancer, what are the therapies that we can use? One of those therapies is based on hormones that your body produces. Your body makes chemicals or hormones that tell various organs what to do. For example, the female hormone estrogen controls the development of female secondary sexual characteristics like breast growth or regulation of the menstrual cycle. The male hormone testosterone tells male reproductive tissues such as the testicles and prostate to grow as well as promotes increased muscle, bone mass, and body hair. Hormones can also stimulate cancer to grow. For example, the female hormone estrogen stimulates breast cancer growth and as you'll see anti-estrogen agents are used to help treat breast cancer. The male hormone testosterone stimulates prostate cancer growth and anti-testosterone agents are used to treat prostate cancer. Chemotherapy works differently. Almost all chemotherapy drugs have been designed to keep cells from dividing. Cancer cells tend to divide more rapidly than normal cells, and therefore, they are more likely to die from chemotherapy treatment. Normal cells in the body, like cells in hair follicles, white blood cells that fight infection, and the lining of the colon are also dividing. And that is why the main side effects of chemotherapy are hair loss, infection risk, and nausea, and diarrhea. There are two broad classes of chemotherapy drugs. Agents that interfere with replication of DNA and agents that interfere with cell division by blocking mitosis. To turn first to inhibiting replication of DNA, there are several ways that this can be done. And therefore several classes of drugs that have been developed to inhibit replication. One class of drugs is called the anti-metabolites. These are base pair drugs that are intercalated into the DNA strand. And therefore, do not let it be replicated. Topoisomerase enzymes are used to unwind the DNA for replication and then rewind it. And so another class of drugs are drugs that inhibit these enzymes called topoisomerase inhibitors. And then we have a broad group of DNA intercalators that include metals, alkylators, and antibiotics that all intercalate into the DNA strand, and prevent it from reproducing itself correctly. The chemotherapy agents that interfere with replication of DNA then include the metals, platinum agents like cisplatin, carboplatin, and oxaliplatin. The anti-metabolities include 5-fluorouracil, or 5FU, capecitabine, or Xeloda. Gemcitabine or Gemzar, and pemetrexed or Alimta. The most famous alkylating agent is Cyclophosphamide or Cytoxan. The most famous antibiotic, and the most widely used, is Doxurubicin, or Doxil. The two most common topoisomerase inhibitors are etoposide, otherwise known as VP-16, and irinotecan, which is otherwise known as Camptosar. As I mentioned, the other major class of agents that are used to treat cancer are those that inhibit cell division. As we learned in previous lectures, microtubules are used to pull apart dividing cells, and pull the chromosomes to the separating cell bodies. The drugs that inhibit microtubules do so in two ways. The vinca alkaloids like vinorelbine, vinblastine and vincristine prevent microtubules from assembling. The taxanes like docetaxel, paclitaxel, and cabazitaxel all prevent microtubule disassembly. As these drugs interfere with microtubule function, the cells are caught in cell division, and again, undergo program cell death. Let's turn now to targeted therapy. Targeted therapy inhibits proteins that are mutated or overexpressed and are helping the cancer to grow. Theoretically, this makes the therapy more cancer specific since these proteins are not normally mutated or overexpressed in your regular host body cells. This should make the treatment more specific to the cancer cells, without causing as many side effects, as you see with chemotherapy and hormonal therapy. Some examples of targeted therapy treatments include those that target vascular endothelial growth factor, or VEGF. The most common drug used here is a drug called Bevacizumab or Avastin. Drugs that target epidermal growth factor receptor or EGFR, and the most common drug used there is Tarceva. Drugs that target the growth factor receptor HER2 like Herceptin in tie curve. As well as other drugs that target ankA genes like ALK signal transduction pathways like mTOr, and other drugs that attack cyclin kinases like lbrance. Let's take a closer look at some of these targeted therapies. As we have seen previously in other lectures. Vascular endothelial growth factor stimulating angiogenesis is a key part of cancer growth. If a small tumor mass does not induce new blood vessel growth, it won't get bigger than a millimeter in size. These blood vessels are stimulated by vascular endothelial growth factor which is secreted by the cancer cells. It binds to its receptor, the VEGF receptor on vascular endothelial cells and stimulates those cells to grow. The bevacizumab is an antibody that sops up the extra growth factor by binding to it, so there's none to bind to the growth factor receptor. Alone, Avastin is not a treatment for cancer, but it is used in combination with multiple different chemotherapies in multiple different diseases. Other targeted therapies, again, inhibit at the level of the receptor, like the growth factor and receptor inhibitors. Or inhibit at the level of signal transduction. So two examples of this is shown on the slide, are drugs that inhibit HER2 as a growth factor receptor like the drug Trastuzumab or Herceptin. The drugs that inhibit growth factors receptors since they're outside the cell can either be antibodies or small molecules. If drugs are develop that inhibit signal transduction molecules like mTOR, these drugs tend to be small molecules which can be taken up by the cancer cell, and then inhibit the signal transduction. A drug like this for mTOR, for example, is everolimus, or Afinitor. Let's move onto immunotherapy. Immunotherapy is the use of medicines to stimulate a patient's own immune system to recognize and destroy cancer cells more effectively. An important part of the immune system is its ability to keep itself from attacking normal cells in the body. To do this it uses checkpoints, molecules on the immune cells that need to be turned on or off. For example, CTLA-4 and PD-1. This allows the immune response to start. Cancer cells sometimes use these checkpoints to avoid being attacked by the immune system. So let's take a look at this in a little bit more detail. T cells, if they can be turned on, are the cells that attack the cancer cells. Dendritic cells and macrophages are cells that help the T cell recognize that a tumor cell is nearby. If the tumor cells or the macrophages interact with the PD-1, PD-L1 lag end receptor complex, the T cells are turned off. If dendritic cells bind to the T cells through the CTLA-4 lag end receptor complex they are turned off. Therefore, the major advance in immunotherapy in the last ten years has been the development of checkpoint inhibitors that target these two ligand receptor axis, PD-1, and CTLA-4. By blocking PT-1, these drugs boost the immune response against cancer cells. These drugs include Nivolumab and pembrolizumab. The drug that blocks and targets CTLA-4 is Ipilimumab or Yervoy. Again, let's take a look at that more graphically. Here you see the anti-CTLA4 drug blocking the interaction between the dendritic cell and the T cell through CTLA-4, and the anti-PD-1 drugs blocking the interaction of PD-1 and PD-L1. This allows the T cell to be turned on and attack and kill the tumor cell. This brings to a close section A, where we discussed the major types of treatment for cancer, including surgery, radiation, hormonal therapy, chemotherapy, targeted therapy, and immunotherapy.
