Cancer gene therapy. Viruses and HIV enzymes against tumors. 7

Gene therapy as a magic bullet against cancer. It captures imagination. But progress has been slow. Leading cancer expert and researcher shares new ideas on subverting viruses to treat tumors.

You work also on the gene therapy for treating colorectal cancers. You use viral vectors. Could you discuss your gene therapy work in colorectal cancer? Dr. Anton Titov, MD. Yes, you just have to emphasize that this is still experimental. This week we are going to do gene therapy on first colon cancer patients. Dr. Nadir Arber, MD. We’re going to give gene therapy for terminally ill cancer patients. It’s like mercy therapy. Dr. Nadir Arber, MD. We are going for the last resort of mercy. Because some colon cancer patient is going otherwise to die. Dr. Anton Titov, MD. Patient has nothing to lose. Dr. Anton Titov, MD. It’s a lot of hope. But gene therapy for colon cancer expectations are very much conservative. This is, again, we’re trying to think outside of the box. Sometimes you have normal cells turn into malignant cells. They usually having some mutations. One mutation is KRAS. And cancer cells constantly dividing, dividing, dividing and becoming cancer. And it’s not controlled divisions, very basically. Dr. Anton Titov, MD. With chemotherapy or additional cancer therapy we are trying to stop these active molecular pathways. They turn normal cells into malignant cells. Usually cancer therapy leads to tumor growth arrest. Cancer cells stop growing because this active cancer growth pathway was shut down. And then after a while the cancer finds some other growth-enabling pathways. Cancer growth bypasses this molecular pathway stop that was put into cancer. Now cancer resumes activity via other different molecular pathway. Usually we have seen in a clinic. After cancer growth started again, then all of a sudden there is a rapid deterioration. The colon cancer patient dies quickly. Dr. Anton Titov, MD. What we tried in my lab to use a different cancer treatment. I call it the Trojan horse strategy. Instead of inhibiting these active cancer growth pathways that exist only in cancer cells. They don’t exist in normal cells. Now we are using cancer growth molecular pathways to specifically kill colorectal cancers. What you use is the strategy that has five components. Dr. Anton Titov, MD. First, you have to identify these active cancer molecular pathways. Obtain medical second opinion on cancer. Then you have to identify where the cancer pathway attaches to the nucleus. It is the DNA responsive elements. Sometimes cancer growth message comes from the membrane into the cytoplasm. Obtain medical second opinion on cancer. Then cancer message goes into the nucleus. It is telling the cells to divide. Dr. Nadir Arber, MD. We can hook to it, you can identify it, and we can hook a lethal gene to the message. Dr. Anton Titov, MD. It is going to be activated only in the cancer cells and not in the normal cells. In order to improve the strategy we are using usually viruses to deliver a lethal gene construct into the cancer cells. Dr. Nadir Arber, MD. We want to selectively bring the gene therapy only to cancer cells. Dr. Nadir Arber, MD. We are expressing on the top of the viruses specific antibodies to CD24. It is, as we spoke before, expressed in malignant cells but not in normal cells. The final component is that we are expressing very lethal genes that are based on the active cancer growth pathway. Dr. Nadir Arber, MD. We also have the antidote that is regulated by tumor suppressor genes. They are expressed in the normal cells but not in the malignant cells. Dr. Anton Titov, MD. We can keep the balance of just killing the colorectal cancer cells. As we know, there is also some “leak” in any biological system. Dr. Nadir Arber, MD. We can express antitoxins in the normal cells. In that way we can use even higher doses of gene therapy to selectively kill colorectal cancer cells. But at the same time we make sure that healthy cells are going to state alive. This is very promising gene colorectal cancer therapy. What is good about it? Dr. Anton Titov, MD. This is a gene therapy platform for many types of cancer. It’s not just for any specific cancer. Because using this gene therapy strategy, you can change every part of it. You can adapt cancer gene therapy to the person or to the tumor. This is precision medicine at its best. Dr. Anton Titov, MD. It is very promising. Dr. Nadir Arber, MD. We are looking into the future. This may change the landscape of cancer therapy. And that’s clearly the goal of every clinician and clinician-scientist. Absolutely! Another cancer therapy clinical trial that we are doing now. It’s taken a new medication that is used to treat HIV patients. It’s using the integrase of the HIV virus. Dr. Nadir Arber, MD. We are using this technology to treat cancer. It is cancer therapy clinical trial we are starting now. It looks very promising. This is how we are using some viruses that were developing in my lab as cancer therapy. Dr. Nadir Arber, MD. We specifically target cancer cells, and only the cancer cells. Viruses bring this integrase enzyme. It is causing cuts in the DNA. When there is a lot of cuts in the DNA, the immune system is going to recognize these cells as cancer cells. Immune cells will execute the program of cell death, apoptosis. That selectively kills cancer cells. Dr. Anton Titov, MD. This is a fascinating new cancer therapy. That is a thinking “outside of the box”. Cancer gene therapy might give another hope for cancer therapy. This is certainly interesting. Because cancer gene therapy utilizes the true precision medicine. Yes, that’s the way!