An Exciting Moment In Time For Cancer Research
12 Jan, 2007 02:01 pm
Dr. Kenneth Kinzler is a professor of oncology at the Johns Hopkins School of Medicine. He is also a MERIT Award recipient at the National Cancer Institute. His current research is directed at the identification and characterization of the genetic changes that cause colorectal cancer. Dr. Kinzler answers our questions, introducing us to the prevention, characteristics, and treatment of cancer.
There are several different steps to causation, but basically every cell in the body has a complete set of genetic instructions, every replicating cell that is, that tells it what it is supposed to do in a certain circumstance. These [sets are] our genetic instructions, which is called the genome. What happens in cancers is that some of these instructions allow, by mutations or extra copies or deletions, the cell to replicate in times it is not supposed to. One answer to that question is that cells replicate because of mutations in genes, mutations in their genetic instructions. Another answer as to what causes these mutations, which is not something I’m an expert on, is that these can be mutations that occur by chance, random mistakes that happen when you copy these instructions. Some of the instructions are caused by environmental exposure to carcinogens; smoking is a good example of that, sunlight is a good example, where you increase the mutations because of the exposure. That’s the short answer to cancer causation.
There are tumor suppressor genes that discourage cell growth. How do they function?
Suppressor genes function in a variety of ways and it’s hard to summarize briefly how they work, but a large class of genes are called “cell cycle control” genes. These are genes that determine when a cell should reproduce and there are genes that positively regulate the cell cycle control, which tell them to replicate. If [these genes] are mutated or turned on inappropriately, act as oncogenes—they promote the growth of cancer. There are other normal genes that tell cells when they shouldn’t replicate; these are sort of like brakes on a car. If these are disrupted, a cancer results and these are commonly known as tumor suppressor genes because they suppress the growth of tumors. If they are damaged, they allow a tumor to form. We have oncogenes which promote cell growth and uncontrolled cell growth; when they are turned on, they are like an accelerator on a car. If you have a stuck accelerator, meaning if you have a damaged gene that promotes growth, it is called an oncogene. Then you have cells that can start to normally function to control the proliferation of cells, but if they get damaged they allow the cell to grow uncontrollably—those are called tumor suppressor genes.
Some different approaches to cancer research focus on promoting DNA damage response to fight tumors, finding new drug therapies for treatment, or reactivating tumor suppressor genes, among others. Which approaches appear most promising?
That’s sort of a two step question. First, we, as a group, really think in terms of understanding the genes that are damaged, whether they be oncogenes, tumor suppressor genes, or genes that control the integrity genome. Knowing which of these genes are damaged can really provide a critical insight into what went wrong in the cell allowing it to become a cancer. So we think these are a very good target. We then ask which of these would be good targets for therapy because we think that some of these actually do represent good targets; we think that oncogenes are, for a variety of reasons, are a good target. These are genes whose increase or gain in function leads to cancer growth, so we hope that by looking at mutated genes, we’ll find genes that are mutated frequently in cancers, affecting a reasonable fraction of a given cancer. The reason we like that is, is that it is easier to think about making drugs that inhibit an oncogene than it is to think about making any drugs that replace the function of a tumor suppressor gene. Most of the drugs we normally use are inhibitors of proteins in the body, so the thought is if an oncogene is turned on to make an overactive cell, we can make small molecules that inhibit the protein produced by that gene. We think those would be the good targets and there are good examples of drugs that we are most excited about now [which] target mutated oncogenes in human cancer such as Glivec for GIST [a rare cancer that occurs in the stomach), etc.
A recent study (by Dr. Angelo Vescovi at the San Raffaele Institute in Italy) focused on using stem cells to block tumors from growing in the brain of rats. Would this be possible in humans?
I’m not sure I’m familiar with that study…I’m not sure whether that may or may not work. Stem cells are a little out of my area. I think the mechanisms for that are a little less clear than finding a gene that’s mutated, overactive, and shutting it down. But it’s certainly very possible and there are a lot of very exciting therapies coming out. I want to be very clear there are many new biological therapies that are independent genetic changes, which we think are very interesting. In the context of the recent genome paper, it doesn’t necessarily shed light on how these other types of therapies will work.
As you mentioned smoking earlier, lifestyle (smoking, drinking, lack of activity, etc.) affects cancer, but can cancer be prevented? What are some effective prevention methods?
There are avoiding things that are known to increase your chances for cancer—smoking, sunburns, obesity—are one way to reduce your risk; also eating an appropriate diet, generally trying to be as healthy as possible, [among other things, help]. The second thing is by employing early detection methods. There are ways to detect cancer; generally, the good news about cancer is that if they’re caught early enough, they’re pretty curable. Mammograms, Pap smears, colonoscopies for colon cancer, all of these things do work and are effective means of detecting cancer early. If you catch it early, you’re in much better shape, making it often highly curable.
The treatments of cancer include surgery, chemotherapy, radiation therapy, immunotherapy, symptom control, and other alternatives. Are treatments more effective for different kinds of cancers?
For each subtype of cancer, there are different combinations for radiation, surgery, and chemotherapy that is tailored to that cancer. They have largely been determined by trial and error; large clinical trials have been conducted to find out which drugs work against which human cancers. The exciting thing is that some drugs that I mentioned earlier are drugs that are known to target specific molecular changes in the cancer cell, such as genes that are mutated, which result in an overactive protein. It’s possible to look at the tumor and say, “Hey, it has this mutation in particular,” to which we can respond. These only represent a small fraction of the therapies we use now, but it’s hoped in the future that they will be the rule rather than the exception. We’ll be able to look at a cancer, say we know what’s wrong, and be able to treat it. We have a number of therapeutic agents now, but they’ve largely been determined by empirical trials where people test them and say, “This works better than that.” Then they’ll take the next chemical and try it with existing ones or by itself to see what works or what is better. With these trials they’ve come up with a variety of therapies, which are effective, but which are not always effective if the cancer is advanced. It’s a cup-half-full or cup-half-empty kind of thing: if there’s a lot of toxicity, they don’t do well on advanced cancers in many cases. There are a lot of tools out there.
Where are we, in terms of research, of finding a cure for cancer?
I think we are at a very exciting time. In the United States, in the 1970s, I believe, the war on cancer was declared. Now, almost 35 years later, people are saying we aren’t winning this war. On the other hand, we really are at a special time. People have suspected that cancer has had a genetic component for, you could say, almost centuries. People have been known to think so as early as the 18th century, 1700s or earlier. People didn’t really understand it, but they speculated. The last 30 years, actually the last 20 years, have been remarkable in that we now have firm evidence with specific mutated genes that are responsible for human cancer. We are the first people, the first generation, to understand what went wrong in a cancer cell. The second thing, coupled with the first, is that while people [have been] looking at the individual genes, which ones are damaged in cancer, the entire human genome has been sequenced. So all of the instructions that encode our genetic code have been read for the first time in our generation. We really are at a unique time: knowledge of cancer as a genetic disease, which is being used in a variety of applications in the clinic, knowledge of our complete genetic instructions, which we can then use to compare with that which exists in the cancer cell, and seeing which genes are damaged to see why this normal cell became a cancer. We are just learning about the full spectrum mutations, we are seeing the first sets of drugs targeting mutations—I think we are very close to where we were when the AIDS virus was first discovered and the first drugs were coming out. In the next decade or two we’ll see a real change in the way cancer is managed and treated.
If you could briefly speak about your recent paper in Science, which is a complementary study to the Cancer Genome Project?
The paper provided our most complete and first glimpse of the complexity of the mutations that occur in a cancer versus a normal cell. It provided a lot of candidates that can be pursued for understanding why a cancer cell becomes a cancer cell and can be thought about in terms of whether they would make good markers for early diagnosis or development of therapy.
Sjöblom, T., Jones, S., Wood, L.D., Parsons, D.W., Lin, J., Barber,T.D., Mandelker, D., Leary, R.J., Ptak, J., Silliman, N., Szabo, S., Buckhaults, P., Farrell, C., Meeh, P., Markowitz, S.D., Willis, J., Dawson, D., Willson, J.K.V., Gazdar, A.F., Hartigan, J., Wu, L., Liu, C., Parmigiani, G., Park, B.H., Bachman, K.E., Papadopoulos, N., Vogelstein, B., Kinzler, K.W., Velculescu, V.E. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Originally published in Science Express on 7 September 2006. Science 13 October 2006: Vol. 314. no. 5797, pp. 268 – 274. DOI: 10.1126/science.1133427.