Deciphering melanoma's genetic mysteries

LOS ANGELES Kathy Hermes loves to tan although the dangers of sun bathing have crossed her mind.

"Skin cancer is a big concern, but it's not going to keep me out of the sun," said Hermes.

But she should be cautious. Researchers explain how our skin thins as we age.

"As you age, this upper layer of the skin gets very thin and flattened. Now you've lost your protection that normally keeps the sun from penetrating deep into the skin," said Elaine Jacobson, Ph.D. Biochemist University of Arizona.

University of Arizona researchers developed a new drug aimed at preventing the most common non-melanoma skin cancer -- actinic keratosis.

These patches or spots can develop into basal or squamous cell carcinoma.

The drug, from the vitamin niacin, is called myristyl nicotinate. It works with receptors in the upper layers of the skin to give it greater protection from the sun.

"The amount of ultraviolet light that you can be exposed to before you get a sunburn is increased 10 to 20 percent," said Dr. Jacobson.

In two preliminary clinical trials, researchers say the experimental cream strengthened the skin's barrier.

"In a sense, myristyl nicotinate is giving you a biological SPF," said said Dr. Jacobson.

"The melanoma was actually right here on my upper back, right in the middle," said Melissa Parreli, who is a melanoma patient.

Hearing the word melanoma turned Melissa Parrelli's world upside down.

Dana Farber Cancer Researchers think a drug used to fight other cancers like leukemia may help patients battle this most deadly form.

One type of melanoma can show up inside the mouth or throat. The drug Gleevac works on the gene that causes this.

"The Gleevec actually goes in and blocks that gene that's turned on and kind of shuts the switch off," said Dana Farber Cancer Institute researcher Dr. Stephen Hodi.

One woman's melanoma spread to her abdomen, but after nine months on Gleevac, her tumor got much smaller.

"This patient went on to get Gleevec and had a dramatic response from just a few weeks to the drug, where more than 80 percent of her tumor shrunk," said Dr. Hodi.

Scientists say understanding the genetics behind this rare tumor could unlock the mystery of other melanomas.

"It makes me feel better knowing that the doors are open. Once you are in that exploration stage you never know what you can find," said Parreli.

Possible Gleevac side effects include water retention and rashes. As for the niacin cream, Dr. Jacobson says it's not designed to take the place of sunscreen.

A national FDA supervised clinical trial is next to see if the niacin cream can prevent skin cancers in those who have already had the disease.

Web Extra Information:

F. Stephen Hodi, M.D., a researcher at the Dana-Farber Cancer Institute in Boston, explains how the drug Gleevec may help put melanoma patients into remission.

Tell me about the research that you are working on with Gleevec and melanoma?

Dr. Hodi: This started from a very important finding over the past couple of years where we trying to re-categorize melanomas, not just based on what it looks like under the microscope, but where they start from anatomically in the body and also the genetics, to try to get a better understanding of what is causing melanomas and what we can do to actually prevent them. And one of the sensible findings has been looking at the genetics of melanoma, a gene called KIT. This gene is interesting in the fact that its known to drive other kinds of cancers and its been looked at indirectly in melanomas where the drug Gleevec has been used in other melanoma trials. But when this finding came out a couple of years ago that showed that certain melanomas, maybe not the most common ones, have these mutations in the KIT gene. When the mutations are there, that causes the gene to be overactive and drive the cell to want to divide and grow. And so this finding has made us think in these substances of melanomas, maybe we should try to target this gene in these subsets to get some good drugs that target the KIT gene --Gleevec being just one of them.

What exactly did the Gleevec do?

Dr. Hodi: We found that in some of these melanomas where you have this activating KIT mutation, the Gleevec actually goes in and blocks that gene that is turned on and shuts the switch off. So if the gene is mutated the switch is on, and the light is always on, and the cell always wants to divide and grow and become cancer and metastasize or spread, the Gleevec goes in and tries to shut that switch off and block that mutation in causing the gene to want to drive that cell to divide more.

Tell me about the patient study you did?

Dr. Hodi: So these clinical studies take a bit of time because it took a while for us to understand the science behind it. Common melanomas that start on the mucosa surfaces and also on the palms, soles or nail beds are called acral melanomas. And also melanomas that start on chronically sun-damaged skin, which would be different than other types of melanomas. So we found this one patient that had a mucosa melanoma, a mutation in the gene KIT in her tumor and we had a trial that was set up so that patients who have this mutation can go on to get Gleevec. And this patient went on to get Gleevec and had a dramatic response in just a few weeks -- more and 80 percent of her tumor shrunk.

What did that tell you?

Dr. Hodi: Well, being someone who is focused on melanoma in my research and my clinical work, melanoma has always been one of those cancers that I've always thought, gee, is there an Achilles heel or not? And now I finally think there is hope that this is the first hint that there is an Achilles heel to melanoma and we can go about this rationally. We can actually pick individual tests that are therapeutic for patients based on what their tumor is, not just what it looks like under the microscope. We can actually profile a patient specifically and say, 'This patient has an Achilles heel being KIT in this case,' now we can try to target KIT in a patient like this.

What else is Gleevec used for?

Dr. Hodi: So Gleevec is used for a type of sarcoma called gastrointestinal stromal syndrome (GIST) and its also been used in chronic myelogenous leukemia or CML. Really, the KIT mutations found in GIST and response to Gleevec that has been known in GIST seems to give us really a great foundation to base this work in what may be a rather small subset of melanoma in patients.

Where are the types of melanoma you're talking about found on the body?

Dr. Hodi: We're still in chapter one of the story; it's based on certain anatomic locations, in certain parts of the body where the melanomas from. And they are the mucosal surfaces, which are rare but can be in the anal region, the monocalcic region, the mouth and the sinuses. What is called acral melanomas occur on the palms, soles of the feet or nail beds. And then there are chronically sun damaged skin melanomas. Melanomas that arise in areas like the face that had a lot of sun exposure, and those are the areas that have been found to have the significant KIT mutations, the KIT gene mutated that will then drive that gene to want the cell to grow and divide.

Where do you go from here with the study?

Dr. Hodi: The fact of the matter is, as a melanoma community we need to get together and really define what patient populations can be benefited from a drug like a KIT inhibitor. Because its probably a relatively small percentage of patients and that small percentage could get a dramatic benefit from it, but since its not the most common in terms of all melanomas, we need to spread such a study out so that its done in a logical way, where we analyze patient's tumors for the KIT mutation, and are also looking at whether the KIT could be amplified, meaning that there is no mutation in the genetic code of the gene, but more copies are around so it makes more of the protein. And that more of the protein can drive the cancer cell. So we need to answer the question of whether these drugs can also effect the genes that are not having mutations but are overexpressed in a cancer.

So there are a couple of questions we need to answer. One is what is the true frequency of this KIT mutation in melanomas and what subpopulation of melanomas does it effect -- the mucosal, acral or the chronically sun-damaged skin melanomas. The second is what are the drugs that are best effective against these kinds of mutations, and the third being what does application mean and can we actually have effective drugs against tumors that not have mutations in KIT but are amplified.

Are there any side effects to Gleevec?

Dr. Hodi: Now with any of these drugs there are certain side effects; fluid retention, rashes. You have to watch blood counts and things like that. But you have to get a certain level of the drug to have effectiveness. If you try to back off too much it may not hit that KIT gene where you want it to.

What does this mean for the future of treating melanoma?

Dr. Hodi: I think this is a very exciting time for doctors that see melanoma patients because it's a hint into the future. Does melanoma really have an Achilles heel and can we really cause the melanoma cell to die in patients significantly where we get a clinical benefit and can we do so in a very rational way? And while the KIT gene story may be just a very small subset of patients with melanoma, hopefully, it's a beginning for a bright future for us to develop further therapies for patients with melanoma that really are rational, are individualized medicine. So we can have effective therapies for more than this subset population.

Elaine Jacobson, Ph.D., a biochemist at the University of Arizona and Arizona Cancer Center and chief operating officer of Niadyne Development, talks about a new drug that may help prevent a common type of skin cancer.

What kind of skin cancer are you targeting in your research?

Dr. Jacobson: We're interested in prevention of squamous cell carcinomas. These are the non-melanoma skin cancers that are most prevalent and most costly to maintain, to treat and deal with in the population. Squamous cell carcinomas start quite typically as something we call actinic keratoses. These, in the past, have been referred to as premalignant skin lesions but its very, very clear today that dermatologists and oncologists, after looking at the pathology of these things, feel that these really are indeed very early stage cancers. Many of them never progress to a squamous cell carcinoma, but somewhere between 3 and 15 percent of them might do so. We just don't have good numbers because most of them are either spontaneously reversed or don't develop into bona fide cancers, and are removed by liquid nitrogen by many types of physicians in addition to dermatologists and oncologists. So we don't have good tracking records for the history and progression of AKs in squamous cell carcinomas.

Why is it important to prevent this type of cancer?

Dr. Jacobson: Squamous cell carcinomas are very dangerous. They can become full-blown malignancies that can cause death. Most of the time they do not because we have, in skin cancer, the benefit of studying something that you can see as opposed to being a specialist in pancreatic cancer, for example, where you do not have that privilege of being able to identify very early stages of the cancer. So they can be very, very serious, but in fact, they're treatable with surgical approaches.

How common is this type of cancer?

Dr. Jacobson: AKs and squamous cell carcinomas are very, very common. People who are in the sun, people who age are going to get these.

How does aging play a role in the development of squamous cell carcinomas?

Dr. Jacobson: I think its very, very likely if you live to be old enough you'll have an AK and of course, the tendency to have them is related to skin type. As with all skin cancers, the fair individuals are more susceptible because of additional exposure to ultraviolet light because there's less pigmentation in the skin. So more of those ultraviolet light rays can penetrate through the skin in fair-skin people. And then skin has insults other than ultraviolet light -- chemicals, environmental issues of all kinds -- and these, of course, could potentially be irritants that would lead to AKs as well. Just the aging phenomenon, where one is exposed to what we call reactive oxygen species -- the result of stress -- could potentially activate skin cells to become AKs and eventually be converted to squamous cell carcinomas, but the primary cause is sunlight.

What new drug did you discover, and how did you discover it?

Dr. Jacobson: The drug that we are developing is called myristyl nicotinate. It's a derivative of nicotinic acid, and our interest in it came out of about 25 years of fundamental research trying to understand the basic cell biology, biochemistry and molecular mechanisms by which DNA repair is modified in cells and how that goes awry in cancer cells. So we have been working for a very, very long time with a very academic approach to understanding cellular processes, and one day I was really challenged by a physician colleague who said, "Well, now just how do you plan to translate this?"

How does myristyl nicotinate work?

This drug is a very, very interesting one. As you know, niacin has been used for years as a drug to modulate serum cholesterol levels, elevating HDL, lowering LDL and lowering triglycerides -- risk factors for cardiovascular disease. So niacin is very interesting. It's a very, very complex molecule that is both a vitamin and a drug, and so as I have mentioned earlier, I have been interested in the basic mechanisms of how niacin works and there are many, many pathways in this cell that are affected by niacin -- some in a nutrient manner and some in a drug-like manner. Very recently, we have identified an interesting molecule in the surface of skin cells called the nicotinic acid receptor, a place where niacin binds, enters the cell and begins to activate specific signaling pathways that control proteins that the cell makes. So we feel that niacin is functioning by binding that newly found nicotinic acid receptor and driving this process of maturing the surface of the skin -- that is, the upper layer which we refer to as the stratum cornea. So we think niacin is driving what we biologists call the differentiation process in skin. That is the maturation from a stem cell to a mature surface-type cell.

How does this drug affect the skin? LM: So when you put this cream on the skin with the drug in it, what are you seeing it do to the skin to protect in the way of protected, and lets try to keep this as simple as we can because obviously, you know, what does the drug do?

Dr. Jacobson: The drug builds the stratum corneum. As you age, this upper layer of the skin, it gets very thin and flattened. Now you've lost your protection that normally keeps the sun from penetrating deeply into the skin. Myristyl nicotinate, we have shown, builds that upper layer of the skin, ever so slightly, to provide you much more protection from the sun for one thing.

How does it prevent skin cancer?

Dr. Jacobson: Studies from some of our clinical trials have measured, for example, how long your skin can remain under the ultraviolet before it will turn red -- that is, have an erythemal response, a reddening of the skin due to a sunburn. So we have shown that use of myristyl nicotinate for three months, for example, extends that amount of time by 10 to 20 percent before you will achieve a sunburn in the sun.

What we have determined is that myristyl nicotinate actually extends the UV protection time of the skin. For example, you are familiar with a SPF -- that is, a measure of what kind of protection a sunscreen will give you before you will experience a sunburn. And in a sense, myristyl nicotinate is giving you a biological SPF. What it's doing is building the upper layer of the skin so that the amount of ultraviolet light you can be exposed to before you get a sunburn is increased 10 to 20 percent.

What does the discovery of this drug mean for skin cancer prevention?

Dr. Jacobson: I think we have found a drug that can prevent skin cancer. Of course, only time will tell, and clinical trials -- because the data is dependent upon it's efficacy in humans -- but that is what we have rationalized and seen. So on paper, we can, in fact, rationalize that we have something that will do that. But we're going to have to wait for the data to determine that, and also the approval of the FDA to determine whether we have that.

How exciting is this to you, as a researcher?

Dr. Jacobson: It's always very, very exciting to be able to take something you've studied in a laboratory -- as I call myself an academic egghead, studying the fundamentals -- and then as an academician you never, ever believe you're going to have something that you could really apply to a human. So once you get close to that possibility, it's very, very exciting. It's like a life-culminating event.

What does the development of this drug mean for the future of skin cancer?

Dr. Jacobson: We believe, by the partnership we have formed between Niadyne Development and the Arizona Cancer Center, is that we're on the verge of a first-in-class drug. At the present time, you will not find an FDA-approved agent that claims to prevent skin cancer, and it is our hope that over time that will be a possibility.

How long do you think it will take for this drug to be approved?

Dr. Jacobson: Well, I think that if things go really well that approval in three years is not unthinkable.

If myristyl nicotinate is approved by the FDA, how will it change people's lives?

Dr. Jacobson: This would be an agent that would optimize your own defenses and build your skin to its optimal status. Could you go out and play golf all afternoon unprotected in the sun and never get an AK or an SCC? I don't think so, but this would greatly delay or prevent many of the potential lesions that that kind of behavior would cause. Always, we want to educate everyone to the importance of covering the skin and using good sun exposure practices.


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