Melanoma 2003

SLIDES & TRANSCRIPTS
Monday, May 5, 2003

Commentary: Con

Frank Meyskens, Jr., M.D.

Slide 1:

DR. SONDAK: Our final speaker this session is Frank Meyskens who, if he isn't going to argue for the limitations, he is at least going to bring us back to earth. We are, after all, talking about melanoma. Frank?

DR. MEYSKENS: I think I have been asked to address this because I have been a translational scientist in melanoma for about 25 years.

I have used the basic biological principles understood at that time to try to develop a wide variety of clinical trials in melanoma, all of which have been negative.

Slide 2:

This is my statement here. Turning scientific discoveries, particularly genetic abnormalities, into therapeutic targets.

For therapy? I think very unlikely. Prevention? Pre-vertical phase in the primary? Possibly.

How about some alternative or non-genetic approaches? Vern has asked me to comment a bit on the biology and particularly some studies that we have been doing recently.

Slide 3:

Well, how has my perspective been informed? Well, 25 years of basic and clinical translational research, and really a love of pigment cell biology.

I would like to reiterate what was said by the pro speaker, that we have really neglected, to a significant extent, the biology of the pigment cell until just very recently, although there are a lot of people out there studying pigment cells, and we have been swamped by this interested in immunology, not to say that that is bad, but I think we have neglected the pigment cell biology field enormously.

I have worked closely with many other leaders in the field, the first two clinicians having been very frustrated as well, and the second two being basic scientists who remain more optimistic than I do.

Slide 4:

However, I am not against genetics. There is a genetic part of my make up. Actually, Dr. Trent and I, many years ago, were the first to define chromosome 6q involvement.

An expansion of that led to a publication in Cancer Research, and then a large article in the New England Journal studying this phenomenon.

Slide 5:

I will just take you back 10 years, and what we showed. This is just one of the graphs, that if you had a structural abnormality in chromosome 7, it was a bad, or an abnormality in chromosome 11, it was bad. So, we had some optimism that that might translate for benefit at some future time.

Slide 6:

This is a statement of why therapy based on genetic alterations is likely to produce disappointing results.

I think the Gleevec experience was a very important one. However, what it has also taught us is the rapid emergence of resistance, in a tumor in which CML has no or few other evident genetic abnormalities.

One thing that melanoma has is lots of genetic abnormalities. There are multiple molecular pathways involved early in melanoma pathogenesis, at least early from a clinical point of view, and also, the intrinsic anti-apoptotic nature of the melanocyte. I think all three of those together conspire.

Slide 7:

I just remind you of the pathway. We tend to concentrate up here, after the vertical growth phase, but the tumor really has a long history.

By the time we see it, however, it is usually just about ready to go into the vertical growth phase.

As we know, and have come to respect in the last few years, there is really a very impressive change in the genetic make up of melanoma between the radial and vertical growth phase, by which a large number of genetic abnormalities are accrued.

Slide 8:

I would submit to my colleagues who study this area that the nature of why that occurs is a fundamental issue in genetics which has been largely ignored.

We don't have any idea why this genetic change from the horizontal to the vertical growth phase, transition in primary melanoma, occurs, and it presages the metastatic phenotype.

Once you have gone vertical and acquired all of these genetic abnormalities, I think the game is up.

Multiple molecular pathways become involved at that point. In fact, almost anywhere you look, there is an abnormality in a molecular pathway, and the anti-apoptinocyte becomes evident, which is probably a retention of the normal properties of the melanocyte, which has just been commented on earlier, but really just recognized in the last few years.

Slide 9:

Where do I think the genetics may play an important role in the management of melanoma? Certainly I think in identification of individuals at high risk, as commented elegantly by Dr. Tucker earlier, perhaps in prevention.

We know that early diagnosis is the key, and I will comment more and more on this tomorrow in the chemoprevention symposium, as to what group it might be useful to actually entertain prevention strategy.

If I were a betting man, I would bet on BRAF, because I think it is a very important first step, immortalization step, and probably would be very important in prevention and potentially treatment. So, that is my one optimistic statement.

Slide 10:

How about some alternative treatment strategies? How about anti-apoptotic approaches?

Abnormal reactive oxygen species regulation is an area we have been involved in, and manipulation of melanin pathway, or melanin itself.

Slide 11:

Well, I think there have been a couple of papers that have come out recently that have looked at the presence of a number of apoptotic proteins in melanocytes.

One thing that is quite impressive is that all of the apoptotic proteins are expressed abundantly except survivin, which becomes expressed in the vertical growth phase and later.

So, it is really not surprising, since melanocytes have to stick around for the life of the animal and divide rarely, that they have to be protected against cell death.

That is, the phenotype of the untransformed cell is anti-apoptotic, and melanoma, being fairly clever, doesn't get rid of that, but keeps that when the cell becomes transformed.

Slide 12:

Well, looking at a whole series of studies of reactive oxygen species and chelators has led us to, surprisingly, end up looking at a compound called disulfiram, which is used in alcohol aversion therapy.

We have found very, very potent effects of this particular compound.

Slide 13:

This is just an XN5 analysis of a low dose of disulfiram, with a marked appearance of apoptosis after treatment for 24 hours, suggesting that melanoma might be sensitive to this class of agents, which has not been widely explored in anti-melanoma therapy, and we have just started a phase one trial of this compound.

Slide 14:

I want to take you back about 15 years. Many of you may remember the attempts of Wicke and others at Harvard to capitalize on the unique pathway of the melanocyte, that pathway which generates melanin.

They tried to develop a number of analogs of dopa and related molecules. They weren't successful, but I think it is a pathway that still needs to be looked at.

I don't mean manipulation of this pathway for therapeutic reasons but, if you will, making better compounds that might go into melanin selectively, since even amelanotic melanomas have a large amount of melanin present, usually of the pheomelanin type. I think this whole field has been badly neglected.

An area that we have become quite involved in is using melanin itself, particularly eumelanin, as a target, and I will mention some of those studies tomorrow morning.

Slide 15:

What we have shown, very briefly, is that by studying pure melanin films, we have shown that melanin becomes progressively oxidized through the pathogenetic process of cells becoming a melanoma.

What is generated is a quinone amine which glops onto various types of cations and other molecules, including a number of potent compounds which we have synthesized.

Slide 16:

Our strategy is this, actually, that because melanin in melanoma cells becomes oxidized instead of reduced, as in the normal situation, we are developing a chelator strategy that hooks onto various cations, that then develops and goes through and transports directly to the melanin, which is a sink, if you will, for chelation therapy.

It turns out that this sink then further sets of a redox cyclic mechanism in the presence of oxygen.

Slide 17:

This is just one experiment that -- if you will forgive me the liberty to show -- this is a particular chelator which my colleague, Pat Farmer, has synthesized.

If we look at the effect on melanoma and melanocytes, in melanocytes, there is no effect of any of these manipulations.
If we take a low concentration of this copper chelating complex, you get marked inhibition of proliferation.

In fact, if you put melanoma cells in the presence of 95 percent air, they are very sensitive as well, which was a big surprise.

Then, when you take a combination of this compound plus high levels of oxygen, you have a marked inhibition compared to melanocytes. So, that is another strategy which we are pursuing.

Slide 18:

Finally, I think that genetics is unlikely to guide therapy, perhaps prevention, and I will comment on that tomorrow during the tutorial.

I think the melanin synthesis pathway and melanin itself may be important therapeutic targets.

Third is, apoptotic therapies may be worth considering, but I think we are really going to have a hard time because the cell is just programmed to be anti-apoptotic and melanoma has just made it more so.

I do think that alterations of ROS in melanoma have not been capitalized on, beyond the issue of melanin synthesis, which I don't have time to comment on.