By David N. Leff

Obsessive surfboarders court a hazard that is riskier than sharks, cuts, bruises and fractures. It¿s ultraviolet radiation from the sun.

These high-energy rays beat down on their skin, and attack the melanocytes ¿ pigment-producing cells that result in suntanning the epidermis. That is why melanoma can be described as the Sunbelt cancer. A map of the world delineates its sunniest climes as hotbeds of the deadly skin neoplasm, with sun-drenched Australia in the lead.

But the U.S., with a swathe of sunshine sweeping from Florida to Southern California, recorded 56,900 new cases of melanoma last year, with mortality among males amounting to 27,300. Female deaths were not far behind, at 20,400.

Melanoma takes no prisoners. Its onset usually assumes the form of a small, dark, raised mole or nevus that many women feature as beauty spots. ¿The benign cancer, or nevi,¿ observed immunologist/oncologist Sunil Chada, at Introgen Therapeutics in Houston, ¿are the precursors to melanoma. Not all nevi form cancers,¿ he added, ¿but it¿s believed that in order for them to turn into melanomas, you have to go through this nevi stage.

¿It¿s an aggressive, rapidly invasive cancer,¿ Chada continued. ¿Its cut-off thickness as still a benign tumor is on the order of 1 millimeter ¿ less than a 16th of an inch. Up to that point it¿s quite treatable by simple surgical resection. Any deeper, the suspicion of spread is persuasive and once it¿s metastasized, therapeutic measures are limited, and prognosis poor, with five-year survival around 20 percent. Unlike most cancers,¿ Chada went on, ¿which tend to strike individuals of relatively advanced years, melanoma¿s victims are young people ¿ sun-worshippers. Melanoma is the most frequent cancer in women between 25 and 30 years of age. It has replaced leukemia as responsible for lost work hours in the U.S. ¿ and its incidence is increasing.¿

Chada, Introgen¿s director of research and development, is a co-author of an article in the International Journal of Cancer, dated October 2001. Its title: ¿Down-regulated melanoma differentiation associated gene (MDA-7) expression in human melanomas.¿ Its senior author is immunologist/oncologist Elizabeth Grimm at M.D. Anderson Cancer Center, also in Houston.

New Gene Posits New Paradigm

¿Our principal finding in this paper,¿ Grimm told BioWorld Today, is that the mda-7 gene¿s expression is lost as melanoma tumors progress and metastasize. I think the gene is providing a new paradigm,¿ she continued, ¿a new class of tumor suppressor molecules that may have roles in the immune system as well.¿

¿Mda-7, which resides on the long arm of human chromosome 1,¿ Chada recounted, ¿was discovered in 1945 by Paul Fisher at Columbia University, and licensed to Corixa Corp. in Seattle, which in turn licensed it to Introgen.

¿It turns out to be a novel class of tumor suppressor genes,¿ Chada pointed out. ¿It¿s secreted like immune-system cytokines. So we took this mda-7 tumor suppressor gene and put it into our adenovirus delivery vehicle, which we use to treat a wide variety of cancer cells.

¿Grimm, who runs the melanoma core laboratory at M.D. Anderson,¿ Chada related, ¿evaluated a wide variety of melanoma specimens. Her in vitro experiments, with tissue samples from melanoma patients, showed that the mda-7 protein is expressed by the gene in normal skin melanocytes. They looked at these nevi cells and found that while they did express mda-7 proteins in normal cells, as the melanoma cancer progressed, that mda-7 tumor suppressor is lost.

¿Next,¿ Chada went on, ¿we asked: What happens when we put the gene back in those melanoma cancer cells lacking mda-7?¿ We treated these melanoma cells with our INGN 241 gene vector, and got very high levels of mda-7 gene expression. And the result of that tumor suppressor protein was that these cells underwent apoptosis and died.

¿When we took normal melanocytes, which do express mda-7 protein, and treated them with INGN 241, they expressed higher levels than the normal cells, and those normal melanocytes did not undergo apoptosis.¿

Summing up the results of all these specific tests in vitro, Chada said, ¿I think we¿ve clinched the clinical expression of mda-7 protein in melanoma, and showed that when it is lost, cancer metastasis progresses. Then we¿ve gone back into these cells and showed that when we treat them with the INGN 241 gene delivery vector, those cells specifically undergo apoptosis and die.¿

The Introgen construct is now completing Phase I trials at Baylor University in Dallas. ¿They began at the end of November last year,¿ Chada noted, ¿to look at the pharmacokinetics and dynamics of INGN 241. So we¿re treating patients with various solid tumors, and then at various times afterward resecting their tumor and analyzing them for levels of mda-7 protein expression. Also, how broadly distributed the vector is within the tumor. And what¿s the range of effect of secreted mda-7. We¿ll be reporting interim data on this Phase I trial in December.¿

Human Studies In Vitro, Not In Vivo

¿Safety concerns appear minimal,¿ Grimm observed, ¿but we have to wait for Phase I resolution.¿ Once beyond that hurdle, she added, ¿I¿m particularly interested in the immune potential of mda-7. The fact that the gene is lost when melanocytes become malignant, as we reported in the journal, and because mda-7 appears from many perspectives to have features of interleukin that mediate immune responses, we believe the gene holds promise for immunomodulation, especially at the tumor sites.¿

Her next research move, she observed, is ¿not to go preclinically into an animal, but directly to human trials. Animal trials,¿ Grimm explained, ¿have not had fidelity in cytokines to date ¿ not led to human applications. That¿s why I wouldn¿t go in vivo in preclinical animals, but I would do so in vitro in human materials only, but with fresh human blood lymphocytes and perhaps human tumor cells to study the role of mda-7 as a cytokine. So we would not administer it to the patient at this time.

¿What we really want to do is look at functional studies. Try to induce mda-7 to induce. So our next step,¿ Grimm concluded, ¿is to study the relevance of mda-7 till we can resolve the scientific basis of its functional mechanism with the goal of cancer therapy in mind.¿

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