By David N. Leff

The only good thing you can say about pancreatic cancer is that once it¿s diagnosed, the patient doesn¿t live very long ¿ and so doesn¿t suffer very much.

Some 29,200 men and women in the U.S. will be diagnosed with pancreatic cancer this year, and about 28,900 of them will die in short order. Two percent will succumb within a year, and very few survive five years. Surgery, radiation and chemotherapy scarcely affect these mortality statistics. By the time of diagnosis, the disease in almost all cases will have metastasized to liver and lungs ¿ a swift death sentence.

Pancreatic cancer sets in around 55 years of age. Its warning sign is abrupt weight loss and severe abdominal pain. First aid for this agony is to bend over or curl up in the fetal position. Then as more severe symptoms appear, such as jaundice and gastrointestinal hemorrhage, the pain becomes intense enough to warrant narcotic analgesics, such as morphine.

The pancreas is a 6-inch-long gland that nestles south of the stomach and north of the intestine¿s duodenum. It secretes a whole battery of essential hormones, and synthesizes the islets of Langerhans, which make insulin.

While no respecter of persons, pancreatic cancer seems to favor people in the world of entertainment. Among its well-known victims have been radio and television comedian Jack Benny, composer Henry Mancini, actor Steve McQueen and actress Donna Reed.

¿It seems that in this cancer,¿ observed molecular biologist Paul Fisher, at Columbia University in New York, ¿anything that can go wrong will go wrong. Not only does it go wrong,¿ he added, ¿but later on in the course of the disease a lot of the tumor suppressor genes that normally prevent cancer get mutated. So you have three different active suppressor genes, all of which show high levels of mutation in pancreatic cancer.

¿They are p53, which becomes inactivated in about 75 percent of patients with pancreatic cancer; also the retinoblastoma-1, in greater than 90 percent; and a gene called DCC, which gets inactivated, deleted, in colorectal carcinoma. The list goes on and on. What we believe happens,¿ Fisher continued, ¿is that the whole evolution of this disease goes through changes in oncogenes and in suppressor genes. This may explain why pancreatic cancer is so refractory to conventional therapy. It¿s a real genetic zoo.¿

Fisher is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Aug. 28, 2001. Its title: ¿A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells.¿

¿I think the PNAS observations are very provocative,¿ Fisher told BioWorld Today, ¿and, with a little tweaking, may lead to an effective therapy for this devastating and aggressive disease.¿ He is professor of clinical pathology at Columbia¿s College of Physicians & Surgeons.

The paper reports that mda-7, a gene that stops tumor growth, together with a snippet of DNA that turns off the K-ras cancer oncogene, killed pancreatic cancer cells in vitro, and prevented tumors from growing in mice.

¿At this stage,¿ Fisher pointed out, ¿mda-7¿s essential role in the body is not known. But we do know that it goes from being expressed in a melanocyte to having no expression at all in the majority of metastatic melanomas. We envision from this that mda-7¿s normal physiological role may be in regulating cellular proliferation and growth. It¿s expressed in the thymus, in spleen and peripheral blood lymphocytes. The structure of this gene causes it to be secreted from cells. So it actually turned out to be a cytokine, part of the immune system¿s interleukin-10 gene family.

¿And in the human genome,¿ Fisher went on, ¿the mda-7 gene maps to a superfamily locus right on the long arm of chromosome 1. This is a very important genomic neighborhood in disease. It¿s the only one of that superfamily with the interesting ability to selectively cause the programmed death of cancer cells.¿

It Takes Two To Tango

Mda-7¿s dance partner turned out to be the tumor promoter oncogene K-ras. ¿K-ras is a frequently altered gene in a number of neoplasms,¿ Fisher explained. ¿Besides pancreatic, it¿s in gastric cancer, small-cell-lung carcinoma and a number of other malignant disease states. The normal function of the ras family is to regulate cell growth and cell proliferation. When mutated it results in changes of proliferative ability and response to growth factors. So K-ras acts almost like an on switch that allows cancer cells to continue to proliferate. K-ras in an activated form causes this switch to be continually on. It opens the door and allows cancer cells to keep growing with the throttle pulled down.¿

For Fisher and his co-authors to choreograph the mda-7/K-ras tumor-killing tango, he recalled, ¿took a little bit of serendipity, and also Pasteur¿s inventiveness in favoring the prepared mind. It was quite intriguing to us that we could go in with very high levels of mda-7, see it in messenger RNA in pancreatic cancer, but never get any tumor killing. So we thought: Perhaps this was because K-ras might be blocking the ability of the mda-7 gene to function.¿

¿Then we asked: Is K-ras involved in some way in preventing mda-7 from functioning?¿ So we selectively targeted for inactivation of K-ras, and then asked: Would mda-7 now induce a tumor-killing effect where before it would not?¿ And the answer was a resounding yes.¿¿

Third Patent Pending; Clinicals, Too

¿We blocked K-ras by using antisense oligonucleotides, and made a gene-expression construct that specifically targeted K-ras. This caused a decrease in K-ras protein, and thus let mda-7 enhance the translation and stability of mRNA in producing protein, which then resulted in tumor cell death. That could open up brand-new windows of investigation and potential clinical applications,¿ he suggested.

¿The university applied to patent our invention last Friday, even as we speak,¿ he noted ¿ with Fisher as sole inventor. ¿We already have two patents on mda-7 itself,¿ he said, ¿One covers the ability of mda-7 to inhibit growth of cancer cells; the second its ability to selectively induce apoptosis in cancer cells.

¿We¿ve licensed mda-7 to [Introgen Therapeutics Inc, of Houston],¿ Fisher concluded.

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