By David N. Leff
This year in the U.S., some 26,800 women, most of them post-menopausal, will be diagnosed with ovarian cancer. Even though this malignancy represents only 4 percent of all female cancers, it will kill an estimated 14,200 patients in 1997.
One who has survived ovarian cancer well beyond the life expectancy of her disease is a woman from Oregon in her late sixties, now under treatment at Stanford University Medical Center. On Aug. 20, 1996, this patient entered a Phase I clinical trial at Stanford of an anticancer antisense DNA compound, developed by ISIS Pharmaceuticals Inc., of Carlsbad, Calif.
Her physician, oncologist Branomir Sikic, reported on her case on May 19, to the American Society of Clinical Oncology (ASCO) meeting, in Denver.
"Over the course of about 18 months before going on the study," Sikic said, "this woman had failed the standard chemotherapy regimen in ovarian cancer, which is cisplatin combined with paclitaxel. She'd had 10 cycles of that, and her tumor doubled its size. In the month before beginning antisense treatment, it was a large abdominal mass of eight by five centimeters [about two by three inches] square.
"In the nine months since that patient came to us," Sikic continued, "that tumor has continually decreased to the point that it is now about 40 percent of its original size, about five by three centimeters [one by two inches].
"If she had chosen no new therapy," Sikic said, "she would not have survived for these nine months. It's very likely that she would have died with complications of her cancer."
ISIS Vice President of Drug Development Andrew Dorr told BioWorld Today, "That signal event is simply the first time that an antisense oligonucleotide has been shown to have a causal response in a patient with a solid tumor. That's an important step in the development of this kind of drug against cancer."
Dorr is a co-author of Sikic's poster presentation at ASCO, which bore the heading: "A Phase I trial of an antisense oligonucleotide targeted to protein kinase C-* [ISIS 3521], delivered by 21-day continuous intravenous infusion." (See BioWorld Today, Jan. 25, 1996, p. 1.)
All told, the Phase I study enrolled 17 cancer patients, Sikic said: "four ovarian, three colon, three pancreas, three sarcomas and one of each stomach, breast, esophagus, lung and lymphoma. They were the usual Phase I population," he pointed out, "which means patients who did not have a curative therapy option and were willing to volunteer for a new treatment."
One of those three other ovarian tumor patients, Dorr observed, "clearly did not respond. The two others, however, have dropped their CA-125 readings. CA-125," he explained, "is a very specific and quite sensitive marker for ovarian cancer."
Treatments in the Phase I human study, he observed, "have been well tolerated thus far, with fatigue the main dose-related side effect."
Sikic made the point that only one of the 17 suffered a reaction to the drug requiring blood transfusion. It reversed when the drug was withdrawn. "I would say," he observed, "that in comparison to chemotherapy, the side effects were mild."
The target of ISIS' antisense compound is a protein kinase, PKC-a. "This is a signal transduction protein," Dorr explained, "that relays signals to the tumor from receptors for epidermal and platelet-derived growth factors, things like that, which are important in the malignant process. It tells the cell to grow, to proliferate."
ISIS 3521 is a 20-base antisense-DNA sequence that hybridizes to and inhibits PKC-a.
"One of the key features of this treatment," Sikic pointed out, "is that it's systemic, not a local injection. So the antisense sequence is given by intravenous infusion. It's targeted at one gene, so the beauty of antisense drugs is that they can be extremely specific. When you get to 20 base pair lengths of DNA, you can actually pick sequences that no other gene has."
Given intravenously, Dorr pointed out, ISIS 3521 doesn't head straight for the target tumor. Rather, it spreads from the bloodstream to all bodily tissues, including the tumor, in order to deprive the cancer of its PKC-a co-conspirator. "The targets that we've chosen," he said, "are those we believe cancers may be more dependent on, and don't have any salvage pathways around. We're inhibiting the synthesis of those proteins, which don't seem to be as important to normal tissues as they are to malignancy."
Doubling Up On Anticancer Compounds
Preclinical experiments indicated that in addition to depleting PKC-a, ISIS 3521 sensitizes most cancers to chemotherapy. "So in my view," Sikic said, "this rather dramatic remission in that patient with ovarian cancer in our Phase I trial doesn't necessarily mean that we'll be using antisense DNA treatment by itself in the future.
"We now plan to follow up on these results," he went on, "by doing a Phase II trial specifically targeted at patients with advanced ovarian cancer, beginning in August of this year at Stanford. But we also are going to do another Phase I study as a sequel to this one, which will add carboplatin and paclitaxel to the antisense treatment. Those two drugs are used together in ovarian and lung cancers, and they would be natural targets for combination with antisense.
"So in the next Phase I," Sikic concluded, "I would hope to attract patients who have incurable, metastatic lung cancer, and who would like to try something new. Then, if we have an interesting remission rate with PKC-a plus the chemotherapy, the natural progression of studies would be a comparison of chemo alone vs. chemo with antisense DNA." *