By David N. Leff
The prostate gland — to adapt a famous phrase — is a riddle wrapped in a mystery inside an enigma.
This protean puzzle will bedevil U.S. urologists with multi-choice dilemmas over 300,000 times in 1997, as they diagnose and treat that many new cases of prostate cancer. And some 42,000 men, most of them along in years, will die of prostatic adenocarcinoma.
Prostates tend to grow at first in a non-cancerous mode, called benign prostatic hyperplasia (BPH). So the first riddle is to determine whether a swollen gland is malignant or benign.
Short of a biopsy, itself invasive, the best differential diagnostic to date is a blood test for prostate-specific antigen (PSA). This protein’s increase reflects the growth of the gland, but only repeated sampling over time tells the rate at which PSA accumulates in blood, a clue as to malignancy.
Then comes the mystery: Is that probable cancer contained within the walls — the capsule — of the gland, where it does little harm? Or has it jumped that reservation, and spread to other organs in the body? Second-guessing is too late. Once metastasized, there is virtually no curative treatment. (See BioWorld Today, Oct. 15 and Nov. 22, 1996, p. 1.)
A recently discovered prostate-related gene shows potential in unmasking prostate cancer, monitoring its home-base growth and metastatic spread. Conceptually, at least, this prostate-tumor-inducing gene (PTI-1) — may some day harness antisense technology to reverse the cancer in its tracks.
An article in the current issue of Cancer Research, dated Jan. 1, 1997, tells this still-unfolding story. Its title: “Human prostatic carcinoma oncogene PTI-1 is expressed in human tumor cell lines and prostate carcinoma patient blood samples.“
The article’s senior author is molecular biologist Paul B. Fisher, who directs the neuro/oncology program at Columbia University’s College of Physicians & Surgeons in New York.
“What’s newsworthy about this PTI-1 gene,“ Fisher told BioWorld Today “is, first, the fact that it turns out to be an extremely sensitive indicator of potential prostatic cancer beyond the capsule into the blood stream. Second, that it’s expressed as well in other adenocarcinomas, including breast, colon, kidney and lung. This indicates that we should be able to detect it in a broad spectrum of cancer tissues.“
This very potential raises problems of its own: “We’re all caught in the same dilemma,“ Fisher observed. “How do you know you have detected a cancer that’s going to turn out to be aggressive, versus one that’s going to be indolent — easily treatable?“
He and his co-authors spiked a large quantity of normal cells with a small aliquot of prostate tumor cells. “We could pick up a single PTI-1 expressing cell in 100 million normal ones,“ Fisher said, and observed, “That is at least 100-fold more efficient than PSA.“
In a somewhat more clinical in vitro mode, they analyzed 30 unidentified samples of various cells from as many cancer patients, coded one through 30. All tested negative for PTI-1, indicating they did not come from prostatic cancer patients. But one sample checked positive for metastatic renal cell carcinoma, to which the gene is also sensitive.
Gene Goes For Metastases Only
Analysis of RNA from the 30 blood samples indicates that PTI-1 is expressed in patients with prostate cancer that has spread beyond the gland, but not in patients whose cancer is confined to the prostate or those without prostatic cancer.
“Not only did we not get any false positives,“ Fisher pointed out, “but the one supposedly false positive turned out to be a true positive. We couldn’t have asked for anything better.“
But trouble erupted in this laboratory paradise.
The full-length 2,123-base pair PTI-1 cDNA encodes a truncated and mutated human elongation-factor peptide. One of its domains, the 5’ untranslated region, has 85 percent of its DNA sequence identical with that of a particularly vicious and elusive pathogen, Mycoplasma hypopneumoniae.
The propensity of this minute (two to three microns in diameter), wall-less bacterium to contaminate cultures, and indeed whole laboratories, is legendary. Decontamination consisted, traditionally, of “burning down the lab and rebuilding.“
Fisher’s lab followed a different route to cleanse the smirch from their gene’s good name.
“This allegation,“ he recalled, “opened up a Pandora’s box in a good way and a bad way. The bad way, of course, was that the first thing you get hit with from your adversary is that this sequence homology is a sign of mycoplasma contamination of our cDNA library. That forced us to go back in and prove the legitimacy of this gene.“
They found that “this unique region, which shouldn’t be in the human genome, actually is, and in normal tissue.“ The team was able to demonstrate the suspect sequence in normal human kidney and brain cells.
Early in evolution, Fisher said, that primitive mycoplasmal-like sequence may have been transactivated — as an infected cell reproduces a viral genome — into some ancestor of the PTI gene.
Solving Sinister Enigma Of Mycoplasma
“We were able to show that this unique mycoplasmal-like sequence, fused to the eukaryotic gene, is in fact expressed only in cancer,“ he said. “If the gene were simply a mycoplasmal contamination, why would it pick up only prostatic cancer in coded samples?
“We’re predicting,“ Fisher said, “that this gene will be a dominant oncogene. So whereas p53 is a tumor suppressor element, a stop signal, PTI-1 could be the accelerator for cancer progression.“
Columbia has filed a patent application for the PTI-1 invention, which will be assigned to GenQuest Inc., of New York. (See BioWorld Today, July 17, 1996, p 1.)
And Physicians & Surgeons is now initiating collaborations with two other major New York hospitals, Sloan-Kettering and Mt. Sinai, to validate the diagnostic and prognostic potential of Fisher’s PTI-1 gene in an expanded patient population.
“Taking the gene out of a single institution into multiple centers,“ Fisher said, “may be useful for determination of carcinomas in general that have escaped, and now have metastatic potential.
“Theoretically, this could be part of a routine blood test for screening populations at risk of cancer, as well as patients undergoing chemotherapy,“ he said. “It would look for the absence of cells in the circulation, the presence of which would indicate residual tumor mass.“
Beyond that, Fisher concluded, “the second avenue is therapeutics. My business is to find a way to really treat the diseases as non-invasively as possible.“