Medical Correspondent, OncoLink
Last Modified: November 1, 1999
"Can chemopreventive therapy restore molecular defects in target tissues?" That was the key question posed by Dr. Wang Ki Hong, Chair of Thoracic Oncology at the University of Texas M.D. Anderson Cancer Center, in his keynote address to a packed hall this morning.
Speaking on "The Genetic and Molecular Basis for Prevention: Head and Neck Cancer as a Model," Dr. Hong described the research that he and his colleagues in the Radiation Therapy Oncology Group (RTOG) have done on this very question for more than ten years. Overall, they have found that chemoprevention with an agent called retinoic acid can reverse lesions in the larynx and return the tissue to a normal appearance. However, as Dr. Hong noted, the "genetic scars" that are associated with cancer remain, suggesting that later cancer development is still a distinct possibility-and that more studies are necessary.
Thus, the talk was an appropriate beginning for the conference's first day of scientific sessions. Dr. Hong's chronological overview of his team's work since the mid-1980s eloquently demonstrated the nature of research as a cumulative process. And the fact that he ended the talk with unanswered questions and plans for future research suggested the importance of the exchanges that will take place in San Antonio over the next three days.
Chemoprevention is the use of natural or synthetic agents to reverse, suppress, or prevent the progression of premalignant disease before it develops into invasive cancer. Dr. Hong pointed out that oral and laryngeal cancers are excellent candidates for chemopreventive studies because of the easily identifiable precancerous lesions that develop first (for example, the white mouth patches called leukoplakia that develop into oral cancer). These cancers also prevent certain treatment challenges. In addition to dealing with the cancerous lesions, physicians must look forward to the possibility of three main "roadblocks": local-regional recurrence, distant metastases, and the development of second primary tumors. Combining molecular, genetic, and treatment studies, Dr. Hong and his colleagues set out to determine whether chemoprevention with an agent called retinoic acid could actually halt the process whereby precancerous lesions turn into cancer. Their concern was not just with returning the abnormal tissue to normal, but also correcting defects at the molecular and genetic levels-in other words, correcting not just appearance but the biological basis for the disease.
Dr. Hong outlined the series of clinical trials that were conducted in the mid-1980s through the early 1990s. These studies demonstrated that chemopreventive therapy using retinoic acid (more specifically, high-dose 13-cis-retinoic acid) reversed the development of oral leukoplakia and prevented the development of second primary tumors in patients who had been cured of an initial cancer. But there was one "catch": once the retinoid treatment was stopped, its protective effect started to decline after three years. As time passed, the rate of cancer development for those participating in the trial was the same, regardless of whether or not they had received the retinoid treatment. In other words, said Dr. Hong, the "biological effect" was only temporary. Also, the researchers found that, while some patients were responsive to the therapy, others were "retinoid resistant."
Through molecular studies, said Dr. Hong, the researchers were able to identify some of the biological reasons behind retinoid resistance. The suppression of a certain Retinoic Acid Receptor, or RAR, appeared to play a role in early-stage head and neck carcinogenesis, suggesting a breakdown in the hormone signaling pathway that would allow retinoic acid to take effect. More advanced premalignant lesions that were therapy-resistant also were associated with p53 protein expression and genetic instability. This led the researchers to look for ways to combine chemopreventive therapy with biological therapy, in an attempt to overcome this resistance.
Dr. Hong described how he and his colleagues developed yet another clinical trial, this one involving patients with moderate to severe dysplasia of the mouth and larynx. Some patients received the chemopreventive retinoid therapy along with vitamin E and the immune-system booster interferon. The results, which were just published last month, showed what Dr. Hong called "a striking difference in response by site." Lesions of the larynx were much more responsive to this combined therapy than oral lesions, with the tissues returning to a strikingly normal appearance. But molecular studies showed that "there were persistent genetic changes, even in those who responded," said Dr. Hong. While p53 mutations were found to be less frequent, certain abnormal genetic changes-what Dr. Hong called "genetic scars"-persisted. He suggested that this was in line with researchers' earlier conclusion about retinoid chemoprevention: while it may delay cancer onset, perhaps it cannot prevent cancer development completely.
Dr. Hong closed his research overview by posing the question that he and his colleagues now want to answer: "Can you get rid of these persistent genetic scars?" In other words, could molecularly-targeted chemoprevention work? He described how the group is now focused on studies that would integrate p53 gene therapy with retinoid-based chemoprevention. In other words, researchers will attempt to lower p53 expression in precancerous lesions before administering the chemoprevention. Dr. Hong also reviewed his work on developing a risk model for the development of second primary tumors that combines genetic, molecular, and behavioral factors. He pointed out that such a model could provide the basis for tailoring chemoprevention to the particular situation.
While more studies remain to be done, the work done thus far provides a useful glimpse into the research process-and the promise of the newest strategies for halting the carcinogenic process before tissues actually become cancerous.
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