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Researchers have shown, via a phase I trial, that the relationship between nerves and prostate cancer in perineural invasion is susceptible to therapeutic intervention with neurotoxic agents such as onabotulinumtoxinA (Botox).
Houston-Gustavo Ayala, MD, and colleagues at the University of Texas Health Science Center, Houston, have been exploring the interaction between nerves and prostate cancer in perineural invasion for more than a decade. They have shown that nerves and cancer cells establish a symbiotic relationship that promotes growth of both cell types. The Houston team was the first to describe the nerve-cancer cell microenvironment and its regulatory mechanisms in detail.
Now they have shown, via a phase I trial, that the relationship is susceptible to therapeutic intervention with neurotoxic agents such as onabotulinumtoxinA (Botox).
“This is a proof of principle. We wanted to show that the biology of nerves and cancer cells that we found in earlier work exists in humans, and we have done that. This is a new biology, one that has not been targeted until now,” Dr. Ayala told Urology Times. Dr. Ayala, professor and distinguished chair in pathology and laboratory medicine at the University of Texas Health Science Center, presented the findings at the 2012 AUA annual meeting in Atlanta.
To arrive at these conclusions, Dr. Ayala and his colleagues evaluated the effect of onabotulinumtoxinA injections in tissue samples obtained from three patients with bilateral Gleason 6-7 tumors. The neurotoxin (100 U in a 2.0-mL volume) was injected unilaterally into one lobe, with the contralateral lobe receiving a saline injection as a control. The patients underwent a radical prostatectomy at 4 weeks and tissues were evaluated for endpoints.
Atrophy observed in cells injected with toxin
Cancer cells taken from the onabotulinumtoxinA-injected lobes exhibited a general atrophic effect and extensive degenerative characteristics compared to cells in the saline-injected lobe. Nerve density was significantly decreased in one patient and showed a trend toward decrease in the other two patients. Microvessel density increased in one patient and showed no change in the other patients. Taken as a whole, the data suggest that the neurotoxin has a selective atrophic effect on the organ’s nerves but little to no impact on its vasculature.
The authors noted that the gene profile of onabotulinumtoxinA-treated tumors had extensive similarities to profiles of prostate cancer tumors arising in spinal cord injury patients. They felt this confirmed that the effects of onabotulinumtoxinA in the prostatic environment were primarily denervation.
“The Botox strategy could be easily translated to an active surveillance cohort,” the authors concluded.
“The question is how are we going to use this in phase II. Should it be used as a neoadjuvant agent in high-grade cancer, or are we going to use it in a watchful-waiting cohort or use it as a localized therapy in intermediate cases? All of the above are possible,” Dr. Ayala told Urology Times.
Dr. Ayala noted that nerve-cancer cell phenomena were not confined to prostate cancer and that onabotulinumtoxinA was not the only neurotoxin that might have utility. He said he was working with a number of groups exploring the potential of these and earlier findings in a variety of cancers.UT