Targeting the Neural Microenvironment in Prostate Cancer: A Neoadjuvant Botox Clinical Trial
Diego Floretin, Yi Ding, Dandan He, Chad Creighton, Anna Frolov, Olga Dakhova, Yiqun Zhang, Christopher Smith, Michael Ittmann, Gustavo Ayala. Baylor College of Medicine, Houston, TX; Diana Helis Henry Medical Research Foundation, New Orleans, LA; University of Texas Health Sciences Center Medical School, Houston, TX
Background: Nerve-cancer interaction provides a survival advantage for prostate cancer through perineural invasion, neurogenesis, and regulation of epithelial homeostasis. Physical and chemical (Botox) denervation affect tumor growth in vivo, using similar mechanisms. As clinical translation and proof-of-concept study, we next evaluated tissues from three patients enrolled in a Phase I clinical trial to assess the effects of Botox injections on specific endpoints of prostate tumor biology.
Design: Patients with bilateral Gleason 6-7 tumors received unilateral Botox injections (100 U in a 2.0-ml volume) into one lobe and a vehicle control injection into the contralateral lobe. Radical prostatectomy was performed 4 weeks later and biological endpoints studied in the pathologic specimen.
Results: Examination of tissues revealed a general atrophic effect in prostate cancer cells obtained from Botox-injected lobes. We identified extensive degenerative features, reduced cytoplasm and pyknotic nuclei. TUNEL studies revealed a significant increase in the apoptotic ratio in the botox side than saline injected tumor. No significant changes were observed in the proliferation index, measured by Ki67. No significant changes were noted in microvessel density while nerve density was significantly decreased. These data suggest that Botox has an atrophic effect on the nerves, without affecting the tumor vasculature. The gene profile of the Botox treated tumors had extensive similarities with those of prostate cancer arising in patients with spinal cord injury, confirming that the effect is due mainly to denervation.
Conclusions: Together, previous experimental tumor study, preliminary Phase I Clinical trial study, and gene expression analysis of prostate tumors from patients with spinal cord injuries suggest that the nerve-cancer cell interaction is a key and critical element in prostate cancer cell survival and tumorigenicity. Targeting the neural microenvironment is becoming a necessity. Botox, as a chemical denervation agent, has effects on human prostate cancer.
Category: Genitourinary (including renal tumors)
Wednesday, March 6, 2013 1:00 PM
Poster Session VI # 151, Wednesday Afternoon