innovative therapies for human prostate cancer

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Oa22-5347~601-0002$03.00/0 Copyright 0 1998 by AMERICAN UROLOGICAL ASSOCIATION, INC. THE JOLWAL OF UROLQGY Vol. 160, 2, July 1998 Printed in U.S.A. This Month in Investigative Urology INNOVATIVE THERAPIES FOR HUMAN PROSTATE CANCER Despite improvements in prevention and early detection, refinements in surgical technique, and advances in radio- and chemotherapy, the ability to cure many patients of prostate cancer remains elusive. The continuing challenge is the successful management and eradication of both recurrent and metastatic disease. Recent years have seen much investigation into potential therapies for prostate cancer. Several therapeutic applications have demonstrated promise in pre-clinical studies. In this month‘s Investigative Urology, Miki and associates focus on anti-angiogenic therapy, and Troy and associates highlight dendritic cell therapy. Ultimately, the outcome of prostate cancer depends upon the cancer’s capacity for unhindered growth, local invasion, and the establishment of distant lesions. Endothelial cells from the surrounding stroma must be recruited to establish a microcirculation to support and disseminate the proliferating cancer cells, a process called angiogenesis. The mechanisms of angiogenesis extend far beyond the formation of new blood vessels. Many factors that mediate neovascularization also influence tumor cell invasion, migration, and spread. Anti-angiogenic theory holds that the inhibition of these factors will prevent vascular support to the primary and metastatic lesions, and curtail essential components of the metastatic cascade. Over the past few years our understanding of the mechanisms of angiogenesis has matured. A plethora of anti-angiogenic agents have recently become available for study, including TNP-470. TNP-470, a synthetic analogue of the antibiotic fumagillin, limited androgen-independent prostate cancer cell growth in a mouse xenograft model.’ Miki et al. investigated the inhibitory effects of TNP-470 on primary tumor growth and pulmonary metastases in athymic mice inoculated with AT6.3 rat prostate cancer cells. At higher doses, TNP-470 significantly decreased the quantity and size of lung metastases after both subcutaneous implantation and intravenous injection, suggesting a role for this agent in preventing tumor dissemination. The ATC6.3 pulmonary metastasis xenograft system, however, is a poor surrogate for clinical human prostate cancer, which metastasizes primarily to bone, not lung. Sophisticated in vivo prostate tumor progression and bone metastasis models will evaluate the application of TNP-470, as well as newer anti-angiogenic agents, in systems that better recreate the natural history of human prostate disease. The true significance of anti-angiogenic agents in prostate cancer will not be known until after clinical trials are completed. Some cancer therapies have been directed at modulating and exploiting components of the immune system, the goal being to stimulate host T-lymphocytes to attack primary and metastatic tumor sites. Dendritic cells, potent antigen presenting cells, are critical for eliciting T-cell mediated immune responses. Dendritic cell therapy for prostate cancer employs host dendritic cells to introduce processed prostate cell membrane antigen to T-lymphocytes. If such antigens are viewed as “foreign”by the T-cells, a vigorous immune response may develop against established prostatic lesions. Immunologic memory may be induced to prevent recurrent disease. Clinical dendritic cell therapy for prostate cancer has involved ex vivo exposure of dendritic cells to processed PSM antigen, with subsequent expansion and re-introduction to the host. The results have been disappointing. Troy and associates attempted to characterize the dendritic cells present in primary prostate tumors. The results suggest that only a modicum of dendritic cells traffic into primary lesions and those that are present are only weakly activated. This could result from inhibitory influences within the prostate tumor milieu, but most likely represents the absence of a robustly immunogenic prostate tissue surface antigen. Without such proteins, effective anti-tumor immune response is unlikely. The future of dendritic cell therapy depends on the identification of suitable antigenic targets from the surface of primary and metastatic lesions, which could be used to induce an immune response. Novel immunogenic prostate tissue specific antigens, and techniques to enhance the expression of antigens that are already present, must be devised in tandem with strategies to repress immuno-inhibitory influences within the prostate tumor environment. Mitchell H. Sokolofi M.D. Molecular Urology and Therapeutics Program Department of Urology University of Virginia School of Medicine REFERENCES 1. Yamaoka, M., Yamamoto, T. and Ikeyama, S.: Angiogenesis inhibitor TNP-470 potently inhibits the tumor growth of hormone- independent human breast and prostate carcinoma cell lines. Cancer Res., 53 5233, 1993. 2

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Oa22-5347~601-0002$03.00/0

Copyright 0 1998 by AMERICAN UROLOGICAL ASSOCIATION, INC. THE JOLWAL OF UROLQGY Vol. 160, 2, July 1998

Printed in U.S.A.

This Month in Investigative Urology

INNOVATIVE THERAPIES FOR HUMAN PROSTATE CANCER Despite improvements in prevention and early detection, refinements in surgical technique, and advances in radio- and

chemotherapy, the ability to cure many patients of prostate cancer remains elusive. The continuing challenge is the successful management and eradication of both recurrent and metastatic disease. Recent years have seen much investigation into potential therapies for prostate cancer. Several therapeutic applications have demonstrated promise in pre-clinical studies. In this month‘s Investigative Urology, Miki and associates focus on anti-angiogenic therapy, and Troy and associates highlight dendritic cell therapy.

Ultimately, the outcome of prostate cancer depends upon the cancer’s capacity for unhindered growth, local invasion, and the establishment of distant lesions. Endothelial cells from the surrounding stroma must be recruited to establish a microcirculation to support and disseminate the proliferating cancer cells, a process called angiogenesis. The mechanisms of angiogenesis extend far beyond the formation of new blood vessels. Many factors that mediate neovascularization also influence tumor cell invasion, migration, and spread. Anti-angiogenic theory holds that the inhibition of these factors will prevent vascular support to the primary and metastatic lesions, and curtail essential components of the metastatic cascade.

Over the past few years our understanding of the mechanisms of angiogenesis has matured. A plethora of anti-angiogenic agents have recently become available for study, including TNP-470. TNP-470, a synthetic analogue of the antibiotic fumagillin, limited androgen-independent prostate cancer cell growth in a mouse xenograft model.’ Miki et al. investigated the inhibitory effects of TNP-470 on primary tumor growth and pulmonary metastases in athymic mice inoculated with AT6.3 rat prostate cancer cells. At higher doses, TNP-470 significantly decreased the quantity and size of lung metastases after both subcutaneous implantation and intravenous injection, suggesting a role for this agent in preventing tumor dissemination. The ATC6.3 pulmonary metastasis xenograft system, however, is a poor surrogate for clinical human prostate cancer, which metastasizes primarily to bone, not lung. Sophisticated in vivo prostate tumor progression and bone metastasis models will evaluate the application of TNP-470, as well as newer anti-angiogenic agents, in systems that better recreate the natural history of human prostate disease. The true significance of anti-angiogenic agents in prostate cancer will not be known until after clinical trials are completed.

Some cancer therapies have been directed at modulating and exploiting components of the immune system, the goal being to stimulate host T-lymphocytes to attack primary and metastatic tumor sites. Dendritic cells, potent antigen presenting cells, are critical for eliciting T-cell mediated immune responses. Dendritic cell therapy for prostate cancer employs host dendritic cells to introduce processed prostate cell membrane antigen to T-lymphocytes. If such antigens are viewed as “foreign” by the T-cells, a vigorous immune response may develop against established prostatic lesions. Immunologic memory may be induced to prevent recurrent disease. Clinical dendritic cell therapy for prostate cancer has involved ex vivo exposure of dendritic cells to processed PSM antigen, with subsequent expansion and re-introduction to the host. The results have been disappointing.

Troy and associates attempted to characterize the dendritic cells present in primary prostate tumors. The results suggest that only a modicum of dendritic cells traffic into primary lesions and those that are present are only weakly activated. This could result from inhibitory influences within the prostate tumor milieu, but most likely represents the absence of a robustly immunogenic prostate tissue surface antigen. Without such proteins, effective anti-tumor immune response is unlikely. The future of dendritic cell therapy depends on the identification of suitable antigenic targets from the surface of primary and metastatic lesions, which could be used to induce an immune response. Novel immunogenic prostate tissue specific antigens, and techniques to enhance the expression of antigens that are already present, must be devised in tandem with strategies to repress immuno-inhibitory influences within the prostate tumor environment.

Mitchell H. Sokolofi M.D. Molecular Urology and Therapeutics Program Department of Urology University of Virginia School of Medicine

REFERENCES

1. Yamaoka, M., Yamamoto, T. and Ikeyama, S.: Angiogenesis inhibitor TNP-470 potently inhibits the tumor growth of hormone- independent human breast and prostate carcinoma cell lines. Cancer Res., 53 5233, 1993.

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