Current Drug Targets, Volume 4, No. 3, 2003

Contents

Prostate Cancer

Guest Editor: Dr. Martin Tenniswood

Tumor Cell Hypoxia and the Hypoxia-Response Signaling System as a Target for Prostate Cancer Therapy Pp.191-196

Aristotelis G. Anastasiadis , Debra L. Bemis , Brian C. Stisser , Laurent Salomon , Mohamed A. Ghafar and Ralph Buttyan

[Abstract]

TGF-ß/Smad Signaling in Prostate Cancer Pp.197-207

Diana Bello-DeOcampo and Donald J. Tindall

[Abstract]

Antisense Targets to Enhance Hormone and Cytotoxic Therapies in Advanced Prostate Cancer Pp.209-221

Martin Gleave , Colleen Nelson, and Kim Chi

[Abstract]

Par-4 for Molecular Therapy of Prostate Cancer Pp.223-230

James Butler and Vivek M. Rangnekar

[Abstract]

Phytoestrogens and Prostate Cancer Pp.231-241

Colm Morrissey and R. William G. Watson

[Abstract]

From TGF-b to Cancer Therapy Pp.243-250

Xuemei Huang and Chung Lee

[Abstract]

Therapeutic Targets for Metastatic Prostate Cancer Pp.251-261

Terry L. Timme , Takefumi Satoh , Salahaldin A.Tahir , Hongyu Wang , Bin S. The , E. Brian Butler , Brian J. Miles , Robert J. Amato , Dov Kadmon , and Timothy C. Thompson

[Abstract]

Mouse Strains for Prostate Tumorigenesis Based on Genes Altered in Human Prostate Cancer Pp.263-279

W. C. Powell , R. D. Cardiff , M. B. Cohen , G. J. Miller and P. Roy-Burman

[Abstract]

Abstracts

[Back to top] Tumor Cell Hypoxia and the Hypoxia-Response Signaling System as a Target for Prostate Cancer Therapy

Aristotelis G. Anastasiadis , Debra L. Bemis , Brian C. Stisser , Laurent Salomon , Mohamed A. Ghafar and Ralph Buttyan

The accumulation of cancerous cells within a growing prostate tumor can deprive them of adequate vascular support. Without this support, the affected tumor cells become hypoxic, a condition that is usually unfavorable for the further growth and survival of eukaryotic cells. Mammalian cells, however, have the ability of responding to a hypoxic environment by activating a “hypoxia-response” signaling system. Ultimately, this signaling system upregulates the expression of a network of gene products that increase the propensity of the cell to survive even in this adverse environment. With increasing evidence that hypoxia and an activated hypoxia-response signaling system can influence progression (via increased angiogenic propensity and apoptotic resistance) and the therapeutic responsiveness of prostate cancer cells, this review will examine the concept of targeting hypoxia or the hypoxia-response system of prostate tumor cells as a means to suppress prostate tumor progression and metastasis or perhaps even as a means for eliminating prostate tumors in advanced prostate cancer patients

[Back to top] TGF-ß/Smad Signaling in Prostate Cancer

Diana Bello-DeOcampo and Donald J. Tindall

Adenocarcinoma of the prostate is the most common type of cancer, excluding skin cancer, and the second leading cause of cancer death in adult men in the United States. The lifetime risk for developing symptomatic prostate cancer is one in five for an American man. A pivotal step in carcinogenesis is a shift in the balance between proliferation, differentiation, and apoptosis that favors cell proliferation. Transforming growth factor-ß (TGF-ß) is a key negative growth regulator in the normal prostate. Although TGF-ß inhibits the proliferation of normal prostate cells and functions as a tumor suppressor in early tumorigenesis, it acts as a tumor promoter in later stages of tumor progression. Elevated expression of TGF-ß in prostate cancer cells is associated with poor clinical outcome. Over-expression of TGF-ß aids tumorigenesis by not only stimulating angiogenesis and suppressing the immune system, but also by acting directly on the prostate tumor cells. While prostate cancer cells become resistant to TGF-ß-induced growth inhibition and apoptosis, they retain other TGF-ß-induced responses that enhance tumorgenicity, such as induction of extracellular matrix proteins, cell adhesion proteins and proteases. These direct tumor effects are mediated primarily through Smad signaling. This review addresses the mechanisms by which prostate cancer cells may acquire TGF-ß resistance and promote tumorgenicity. Understanding the mechanisms underlying TGF-ß resistance is important for the identification and development of better diagnostic markers and more effective strategies for treating prostate cancer.

[Back to top] Antisense Targets to Enhance Hormone and Cytotoxic Therapies in Advanced Prostate Cancer

Martin Gleave , Colleen Nelson, and Kim Chi

The main obstacle to improved survival of advanced prostate cancer is our failure to prevent or treat its progression to its lethal and untreatable stage of androgen independence. New therapeutic agents designed to prevent androgen-independent progression are required. Accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anti-cancer agents that specifically inhibit a progression-relevant target. Antisense oligonucleotides, short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene, promise to show enhanced specificity for malignant cells with a more favorable sideeffect profile due to well-defined and tailored modes of action. Although not all of the challenges have been met to date, emerging clinical evidence supports the premise that antisense oligonucleotides stand a realistic chance of emerging as major partners of rationally designed anti-cancer regimens. The status of antisense targeting of several genes, including bcl-2, bcl-xL, clusterin, androgen receptor and IGFBPs, relevant to prostate and other cancers, are reviewed.

[Back to top] Par-4 for Molecular Therapy of Prostate Cancer

James Butler and Vivek M. Rangnekar

Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer deaths in American men. Although many treatment measures such as androgen deprivation, radiation therapy, and cryoablation exist for primary prostate cancer, there is currently no effective treatment for patients presenting advanced or metastatic stages of the disease. Molecular therapy offers an attractive approach to the treatment of primary prostate cancer because the prostate is not a life-sustaining organ, and a number of tissue specific promoters can be used for prostatic gene expression following relatively straightforward delivery routes. This review discusses the general molecular therapy applications in the context of prostate cancer, and most importantly, identifies the prostate apoptosis response-4 (Par-4) gene, which exclusively induces apoptosis in cancer cells and not normal cells, as a prospective molecule for therapy of the disease.

[Back to top] Phytoestrogens and Prostate Cancer

Colm Morrissey and R. William G. Watson

Androgens are required to maintain the integrity of the prostate and the survival of androgen dependent epithelial cells within the gland. Anti-androgens are the primary treatment strategy for non-localized prostate cancer, but ultimately fail over time with the development of androgen independent tumors. Estrogens affect the growth and development of the prostate and may affect the development of prostate cancer. Because of the side effects of estrogen treatment alternative therapies include the use of phytoestrogens as chemopreventative and chemotherapeutic treatment modalities.

Phytoestrogens, can cause growth arrest and in some cases apoptosis in prostate cancer cells in vivo and in vitro. This may be due to the estrogenic properties of the compounds or alternative mechanisms of action. A number of phytoestrogens have been shown to have anti-androgenic effects and anti-oxidant activities. Other mechanisms include inhibition of 5a- reductase, 17b-hydroxysteroid dehydrogenase, aromatase, tyrosine specific protein kinases and DNA topoisomerase II.

This review examines the possible relation between phytoestrogens and prostate cancer and their possible use in prostate cancer prevention or management.

[Back to top] From TGF-b to Cancer Therapy

Xuemei Huang and Chung Lee

This article will introduce a novel concept in the use of TGF-b insensitive host immune cells in cancer therapy. TGF-b is a multi-functional cytokine. At a cellular level, it mediates cellular proliferation, growth arrest, differentiation and apoptosis. Because of the above cellular effects, TGF-b is able to regulate a host of patho-physiological events in vivo , such as normal embryonic development, angiogenesis in tumor tissues, malignant transformation and immune surveillance.

As a general rule, its direct effect on cancer cells is inhibition to cancer growth. However cancer cells are able to acquire the ability to evade this inhibitory effect of TGF-b by becoming insensitive to TGF-b. Furthermore, these malignant cells are able to produce large quantities of TGF-b. The consequence of over expression of TGF-b by cancer cells is an important factor for subsequent tumor progression. The excess amount of TGF-b promotes tumor angiogenesis and immune suppression. The latter effect of TGF-b is the most devastating to the host. The present discussion is focused on the role of TGF-b insensitive immune cells in cancer growth.

The host immune system offers a natural defense program against cancer. But, this natural immune surveillance is rendered ineffective by an overproduction of TGF-b derived from the tumor cells. Rendering the host immune cells insensitive to TGF-b in a gene therapy program offers a hope for us to successfully combat against cancer. Based on the above discussion, it is encouraging that there is a possibility for us to achieve a cure in cancer using TGF-b insensitive immune cells in gene therapy.

[Back to top] Therapeutic Targets for Metastatic Prostate Cancer

Terry L. Timme , Takefumi Satoh , Salahaldin A.Tahir , Hongyu Wang , Bin S. The , E. Brian Butler , Brian J. Miles , Robert J. Amato , Dov Kadmon , and Timothy C. Thompson

Prostate cancer is the most commonly diagnosed non-cutaneous cancer in adult males. Although prostate cancer that is confined to the gland can be cured in many patients using surgery or radiation, these treatments are only effective for localized tumors and the long-term failure rates for these treatments suggests that prostate cancer can metastasize relatively early in the course of the disease. Once prostate cancer has metastasized there are no curative therapies. The greatest challenge in the treatment of advanced prostate cancer is to access and eliminate metastatic cells. Therefore, effective prostate cancer therapy will require novel strategies to target cancer cells both at the site of the primary tumor and at distant metastatic sites. In this article we review several therapeutic targets and approaches that may provide new treatments for metastatic prostate cancer. We discuss the use of small molecules to target specific molecular events associated with metastatic prostate cancer, the use of specific antibodies that target unique metastasis associated molecules and the use of various gene therapy strategies to achieve anti-metastatic activities.

[Back to top] Mouse Strains for Prostate Tumorigenesis Based on Genes Altered in Human Prostate Cancer

W. C. Powell , R. D. Cardiff , M. B. Cohen , G. J. Miller and P. Roy-Burman

Animal models of prostate cancer have been limited in number and in relevance to the human disease. With the advancement of transgenic and knockout technologies, combined with tissue specific promoters and tissue-specific gene ablation, a new generation of mouse models has emerged. This review will discuss various animal models and their inherent strengths and weaknesses. A primary emphasis is placed on mouse models that have been designed on the basis of genetic alterations that are frequently found in human prostate cancer. These models display slow, temporal development of increasingly severe histopathologic lesions, which are remarkably restricted to the prostate gland, a property similar to the ageing related progression of this disease in humans. The preneoplastic lesions, akin to what is considered as prostatic intraepithelial neoplasia, are consistent major phenotypes in the models, and, therefore, are discussed for histopathologic criteria that may distinguish their progressions or grades. Finally, considering that prostate cancer is a complex multifocal disease, which is likely to require multiple genetic/epigenetic alterations, many of these models have already been intercrossed to derive mice with compound genetic alterations. It is predicted that these and subsequent compound mutant mice should represent “natural” animal models for investigating the mechanism of development of human prostate diseases, as well as, for preclinical models for testing therapeutics.