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Targeting Metastatic Prostate Cancer: The Search for Innovative Systemic Therapies

Targeting Metastatic Prostate Cancer: The Search for Innovative Systemic Therapies

Metastatic hormone-resistant prostate cancer has proven largely resistant to cytotoxic therapy. Since 2004, docetaxel (Taxotere)/prednisone has become the standard chemotherapy used to treat advanced hormone-resistant prostate cancer. However, the survival advantage is modest and a significant number of patients do not respond to chemotherapy. It is hoped that an increased understanding of the mechanisms underlying the progression of prostate cancer will lead to new treatment modalities. With the growing number of biologic and targeted agents under development, the potential armamentarium of prostate cancer treatments is steadily growing. However, none of the new treatment modalities has yet been shown to be more effective than standard treatments. This article will provide an overview of targeted or innovative therapies in the treatment of prostate cancer.

In 2004, the US Food and Drug Administration (FDA) approved the use of docetaxel (Taxotere) in advanced prostate cancer based on the publication of two large randomized clinical trials, namely the TAX 327 trial[1] and Southwest Oncology Group (SWOG) 9916 trial.[2] The TAX 327 study involved 1,006 patients, randomized into three equivalent arms comparing mitoxantrone (Novantrone), weekly docetaxel, or 3-weekly docetaxel, each with prednisone. The survival advantage in the 3-weekly docetaxel arm was 2.5 months over the mitoxantrone arm. Similar results were obtained in the SWOG 9916 study. These were the first studies to demonstrate a survival benefit in hormone-resistant disease with the use of docetaxel. The prostate-specific antigen (PSA) response rate was approximately 50% and the median survival was 18 months. An effective second-line chemotherapy regimen has not yet been established. Therefore, new approaches are highly desirable.[3-6]

With the recent discovery of new pathways involved in prostate cancer progression, progress has been made in the understanding of the biology of the disease. Also, a variety of new molecules—for example, tyrosine-kinase inhibitors, antiangiogenic agents, and differentiation therapies—have entered clinical testing. This article will discuss the novel agents in clinical trials for prostate cancer (Table 1).

Prostate Cancer Growth

Normal and neoplastic prostate tissue responds to androgenic stimulation through the androgen receptor. The androgen receptor plays a crucial role in prostate cancer progression.[7] Overexpression of the androgen receptor has been associated with higher Gleason scores and earlier relapse. Significant attempts have been made to determine androgen receptor expression reliably, for use as a biomarker. Recent progress has been made in quantification of the androgen receptors in pathologic specimens.[8,9]

Hormone-Independent Prostate Cancer

The progression of prostate cancer despite androgen ablation has several causes. In fact, in most prostate cancers, the androgen receptor is still functioning and frequently overexpressed in order to counteract the low levels of androgens during androgen-deprivation therapies. However, other mechanisms such as mutation of the androgen receptor or a response to other ligands have been described. Further, there are a number of androgen receptor-interacting proteins, which have been characterized from a biochemical point of view but less from a functional perspective. Some of these cofactors might be overexpressed, and therefore, there is a reduced need for androgenic steroids to activate the androgen receptor.[10]

Apart from the androgen receptor-related progression models, other relevant pathways can promote prostate cancer growth. Growth factors such as HER2, insulin-like growth factor, kerationcyte growth factor, and epidermal growth factor, as well as interleukin (IL)-6, can activate the androgen receptor.[11-13] Other mechanisms are represented by the reduction of HER-kinase inhibitors. In fact, a large percentage of prostate cancer cells have reduced levels of PTEN, which leads to an increased activation of AKT and, further down the signaling cascade, to the activation of mammalian target of rapamycin (mTOR)—another crucial cellular checkpoint for tumor growth and protein synthesis.[14]

There is a fine balance between the various promoters and control mechanisms of cell proliferation and apoptosis. Many of these potential targets are reduced in their function by molecules we are able to synthesize.

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