Saturday, April 6, 2013

Prostate Cancer and Castration Resistance


Journal of Clinical Oncology:
The spectrum of prostate cancers that are progressing despite castrate levels of testosterone includes tumors that have shown varying degrees and durations of response to primary hormone treatment, and clinical manifestations that range from a rising prostate-specific antigen (PSA) alone, a rising PSA with osseous and/or soft-tissue spread, or a predominantly visceral disease pattern. This evolution, from the clinically localized hormone-naïve state to a castration-resistant metastatic state, involves the complex interplay of a network of signaling molecules that collectively promote net cell proliferation relative to cell death. This range of clinical phenotypes is associated with different genotypes that are also influenced by both the microenvironment of the tumor in the location to which it has spread. That prostate cancers that have spread to lymph nodes often regress completely and rarely recur in this location while tumors in bone are rarely eliminated and are often the first site of clinical progression is consistent with this view. Further support is provided by a study showing that prostate cancer metastases in different sites from an individual who as a result of the disease are biologically distinct. The biology of the progressing tumor is also influenced by the specific therapy to which it has been exposed. This concept, which we have termed “therapy-mediated selection pressure,” must also be considered when considering treatment options.

In 2004, the combination of docetaxel and prednisone was established as the new standard of care for patients who have progressed on androgen deprivation based on two prospective randomized trials showing a prolongation of life relative to mitoxantrone and prednisone, the previous standard. However, docetaxel and prednisone are not curative, and optimal timing of administration remains controversial. Consequently, many groups are focused on developing new approaches, and are focused in particular on the identification and targeting of critical signaling molecules and pathways that contribute to tumor growth in the different clinical states.

Androgens are the primary regulators of prostate cancer cell growth and proliferation. When androgens are ablated or withdrawn, apoptosis is observed in a proportion of cells, while those that survive arrest in the G1 phase of the cell cycle. Clinical progression is the result of the regrowth of cells that were primarily resistant to androgen ablation, or which, after a period of growth arrest, adapted to the low-androgen environment and resumed proliferation. It is possible, but not proven, that cells primarily resistant to androgen-deprivation therapy are those with stem-cell properties that never required androgens for survival and growth.

Studies in xenografts in which androgen ablation–naïve tumors were propagated sequentially in male mice with low levels of testosterone and once established, propagated again in female mice with testosterone levels that are below the level of detection, showed a sequentially increasing degree of gene dysregulation. From a mechanistic and clinical point of view, it is critical to recognize that progression despite androgen deprivation is associated with an active androgen receptor (AR) –signaling pathway. This is shown by the fact that progression is accompanied by a rise in PSA in virtually all cases, and that many of these tumors are sensitive to secondary and tertiary hormonal manipulations such as the discontinuation of steroidal and nonsteroidal hormones, or to the addition of antiandrogens, estrogens, progestational agents, glucocorticoids, or enzymatic inhibitors of the adrenal androgen synthetic pathway. As it is difficult to determine a priori which tumors will respond to these hormonal therapies, the terms “hormone refractory,” “hormone resistant,” “androgen resistant,” or “androgen refractory,” widely used to describe these tumors, illustrate a fundamental misunderstanding of the mechanism of disease relapse. More appropriate is to focus efforts on the development of clinical descriptions that reflect the mechanisms that are contributing to continued signaling through the receptor or the action of ligand on the receptor, rather than on the ligand itself.

To date, the targeted approaches that have been the most successful approaches have been those directed against specific oncogenic alterations in tumors, such as the Bcr-Abl fusion protein in CML, point mutations in c-Kit, platelet-derived growth factor-alpha kinases in gastrointestinal stromal tumors, or point mutations in the epidermal growth factor receptor tyrosine kinase domain in lung cancer. Although analogous genetic alterations in kinases have not been reported in prostate cancer, profiling studies of prostate cancers representing different clinical states have shown that a range of receptor tyrosine kinases, including members of the HER kinase family (epidermal growth factor receptor [EGFR], HER2), platelet-derived growth factor and c-met, are expressed in a proportion of these tumors. Perhaps the most frequent genetic alteration is loss of the phosphatase and tensin homolog (PTEN) tumor suppressor, which can lead to increased activity of Akt and mammalian target of rapamycin (mTOR). But, despite the presence of the target on or in tumor cells, clinical results with single agents directed at these targets have been disappointing at best.

More information:
» NCI's Urologic Oncology Branch uses advanced MRI device for prostate imaging

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