Prostate cancer: a biologic approach to lethal disease
Howard I Scher
Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, USA
The clinical spectrum of prostate cancers that are progressing despite androgen depletion includes a rising PSA alone, a rising PSA with osseous and/or soft-tissue spread, and a predominantly visceral disease pattern with or without osseous disease. These clinical phenotypes reflect a range of genotypes that represent not only the intrinsic properties of the tumor, but also the influence of both the microenvironment in the location to which the cancer has spread [1],and the specific therapy(ies) to which it has been exposed [2]. At this time, there is no uniform approach to disease management, but the demonstration that every 3 week docetaxel can prolong life [3, 4] has focused drug development efforts on pre-chemotherapy, in combination with docetaxel as first-line therapy, and post-docetaxel where there is no standard. Key questions are how to (a) identify and direct therapies toward determinants and pathways that are either present on prostate cancer cells or contributing to their growth, and (b) test new agents and prove that they work. An additional question is defining when a patient with progressive castration-resistant prostate cancer (CRPC) should be given taxotere, recognizing that some of these tumors may still be sensitive to hormone treatments.
Target identification has been based in part on molecular profiling studies showing that the loss of the PTEN tumor suppressor gene and translocations of the prostate-specific TMPRSS2 promoter to ETS transcription factors as early events, and, in later state tumors, showing expression without mutation of a number of receptor tyrosine kinases (RTKs), including members of the HER kinase family (EGFR, HER2), platelet derived growth factor, c-MET, and the insulin-like growth factor 1 receptor. In the clinic, the most successful targeted approaches are those directed at specific oncogenic alterations in tumors, but as the oncogenic role of many of these has yet to proven, it is not surprising that the clinical results with single agents directed at these specific RTKs have been disappointing. These agents may have a separate and unique role in the treatment of prostate cancers that have metastasized to bone.
More recently, the oncogenic role of continued androgen receptor signaling in CRPC has been recognized. Alterations in the receptor include amplification of the AR gene, gain of function-activating mutations, AR protein overexpression, alterations in coregulatory molecules, and ligand-independent activation [5]. Overexpression of the enzymes responsible for androgen synthesis has also been documented, leading to an increase in intratumoral androgens that alone are sufficient to stimulate growth [6]. The recently reported results with abiraterone acetate, a 17,20-lyase inhibitor [7], and MDV-3100 [8], a novel AR antagonist engineered for activity against tumor cells with overexpressed AR, are consistent with the molecular profiles.
Urgently needed for prostate cancer drug development are reliable indicators of clinical benefit. Conventional imaging studies do not assess disease status accurately, and the observation of a decline in PSA post-treatment does not necessarily mean that a patient will live longer. To address this, we have applied a framework that divides the disease continuum into states based on the presence or absence of metastatic disease and the measured serum testosterone level in the blood [9]. Using this model, clinical trial and therapeutic objectives for an individual or group of patients are based on controlling, relieving, or eliminating manifestations of disease that are present when treatment is being started, and/or of preventing or delaying future disease manifestations [10]. This paradigm shifts the focus from changes in PSA to time-to-event endpoints, such as preventing or delaying death from disease, that can be applied to any drug regardless of mechanism. It has also led the search for clinically reliable biomarkers to better define patient prognosis, assess whether treatments are effective anticancer therapies, and guide treatment selection. Preliminary data using circulating tumor cells and positron emission tomography suggest that these biomarkers may fulfill these unmet needs.
Acknowledgments
This work was supported by P50-CA92629 SPORE in Prostate Cancer, DOD PC051382 Prostate Cancer Research Program Clinical Consortium Award, and the Prostate Cancer Foundation.
References
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[8] Scher HI, Beer TM, Higano CS, et al: Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC). Proc ASCO 26 (Abstract # 5006) 2008
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