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Results for “Prostatic Neoplasms, Castration-Resistant”

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PubMed2005

Predictors of prostate cancer tissue acquisition by an undirected core bone marrow biopsy in metastatic castration-resistant prostate cancer--a Cancer and Leukemia Group B study.

PURPOSE: Analyzing metastatic prostate cancer tissue is of considerable importance in evaluating new targeted agents, yet acquiring such tissue presents a challenge due to the predominance of bone metastases. We assessed factors predicting a successful tumor harvest from bone marrow biopsies (BMBx) in castration-resistant metastatic prostate cancer patients. MATERIAL AND METHODS: Data from Cancer and Leukemia Group B study 9663 were reviewed. Bone marrow biopsies were obtained from 184 patients who underwent an office-based, unguided bone marrow biopsy of the posterior iliac crest. RESULTS: Forty-seven of the 184 patients (25.5%) had a positive bone marrow biopsy. When considered in a multivariate logistic regression analysis, lower hemoglobin levels, higher alkaline phosphatase, and higher lactate dehydrogenase levels were associated with a higher likelihood of a positive BMBx. The median survival time was 11 months (95% confidence interval, 8.0-14) among patients with a positive BMBx compared with 23 months (95% confidence interval, 19-27) with a negative BMBx. The median time to progression and time to prostate-specific antigen progression-free survival were also significantly decreased among positive BMBx patients. No patients with a positive BMBx survived beyond 3 years, whereas 11 of the 137 patients with a negative BMBx survived beyond 5 years. DISCUSSION: Using common laboratory values, a specific patient cohort can be defined from whom the yield of a nonguided BMBx would be high enough to justify this approach. For studies that require broader entry criteria, a more directed approach with image guidance is recommended.

Aged↗

PubMed2003

Hsp90 as a therapeutic target in prostate cancer.

Prostate cancers are hormone-dependent malignancies that respond to drugs that reduce circulating testosterone levels or prevent binding of this ligand to the androgen receptor (AR). While effective, these approaches are not curative and, in almost all cases, progression to a castration-resistant state is eventually observed. The mechanisms underlying the development of hormone resistance are poorly defined but several molecular changes are commonly associated with this process. Since a common element of these resistance mechanisms is restoration of AR signaling, agents that target AR expression represent an attractive treatment option for prostate cancer patients with disease progression following castration. Prior to ligand binding, AR exists in a complex with heat shock protein 90 (Hsp90) and other co-chaperones. The AR-Hsp90 interaction maintains AR in a high-affinity ligand-binding conformation, which is necessary for efficient response to hormone. 17-Allyamino-17-demethoxygeldanamycin (17-AAG) is an inhibitor of the Hsp90 chaperone protein. Inhibition of Hsp90 function causes the proteasomal degradation of proteins that require this chaperone for maturation or stability. Hsp90 clients include several proteins of potential importance in mediating prostate cancer progression, including wild-type and mutated AR, HER2, and Akt. In murine models of prostate cancer, 17-AAG causes the degradation of these client proteins at nontoxic doses and inhibits the growth of hormone-naive and castration-resistant tumors. These data suggest that inhibitors of Hsp90 may represent a novel strategy for the treatment of patients with prostate cancer and clinical trials to test this hypothesis are currently ongoing.

Androgen Antagonists↗

PubMed2006

Improving the outcome of patients with castration-resistant prostate cancer through rational drug development.

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease.

Antineoplastic Agents↗

PubMed2026

Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.

Prostate cancer progression is predominantly driven by androgen receptor (AR) signaling, and despite initial benefits of androgen deprivation therapy (ADT), most patients eventually develop lethal castration-resistant disease. Cyclic administration of supraphysiologic androgen (SPA) with ADT paradoxically suppresses tumor growth; however, responses are heterogeneous, and the mechanisms underlying the antitumor effects of SPA remain incompletely understood. In this issue of Cancer Research, Kumar and colleagues demonstrate that SPA induces a distinct metabolic response, characterized by AR-dependent induction of polyamine biosynthesis via ODC1 and AMD1. This metabolic rewiring elevates polyamine synthesis while concurrently depleting the methyl donor S-adenosylmethionine (SAM). Although increased polyamine metabolism by SPA may promote adaptive resistance, genetic or pharmacologic inhibition of ODC1 using difluoromethylornithine (DFMO) enhances SPA-induced growth suppression by disrupting protective polyamine pools and further exacerbating SAM depletion, revealing a metabolic vulnerability in SPA-treated prostate cancer cells. Supporting these findings, a clinical trial combining DFMO with bipolar androgen therapy (BAT) demonstrated reduced circulating polyamines in patients, confirming polyamine pathway suppression in patients with different genomic features. Together, this study uncovers a mechanistic link among androgen signaling, polyamine metabolism, and therapeutic response, providing a rationale for targeting metabolic dependencies to improve SPA efficacy. See related article by Kumar et al., p. 1148.

Male↗

PubMed2006

Expression of stress response protein Grp78 is associated with the development of castration-resistant prostate cancer.

BACKGROUND: Induction of molecular chaperone Grp78 (78-kDa glucose-regulated protein) occurs in stress conditions that often characterize tumor microenvironments. We investigated the role of Grp78 in prostate cancer progression and the development of castration resistance, where cancer cells continue to survive despite the stress of an androgen-starved environment. EXPERIMENTAL DESIGN: Immunohistochemistry was done to examine Grp78 expression in 219 prostate cancers from patients with pathologic stage T3N0M0 disease [androgen ablation naive (untreated) and androgen ablation exposed (treated)] and castration-resistant prostate cancer. Classification of tumors was based on intensity of Grp78 cytoplasmic immunoreactivity and percentage of immunoreactive tumor cells. The associations of Grp78 expression with prostate cancer recurrence (clinical and/or serum prostate-specific antigen) and survival were examined in the untreated stage T3N0M0 group. Grp78 expression was also analyzed in the androgen-dependent LNCaP and castration-resistant C42B cell lines. RESULTS: The percentage of tumor cells expressing Grp78 was strongly associated with castration-resistant status (P = 0.005). Increased Grp78 expression was consistently associated with greater risk of prostate cancer recurrence and worse overall survival in patients who had not undergone prior hormonal manipulation. Grp78 expression was also increased in the castration-resistant LNCaP-derived cell line C42B and in LNCaP cells grown in androgen-deprived conditions compared with LNCaP cells grown in androgen-rich media. CONCLUSION: Our findings show that up-regulation of Grp78 is associated with the development of castration resistance, possibly in part by augmenting cell survival as previously suggested, and may serve as an important prognostic indicator of recurrence in a subset of patients with T3N0M0 disease.

Cohort Studies↗

PubMed2004

Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer.

The categorization of prostate cancers that are progressing after castration as 'hormone-refractory' evolved from the clinical observation that surgical or medical castration (i.e. androgen ablation therapy; AAT) is not curative and, despite an initial response, virtually all tumors eventually regrow. Successful AAT is contingent on the dependence of prostate cancer cells for androgen signaling through an intracellular mediator, the androgen receptor (AR) for survival. Current preclinical and clinical data imply that the AR is expressed and continues to mediate androgen signaling after failure of AAT. As AAT does not completely eliminate circulating androgens, sufficient concentrations of dihydrotestosterone may accumulate in tumor cells to maintain AR signaling, especially in the context of upregulated receptor levels or increased sensitivity of the AR for activation. In addition, ligands of non-testicular origin or ligand-independent activation can contribute to continued AR signaling. In many cases, therefore, from the perspective of the AR, a 'hormone-refractory' classification after failure of AAT is inappropriate. Classifying prostate tumors that progress after AAT as 'castration-resistant' may be more relevant. Clinical responses to second- and third-line hormonal therapies suggest that the mechanisms of AR activation are in part a function of previously administered AAT. Accordingly, the increasing trend to utilize AAT earlier in the course of the clinical disease may have a greater influence on the genotype and phenotype of the resistant tumor. In this article, we detail strategies to inhibit the growth of prostate cancer cells that specifically target the AR in addition to those practiced traditionally that indirectly target the receptor by reducing the amount of circulating ligand. We propose that treatment regimes combining AAT with direct AR targeting strategies may provide a more complete blockade of androgen signaling, thereby preventing or significantly delaying the emergence of treatment-resistant disease.

Androgen Receptor Antagonists↗