Tracking the Clonal Origin of Lethal Prostate Cancer

“Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management.”

Understanding Why

“For patients with high-risk prostate cancer, treatment with both androgen deprivation therapy (ADT) and ionizing radiation (IR) improves progression-free and overall survival and has long been the standard of care. Two papers published in Cancer Discovery unveil the molecular mechanisms that underpin this clinical response.”

Genes Upregulated in Prostate Cancer Reactive Stroma Promote Prostate Cancer Progression in vivo

“Marked reactive stroma formation is associated with poor outcome in clinically localized prostate cancer. We have previously identified genes with diverse functions that are upregulated in reactive stroma. This study tests the hypothesis that expression of these genes in stromal cells enhances prostate cancer growth in vivo. Experimental Design: The expression of reactive stroma genes in prostate stromal cell lines was evaluated by RT-PCR and Q-RT-PCR. Genes were knocked down using stable expression of shRNAs and the impact on tumorigenesis assessed using the differential reactive stroma (DRS) system, in which prostate stromal cell lines are mixed with LNCaP prostate cancer cells and growth as subcutaneous xenografts assessed. Results: Nine of 10 reactive stroma genes tested were expressed in one or more prostate stromal cell lines. Gene knockdown of c-Kit, Wnt10B, Bmi1, Gli2 or COMP all resulted in decreased tumorigenesis in the DRS model. In all tumors analyzed, angiogenesis was decreased and there were variable effects on proliferation and apoptosis in the LNCaP cells. Wnt10B has been associated with stem/progenitor cell phenotype in other tissue types. Using a RT-PCR array, we detected downregulation of multiple genes involved in stem/progenitor cell biology such as OCT4 and LIF as well as cytokines such as VEGFA, BDNF and CSF2 in cells with Wnt10B knockdown. Conclusions: These findings show that genes upregulated in prostate cancer reactive stroma promote progression when expressed in prostate stromal cells. Moreover, these data indicate that the DRS model recapitulates key aspects of cancer cell/reactive stroma interactions in prostate cancer.”

Emerging Molecularly Targeted Therapies in Castration Refractory Prostate Cancer

“Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.”

Collaborative Effort Aims to Find Strategies to Preempt Resistance to Prostate Cancer Therapies

The ‘Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer’ 3-year project aims to understand how prostate tumors become resistant to two newer drugs for prostate cancer that target the androgen receptor pathway—enzalutamide and abiraterone acetate. Continue reading…

Advancing Precision Medicine for Prostate Cancer Through Genomics

“Prostate cancer is the most common type of cancer in men and the second leading cause of cancer death in men in the United States. The recent surge of high-throughput sequencing of cancer genomes has supported an expanding molecular classification of prostate cancer. Translation of these basic science studies into clinically valuable biomarkers for diagnosis and prognosis and biomarkers that are predictive for therapy is critical to the development of precision medicine in prostate cancer. We review potential applications aimed at improving screening specificity in prostate cancer and differentiating aggressive versus indolent prostate cancers…”

Simultaneous Spurts of Mutations Drive Prostate Cancer, Whole-Genome Sequencing Study Finds

A large collaborative research effort shows that prostate cancers may evolve in sudden, brief spurts of many simultaneous genetic mutations that disrupt important prostate cancer genes. Using deep-sequencing techniques and computer modeling, scientists have created a detailed temporal map of how genetic aberrations evolve within prostate tumors. This result differs from the traditional model of cancer resulting from the step-by-step accumulation of individual mutations. The study is published in the journal Cell. Continue reading…

Personalized Prostate Specific Antigen Testing Using Genetic Variants May Reduce Unnecessary Prostate Biopsies

Recent studies have identified genetic variants associated with increased serum prostate specific antigen concentrations and prostate cancer risk, raising the possibility of diagnostic bias. By correcting for the effects of these variants on prostate specific antigen, it may be possible to create a personalized prostate specific antigen cutoff to more accurately identify individuals for whom biopsy is recommended. Therefore, we determined how many men would continue to meet common biopsy criteria after genetic correction of their measured prostate specific antigen concentrations…”