Abstract
In the past decade, multi-national and multi-center efforts were launched to sequence prostate cancer genomes, transcriptomes, and epigenomes with the aim of discovering the molecular underpinnings of tumorigenesis, cancer progression, and therapy resistance. Multiple biological markers and pathways have been discovered to be tumor drivers, and a molecular classification of prostate cancer is emerging. Here, we highlight crucial findings of these genome-sequencing projects in localized and advanced disease. We recapitulate the utility and limitations of current clinical practices to diagnosis, prognosis, and therapy, and we provide examples of insights generated by the molecular profiling of tumors. Novel treatment concepts based on these molecular alterations are currently being addressed in clinical trials and will lead to an enhanced implementation of precision medicine strategies.
Highlights
With almost 1 million new cases per year, prostate cancer (PCa) is the most prevalent malignancy in men worldwide and causes about 300,000 deaths annually [1]
Since cancer cells with defects in double-strand breaks (DSBs) repair pathways are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors, the same study tested the potential synthetic lethality of SPOP inactivation with these drugs in vitro: siRNA-based downregulation of SPOP or ectopic expression of its inactive mutant forms lead to decreased cell viability upon PARP inhibition with olaparib [43]. These findings suggest that SPOP mutations could potentially become indicators for a subset of PCa amenable to PARP
The encouraging results of the TOPARP-A study led to a second trial (TOPARP-B), wherein patients were prospectively selected based on the presence of biomarkers predictive of olaparib response, the genotypic status of BRCA2 and ATM
Summary
With almost 1 million new cases per year, prostate cancer (PCa) is the most prevalent malignancy in men worldwide and causes about 300,000 deaths annually [1]. About one-third of patients develop biochemically recurrent disease (rising PSA levels), which is treated with androgen. After initial therapy response, patients eventually become refractory to ADT. At this point, the disease has progressed to castration-resistant PCa (CRPC), which oftentimes develops concurrently with metastasis. Despite remarkable progress in approved PCa treatment modalities in recent years, systemic therapies can only prolong survival for a few months [14]. In recent years, large-scale genomic sequencing projects have catalogued common genomic alterations, which enabled an improved molecular classification of prostate tumors and led to a better understanding of the molecular mechanisms driving the initiation and progression of the disease. The clinical translation of these findings could pave the way towards the implementation of a personalized PCa therapy
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