Mapping the genetics of treatment-resistant prostate cancer

By: David Shifrin, PhD
Science Writer, Filament Life Science Communications

What happens when a disease becomes resistant to all known therapies? The two instances that first come to mind are multi-resistant bacterial infections, and any number of cancers.

In the latter category, metastatic prostate cancer frequently becomes resistant to available therapeutics. Androgen deprivation therapy is a classic mode of treatment for metastatic prostate cancer, due to the high frequency of mutations in genes of the androgen signaling pathway (especially the androgen receptor, or AR). This pathway is heavily involved in regulating gene expression and molecular signaling events. Often, though, metastases reach a point where they do not respond to androgen deprivation, which is called metastatic castration-resistant prostate cancer (mCRPC). Secondary treatments may be effective, but the tumors often reach a point of resistance with them, as well. Understanding what happens in these tumors, as well as finding new modes of treatment that avoid resistance, is therefore critical to effectively treating metastatic prostate cancer.

The key to discovering actionable genomic changes in mCRPC is, simply, getting enough fresh samples from living patients early in treatment. Unfortunately, this has traditionally been a difficult undertaking, and the majority of samples have come from deceased patients.

To get past this limitation and try to break through the complexity of mCRPC, a massive inter-institutional group recently conducted extensive genomic analysis on 150 fresh samples. The results were published in the May 21 issue of the journal Cell, in a study titled “Integrative Clinical Genomics of Advanced Prostate Cancer.” Importantly, the group focused on delineating genetic differences between primary prostate cancer and mCRPC. In theory, understanding these differences could lead to better therapeutic targets in otherwise resistant tumors. Samples were acquired from patients before they began treatment in a clinical study. As a result, the tumors would obviously be unaffected by experimental treatments, so the genomic landscape could be examined prospectively. Additionally, the tumors could be tracked over time to determine how they responded to the treatment used.

Once the 150 samples had been mapped using whole-exome sequencing, matched germline analysis, and transcriptome analysis, the authors compared many of the mutations in mCRPC samples with previous results from primary prostate cancer samples. While several significant mutations were observed in mCRPC but not primary tumors, the opposite was not true. Although on the surface this is not surprising, it does represent one of the most significant general findings in the study. By clearly mapping the differences between primary prostate tumors and difficult-to-treat resistant metastatic tumors, molecular pathways underlying that resistance can be more readily uncovered. In turn, researchers will be able to work on new therapeutic targets.

A number of biological processes were affected by the various mutations. The group pointed to cell signaling, cell cycle, and DNA repair genes in mCRPC, in addition to very common aberrations in the androgen pathway and AR specifically.

Mapping the differences between mCRPC and primary tumors and understanding the details of the defective pathways gives hope that effective, targeted therapies can be developed. The vast majority of mCRPC samples the group looked at contained a “potentially actionable” variant, a hopeful – if daunting – finding. Importantly, the work done in this study will contribute to prospective genetic and molecular mapping. By knowing the exact profile of a tumor, as well as if and how it responded to earlier treatment, the goal of true precision medicine will be much closer than is currently the case.

Additional work needs to be done to validate many of the findings of this study. As massive an undertaking as it was (indeed, had to be, to be considered for publication in Cell), the inter-institutional research group did not try to take it too far. The strength of many studies we have considered in this space come from the ability to take genetic findings and validate or expand on them using biological techniques. Here, the team went through a huge data set, pulled out new insights and compared results with those from earlier studies. This analysis validated a number of previous findings, but also revealed novel genetic signatures in metastatic tumors. The latter will require years of work to understand how they fit into the progression of prostate cancer. Regardless, the results will serve as an important anchor for advances in genetic counseling, pharmaceutical development, and general standards of care for metastatic prostate cancer, a deadly and still all-to-common disease.