Hans Prydz Guest Lecture by Professor Steve Bova
Professor Steve Bova is a Professor and Group Leader at the Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital in Finland.
He will give a talk titled, 'Leveraging the evolutionary history of metastatic prostate cancer'.
Professor Steve Bova. Photo: Prostate Cancer Research Centre, University of Tampere, Finland
Leveraging the evolutionary history of metastatic prostate cancer
The molecular changes necessary and sufficient for prostate cancer metastasis are poorly understood. Genomic studies including both primary and metastatic lesions from the same individual allow tracing of the genomic pattern associated with metastasis, and provide a dynamic context around which both basic science and clinical studies can shed light on means to improve cancer control.
In a pilot series of 33 men in various stages of completion, modifications of current pathology methods supported by new information technology. Whole genome, targeted, and transcriptome sequencing in blood and dissected tissue samples. Bioinformatic methods for tracing clonal evolution, identification of candidate truncal and non-truncal driver and passenger mutations, analysis of druggability of candidate driver mutations, and analysis of clinical timeline in relation tumor phylogeny.
Initial tracing of anatomic origins in the primary site suggest that only a minority of primary cancer cells contain the full set of mutations found in metastases. In the first case with integration of WGS and RNAseq data from multiple sites, WGS analysis revealed convergent evolution of independent AR gene amplification events in four metastases after initiation of androgen deprivation, and AR p.L702H mutation in four liver metastases after corticosteroid initiation. Transcriptome analysis revealed increased expression of AR-regulated genes in AR p.L702H mutant tumors, suggesting a dominant effect by a the mutation present in 1 of 16 copies in each cell. The metastases harbored several alterations to the PI3K/AKT pathway, including duplications of PIK3CA and AKT3, and mutations in PIK3CA and PIK3CG, the latter a truncal mutation. The list of truncal genomic alterations shared by all metastases also included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, second-generation androgen-blockade, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merits further study.
Conclusion and Current Work
The findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials. We are piloting such a trial in Tampere, and will present preliminary results from this work.