Full Genome Characterization of the Culicoides-Borne Marsupial Orbiviruses: Wallal Virus, Mudjinbarry Virus and Warrego Viruses

Viruses belonging to the species Wallal virus and Warrego virus of the genus Orbivirus were identified as causative agents of blindness in marsupials in Australia during 1994/5. Recent comparisons of nucleotide (nt) and amino acid (aa) sequences have provided a basis for the grouping and classification of orbivirus isolates. However, full-genome sequence data are not available for representatives of all Orbivirus species. We report full-genome sequence data for three additional orbiviruses: Wallal virus (WALV); Mudjinabarry virus (MUDV) and Warrego virus (WARV). Comparisons of conserved polymerase (Pol), sub-core-shell 'T2' and core-surface 'T13' proteins show that these viruses group with other Culicoides borne orbiviruses, clustering with Eubenangee virus (EUBV), another orbivirus infecting marsupials. WARV shares <70% aa identity in all three conserved proteins (Pol, T2 and T13) with other orbiviruses, consistent with its classification within a distinct Orbivirus species. Although WALV and MUDV share <72.86%/67.93% aa/nt identity with other orbiviruses in Pol, T2 and T13, they share >99%/90% aa/nt identities with each other (consistent with membership of the same virus species - Wallal virus). However, WALV and MUDV share <68% aa identity in their larger outer capsid protein VP2(OC1), consistent with membership of different serotypes within the species - WALV-1 and WALV-2 respectively

Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol

This is an accepted manuscript of an abstract published by Elsevier in Annals of Oncology on 01/09/2021, available online: https://doi.org/10.1016/j.annonc.2021.08.2098 The accepted version of the publication may differ from the final published version.Published versio

Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre-and post-treatment prostatic biopsies from patients with advanced prostate cancer

Background: Although chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant. Tumour molecular profiles may help identify the mechanisms of drug action and identify potential prognostic biomarkers. We performed in vivo transcriptome profiling of pre- and post-treatment prostatic biopsies from patients with advanced hormone-naive prostate cancer treated with docetaxel chemotherapy and androgen deprivation therapy (ADT) with an aim to identify the mechanisms of drug action and identify prognostic biomarkers. Methods: RNA sequencing (RNA-Seq) was performed on biopsies from four patients before and ~22 weeks after docetaxel and ADT initiation. Gene fusion products and differentially-regulated genes between treatment pairs were identified using TopHat and pathway enrichment analyses undertaken. Publically available datasets were interrogated to perform survival analyses on the gene signatures identified using cBioportal. Results: A number of genomic rearrangements were identified including the TMPRSS2/ERG fusion and 3 novel gene fusions involving the ETS family of transcription factors in patients, both pre and post chemotherapy. In total, gene expression analyses showed differential expression of at least 2 fold in 575 genes in post-chemotherapy biopsies. Of these, pathway analyses identified a panel of 7 genes (ADAM7, FAM72B, BUB1B, CCNB1, CCNB2, TTK, CDK1), including a cell cycle-related geneset, that were differentially-regulated following treatment with docetaxel and ADT. Using cBioportal to interrogate the MSKCC-Prostate Oncogenome Project dataset we observed a statistically-significant reduction in disease-free survival of patients with tumours exhibiting alterations in gene expression of the above panel of 7 genes (p = 0.015). Conclusions: Here we report on the first “real-time” in vivo RNA-Seq-based transcriptome analysis of clinical PCa from pre- and post-treatment TRUSS-guided biopsies of patients treated with docetaxel chemotherapy plus ADT. We identify a chemotherapy-driven PCa transcriptome profile which includes the down-regulation of important positive regulators of cell cycle progression. A 7 gene signature biomarker panel has also been identified in high-risk prostate cancer patients to be of prognostic value. Future prospective study is warranted to evaluate the clinical value of this panel

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial

BACKGROUND: Local treatment of the prostate might not only improve local control, but also slow the progression of metastatic disease. We hypothesised that radiotherapy (RT) to the prostate would improve overall survival in men presenting with metastatic prostate cancer (PCa) and that the survival benefit would be greater in men with a lower metastatic burden. METHOD: STAMPEDE is a multi-arm multi-stage platform protocol that included a randomised phase III comparison to test the above hypotheses. Standard-of-care (SOC) was lifelong ADT, with up-front docetaxel permitted from Dec-2015. Stratified randomisation within 12 weeks on ADT allocated pts 1:1 to SOC or SOC+RT. Men allocated to RT received daily (55Gy/20f over 4 weeks) or weekly (36Gy/6f over 6 weeks) RT, started ≤8 weeks after randomisation or completion of docetaxel. The RT schedule was nominated before randomisation. The primary outcome measure was death from any cause; secondary outcome measures included failure-free survival (FFS). Comparison of SOC vs SOC+RT for survival had 90% power at 2.5% 1-sided alpha for hazard ratio (HR) of 0.75, requiring approximately 267 control arm deaths. Analyses used Cox proportional hazards & flexible parametric models, adjusted for stratification factors. A pre-specified subgroup analysis tested the effects of prostate RT by baseline metastatic burden. RESULTS: 2061 men with newly-diagnosed M1 PCa were randomised from Jan 2013 to Sep 2016. Randomised groups were well balanced: median age 68yrs; median PSA 97ng/ml; 18% early docetaxel; metastatic burden: 40% lower metastatic burden, 54% higher metastatic burden, 6% unknown in the group as a whole. Prostate RT improved FFS (HR=0.76, 95%CI 0.68, 0.84; p=3.36x10-7 60 ) but not overall survival (HR=0.92, 95%CI 0.80, 1.06; p=0.266). Pre-specified subgroup analysis showed 62 improved overall survival for prostate RT in 819 men with a lower metastatic burden 63 (HR=0.68, 95%CI 0.52, 0.90; p=0.007) but not in 1120 men with a higher metastatic burden (HR=1.07, 95%CI 0.90, 1.28; p=0.300). RT was well-tolerated during (G3-4 5% SOC+RT) and after treatment (G3-4 <1% SOC, 4% SOC+RT). CONCLUSIONS: Radiotherapy to the prostate did not improve survival for unselected patients with newly-diagnosed metastatic prostate cancer, but, in a pre-specified subgroup analysis, did improve survival in men with a lower metastatic burden. Therefore, prostate radiotherapy should be a standard treatment option for men with oligometastatic disease