Publications

219 Background: Metastatic castration-resistant prostate cancers (mCRPC) show a diversity of clinical responses and phenotypes, suggesting molecular heterogeneity. Understanding molecular phenotypes is critical for patient stratification and selection of therapeutic targets. Treatment with androgen receptor (AR) pathway inhibitors are thought to drive AR-negative disease and the emergence of neuroendocrine lineages. There are several emerging biomarkers for mCRPC, including novel targets, such as PSMA and STEAP1, and markers of neuroendocrine and aggressive disease, such as INSM1, DLL3, and loss of p53, RB1 and PTEN. Our understanding of the co-expression of such biomarkers across multiple metastatic sites is currently limited. This study aimed to determine biomarker expression in multiple anatomical sites within individual mCRPC patients. Methods: Through the rapid-autopsy CASCADE program at the Peter MacCallum Cancer Centre, tissue was obtained from 5-14 tumor sites from 12 individual mCRPC patients yielding samples from a total of 110 tumor sites (8 primary and 102 metastatic). Ten patients were diagnosed with prostate adenocarcinoma (89 sites), and 2 patients with neuroendocrine histopathology in all sites (21 sites). Tissue was stained for AR, PSMA, STEAP1, INSM1, DLL3 p53, RB1 and PTEN by immunohistochemistry (IHC). Serial sections were reviewed and scored by a pathologist. IHC results were corroborated with genetic information derived from DNA sequencing. Results: In the adenocarcinoma cohort, on average 77% of sites of individual patients had AR expression, suggesting intra-patient heterogeneity. Co-expression of AR and PSMA was common (55/89 sites), but 6/10 adenocarcinoma patients had 1 to 6 PSMA + AR - lesions. Co-expression of PSMA and STEAP1 was also common in adenocarcinoma patients (60/89 sites), although 8/10 patients had 1 to 2 PSMA - STEAP1 + lesions, and 7 patients had 1 to 3 PSMA + STEAP1 - lesions. Expression of INSM1 and DLL3 was mostly seen in the 2 patients (20/21 sites) with neuroendocrine prostate cancer. In contrast, only 2 INSM1 + DLL3 + tumor sites in liver and 1 INSM1 - DLL3 + prostate cancer sample were detected in the adenocarcinoma cohort. Of the 110 sites, p53 loss was observed in 9, RB1 loss in 30 and PTEN loss in 25 sites. Of these, 8/9, 14/30 and 8/25 occurred in INSM1 + DLL3 + sites, suggesting that loss of these markers does not always correlate with INSM1 and DLL3 expression. Conclusions: While AR, PSMA and STEAP1 expression are frequently detected in a single site of disease, this co-expression is not consistent across all sites. In this dataset, INSM1 and DLL3 expression was almost exclusively confined to neuroendocrine prostate cancer. Loss of RB1 and PTEN often occurs without INSM1 and DLL3 expression. Understanding differential biomarker expression in mCRPC may guide future targeted treatments and warrants further research.

Supplementary Figure from Tumor Genomic Testing for >4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib)

<p>Supplementary Figure 8. Proposed mechanisms and clinical application for the ACTIV+Pano treatment.</p>

Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown.To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma.A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017.Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent.The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset.Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03).In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm.ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37.

251 Background: Immune checkpoint inhibitors (CPIs) (anti-CTLA4, anti-PD-1/PD-L1 mAbs) have had limited monotherapy activity in prostate cancer (PC) compared to urothelial cancer (UC). Recent biomarker studies revealed molecular features associated w/ better efficacy/resistance to CPIs in UC. 1 Here we examined the tumor immune microenvironment (iTME) of hormone naïve/sensitive (HSPC) & castrate resistant prostate (CRPC) specimens from primary & metastatic sites, to determine if parallels to UC molecular correlates exist that will allow us to predict subsets of PC pts who are more likely to benefit from rational combination therapies w/ CPIs. Methods: Tumor FFPE archival tissues (HSPC, n = 98; CRPC, n = 46; Unk, n = 6) were sourced from a Royal Melbourne Hospital cohort of PC patients. Tissues were evaluated by H&E for TILs & IHC performed for PD-L1 (clones SP142 & SP263) & CD8. RNAseq was conducted & Lund bladder molecular subtyping performed during bioinformatics analyses. TCGA PRAD dataset was used for further validation. Results: We first applied Lund molecular subtyping to broadly categorize this cohort into luminal/basal subtypes. CRPC tumors were almost entirely luminal, whereas HSPC tumors were mainly basal. Luminal PC tumors enriched for Wnt gene sets (p = 0.026) & enriched for a genomically unstable (GU) subtype w/ higher expression of DNA damage repair (DDR) & cell cycle gene sets (p = 0.082). Compared to CRPC, HSPCs had higher numbers of infiltrating CD8s (p = 4.37e-004), increased expression of T-effector, MHC-I antigen presentation machinery, immune checkpoints, macrophages & activated stromal biology, including the fibroblast TGFβ response signature. PD-L1 on immune cells by SP142 & SP263 was 30% & 17% respectively & was enriched in HSPC samples (SP142: CRPC 18% vs. HSPC 34%, p = 0.08). Within patients w/ CRPC, differences were minimal between primary & metastatic samples. Conclusions: These analyses on the iTME contexture of PC reveal potentially actionable biological nodes for targeted therapies. These findings could inform future clinical strategies to improve CPI responses in CRPC & HSPC w/ rationale combinations.1. Mariathasan et al. Nature 2018.

<p>Supplementary Table 1 - PDF file 57K, Supplementary Table 1. Details of platinum sensitivity and best response to olaparib and post-PARPi chemotherapy of the six patients whose tumor samples were analyzed by massively parallel sequencing. (NE: not evaluable)</p>

<div>Abstract<p><b>Purpose:</b> The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer.</p><p><b>Experimental Design:</b>The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer.</p><p><b>Results:</b> CX-5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN-null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer.</p><p><b>Conclusions:</b> Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer. <i>Clin Cancer Res; 22(22); 5539–52. ©2016 AACR</i>.</p></div>

<div>AbstractPurpose:<p>The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas.</p>Patients and Methods:<p>Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks.</p>Results:<p>Common adverse events were pyrexia (<i>n</i> = 23; 22%), injection site pain (<i>n</i> = 21; 20%), and diarrhea (<i>n</i> = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity.</p>Conclusions:<p>The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.</p></div>

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including

This paper explores the lateral load-carrying behaviour of coupled steel-concrete composite (SCC) wall-frame structures, which comprise concrete-filled steel tubular (CFST) columns, composite beams and composite walls. Both experimental and numerical studies were conducted. The experimental programme includes one single-storey bare frame structure and three single-storey coupled SCC wall-frame structures. The experimental results showed that applying the composite wall can significantly increase the lateral load-carrying capacity of the entire structure. It was also evident that increasing the wall width and lowering the structural height can effectively enhance the lateral load-carrying capacity. The modelling approaches in ABAQUS and OpenSees were proposed to conduct the finite element (FE) analysis. In particular, ABAQUS was used to build single-storey coupled SCC wall-frame structures to assess the effects of several parameters, such as beam stiffness, the thickness of steel tubes and wall faceplates, wall width, concrete grade, steel grade and axial load ratio. It was found that increasing the thickness of steel tubes and wall faceplates as well as wall width can effectively increase the lateral performance of the structure but increasing the steel beam stiffness only results in limited improvement. Increasing the steel grade can improve the lateral performance of the structure much more significantly than the concrete grade. When the axial load ratio reaches 0.6, the lateral strength of the structure is greatly reduced owing to the P-Δ effect. Moreover, one multi-storey bare frame structure and three multi-storey coupled SCC wall-frame structures were constructed in OpenSees as a case study. The multi-storey coupled SCC wall-frame structures display extraordinary lateral load-carrying capacity by analysing the curves of base shear force versus roof drift ratio. Besides that, instead of the nominal inter-storey drift ratio, the destructive inter-storey drift ratio together with the roof drift ratio are recommended to assess the multi-storey coupled SCC wall-frame structures in order to avoid overconservative design.