Citations

Key Points The type III TGF-β receptor is a marker that distinguishes “early” and “late” BFU-Es. TGF-β inhibitors increase early BFU-E cell self-renewal and total erythroblast production.

Purpose We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. Methods Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. Results Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). Conclusion Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.

Targeting three defects with one strategy The neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia are most commonly caused by a mutation in the C9orf72 gene. The mutation is an expanded hexanucleotide repeat in a noncoding region. The expanded repeat produces sense and antisense RNA transcripts, which accumulate in patient cells and appear to sequester RNA-binding proteins. The sense and antisense transcripts are also translated into dipeptide repeat proteins, which are aggregation-prone and accumulate in the brain and spinal cord. Last, loss of function from reduced expression of C9orf72 in neurons and glia could contribute to the disease. Kramer et al. targeted both sense and antisense repeats by blocking a single gene called SPT4 , which mitigated degeneration in human cells by reducing all three types of pathologies. Science , this issue p. 708

Abstract Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P &lt; 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P &lt; 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932

Abstract Motivation: Prediction and prioritization of human non-coding regulatory variants is critical for understanding the regulatory mechanisms of disease pathogenesis and promoting personalized medicine. Existing tools utilize functional genomics data and evolutionary information to evaluate the pathogenicity or regulatory functions of non-coding variants. However, different algorithms lead to inconsistent and even conflicting predictions. Combining multiple methods may increase accuracy in regulatory variant prediction. Results: Here, we compiled an integrative resource for predictions from eight different tools on functional annotation of non-coding variants. We further developed a composite strategy to integrate multiple predictions and computed the composite likelihood of a given variant being regulatory variant. Benchmarked by multiple independent causal variants datasets, we demonstrated that our composite model significantly improves the prediction performance. Availability and Implementation: We implemented our model and scoring procedure as a tool, named PRVCS, which is freely available to academic and non-profit usage at http://jjwanglab.org/PRVCS. Contact: wang.junwen@mayo.edu, jliu@stat.harvard.edu, or limx54@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.

Abstract Background: OPB-111077 is a new chemical entity with anticancer activity in vitro and in human tumor xenograft models. The compound modulates STAT3 phosphorylation but has no marked effect on activity of any of 69 tested human tyrosine or serine/threonine kinases. This P1 study evaluated safety, pharmacokinetics, and antitumor activity of OPB-111077 in subjects with advanced cancers. Methods: Primary objectives determined safety, tolerability, and maximum tolerated dose (MTD) of OPB-111077 given orally once daily to subjects with advanced cancer. Secondary objectives included pharmacokinetics (PK) and antitumor activity. In the first 2 cycles of dose escalation, Day 1 dose was followed by 2 days off study therapy for PK. The starting dose was 100 mg once daily. Single subject cohorts with dose level doublings were studied until the first ≥ Grade 2 AE that was possibly drug-related. Then a 3+3 design was used. After MTD determination, expansion cohorts were opened for subjects with malignancies possibly susceptible to inhibition by OPB-111077, including breast, cervical, colorectal, gastric, kidney, myeloma, non-small cell lung, non-Hodgkin's lymphoma, ovarian, and prostate cancers, as well as “rare tumors” for which STAT3 inhibition might generate clinical activity. Results: Overall 145 subjects received OPB-111077. Mean age was 61 years (range 21-88), and 51% of subjects were female. Dose escalation occurred in 18 subjects. Four DLTs were observed: 2 at 400 mg QD (G3 nausea/vomiting), and 2 at 300 mg QD (G3 vertigo and G3 nausea/vomiting). The MTD was 250 mg QD. All subjects recovered from DLTs after drug discontinuation. Adverse events (AEs) that may be attributable to OPB-111077 include nausea (71%), vomiting (46%), fatigue (44%), dizziness/vertigo (26%), and hypothyroidism (19%). Most AEs were CTCAE Grades 1 or 2 and manageable with supportive treatment. OPB-111077 exposures increase dose proportionally and linearly with increasing single and multiple doses up to 250 mg. Median time to peak plasma concentration (tmax) is about 4 hours. Mean maximum plasma concentration (Cmax) is 16 μmol/L and mean trough concentration is 6 μmol/L after multiple doses of 250 mg QD. Terminal half-life is about 23 hours and steady state was reached by about 1 week. The major metabolites in plasma are pharmacologically inactive and unlikely to contribute to efficacy. Administration with a high fat meal did not significantly alter OPB-111077 bioavailability. Expansion cohorts enrolled 127 subjects, including NSCLC (13), breast (13), ovarian (11), kidney (11), colorectal (10), prostate (8), lymphoma (8), gastric (7), cervical (3) cancers, and myeloma (1). Rare tumors with STAT rationale included sarcomas (13), neuroendocrine tumors (7), squamous cell carcinomas (5), other carcinomas (12), and other malignant tumors (5). One RECIST Partial Response occurred in a subject with Diffuse Large B Cell Lymphoma. In addition, 7 subjects with had stable disease for at least 8 treatment cycles, including gastric (2), cholangiocarcinoma, kidney, prostate, K-Ras mutant colon cancer, and esthesioneuroblastoma. Conclusions: OPB-111077 can be given safely and achieves clinically active drug levels in humans. Single agent clinical activity was observed. Translational work is ongoing to determine factors driving clinical activity Citation Format: Gregory Cote, Kyriakos Papadopoulos, Amita Patnaik, Drew Rascoe, Lon Smith, Andrea Bullock, Keith Flaherty, Geoffrey Shapiro, Jordan Berlin, Manish Monga, Thomas Habermann, Thomas Witzig, Chester Lin, Lin-Feng Tsai, Agnes Elekes, Naoto Ohi, Kunihiko Tatsumi, Anthony Tolcher. A phase 1, open-label multiple dose escalation trial to determine safety and tolerability of once daily OPB-111077 in subjects with advanced cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B118.

Two cancer testis antigens, the New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and the melanoma-antigen family A (MAGE-A), represent promising immunotherapy targets due to the low expression of these antigens in nonmalignant tissue. To assess overexpression patterns in various cancers, we performed a systematic immunohistochemical analysis for NY-ESO-1 and MAGE-A on tissue array samples of 3668 common epithelial carcinomas (CA) and germ cell tumors of high prevalence and mortality. Here, we find significantly higher expression of MAGE-A (>50% on tumor cells) compared with NY-ESO-1 in several CAs including cutaneous squamous cell carcinomas (SCC) (52.8%/2.8%), esophageal SCC (50%/0%), head and neck SCC (41.1%/<1%), bladder urothelial CA (40.4%/8.3%), cervical/anal SCC (37.5%/0%), lung SCC (34%/3.8%), lung adenocarcinomas (27.6%/3.9%), ovarian CA (26.4%/3.6%), endometrial CA (26.3%/1.3%), lung small cell CA (24.4%/2.4%), gastric adenocarcinomas (20%/4%), breast mucinous CA (19.3%/0%), hepatocellular CA (18.8%/1.2%), breast infiltrating ductal CA (16.4%/1.8%), colorectal adenocarcinomas (10.7%/<1%), cholangiocarcinomas (9.8%/0%), thymic CA (9%/4.5%), and mesotheliomas (7.9%/<1%). Furthermore, high expression of MAGE-A, but not NY-ESO-1, was seen in whole slide evaluations of an independent cohort of metastatic SCC (45.5%/3.6%) and metastatic CA (13.5%/0%) of various primaries with significantly higher expression of MAGE-A in metastatic SCC compared with other metastatic CA. MAGE-A is also more highly expressed in germ cell tumors, seminomas (69%/3.5%) and nonseminomas (40.1%/4.7%). In summary, MAGE-A is more highly expressed than NY-ESO-1 in a majority of human malignancies, and targeting MAGE-A may benefit a large number of patients.

Previous genome‐wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine‐mapping study across 2.06 Mb (chr8:127,561,724–129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93–0.97, conditional p = 5.8 × 10−6), rs7815245 (OR = 0.94, 95% CI = 0.91–0.96, conditional p = 1.1 × 10−6) and rs2033101 (OR = 1.05, 95% CI = 1.02–1.07, conditional p = 1.1 × 10−4) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r2 = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.