Citations

Abstract Abstract 905 Introduction: Though dose-intensive strategies using chemoimmunotherapy have significantly improved mantle cell lymphoma (MCL) outcomes with prolonged progression-free survival (PFS), most patients still relapse over time. In the relapsed setting, MCL patients often develop chemoresistance and have a poor overall prognosis. The immunomodulatory agent lenalidomide has demonstrated tumoricidal and antiproliferative effects in MCL and clinical activity and safety in multiple phase II studies in aggressive non-Hodgkin's lymphoma. The objective of the MCL-001 “EMERGE” study was to examine the safety and efficacy of single-agent lenalidomide in subjects with MCL who relapsed or were refractory to bortezomib. Methods: This phase II, multicenter, single-arm, open-label study examined single-agent lenalidomide administered at 25 mg/d PO on days 1–21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal. The subjects were required to have had prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (<12 months) after or were refractory to bortezomib. The primary endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), PFS, time to progression (TTP), overall survival (OS) and safety. Efficacy data were measured by investigators and an independent central review committee according to modified International Working Group criteria and analyzed by SAS. Results: 134 subjects with relapsed or refractory MCL who were heavily pretreated (no limitation in number of prior therapies) were enrolled. The median age was 67 y (range, 43–83), two-thirds of them being 65 y or older and 93% with advanced stage disease (stage III-IV). The median number of prior therapies was 4 (range, 2– 10) with 78% of subjects having received ≥ 3 prior lines of treatment. The ORR to single-agent lenalidomide was 28% (CR/CRu 8%; Table 1) by independent central review, with a median DOR of 16.6 mo (95% CI, 7.7–26.7; Figure 1). The ORR was 32% (CR/CRu 16%) by investigator assessment, with a median DOR of 18.5 mo. Median time to response (central review) was 2.2 mo (3.7 mo to achieve CR). The median PFS was 4.0 mo (95% CI, 3.6–5.6); median OS was 19.0 mo (95% CI, 12.5–23.9). Subjects received an average dose of 20 mg/d of lenalidomide. Lenalidomide was dose reduced in 38% of subjects; treatment discontinuation due to an adverse event (AE; primarily myelosuppression) was reported in 19% of subjects. The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%) and fatigue (7%). Other AEs (any grade) included tumor flare reaction (13 subjects, 10%), deep vein thrombosis (5 subjects, 4%), pulmonary embolism (3 subjects, 2%) and invasive second primary malignancies (3 subjects, 2%). Conclusions: The EMERGE study demonstrated rapid and durable efficacy of lenalidomide in MCL subjects who relapsed or progressed after or were refractory to bortezomib. These results in heavily pretreated MCL subjects (median of 4 prior treatments), and with an expected toxicity profile support single-agent lenalidomide in subjects with relapsed or refractory MCL after bortezomib. Disclosures: Goy: Pfizer: Advisory board member, Advisory board member Other; Seattle Genetics: Advisory board member Other; J&J: Advisory board member, Advisory board member Other; Pharmacyclics: Advisory board member, Advisory board member Other; Millenium: Advisory board member, Advisory board member Other, Speakers Bureau; Celgene: Advisory board member Other. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Sinha:Celgene: Research Funding. Williams:Celgene: Clincial Trial Research Support, Advisory Boards, Data Safety Committee Member, Consultant Other, Consultancy. Drach:Celgene: Speakers Bureau; Janssen: Speakers Bureau; Roche: Research Funding. Ramchandren:Seattle Genetics: Speakers Bureau. Herbrecht:Pfizer: Advisory board member Other. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Witzig:Celgene : Research Funding.

Abstract Aims This observational study characterized cardiovascular disease (CVD) mortality risk for multiple cancer sites, with respect to the following: (i) continuous calendar year, (ii) age at diagnosis, and (iii) follow-up time after diagnosis. Methods and results The Surveillance, Epidemiology, and End Results program was used to compare the US general population to 3 234 256 US cancer survivors (1973–2012). Standardized mortality ratios (SMRs) were calculated using coded cause of death from CVDs (heart disease, hypertension, cerebrovascular disease, atherosclerosis, and aortic aneurysm/dissection). Analyses were adjusted by age, race, and sex. Among 28 cancer types, 1 228 328 patients (38.0%) died from cancer and 365 689 patients (11.3%) died from CVDs. Among CVDs, 76.3% of deaths were due to heart disease. In eight cancer sites, CVD mortality risk surpassed index-cancer mortality risk in at least one calendar year. Cardiovascular disease mortality risk was highest in survivors diagnosed at &lt;35 years of age. Further, CVD mortality risk is highest (SMR 3.93, 95% confidence interval 3.89–3.97) within the first year after cancer diagnosis, and CVD mortality risk remains elevated throughout follow-up compared to the general population. Conclusion The majority of deaths from CVD occur in patients diagnosed with breast, prostate, or bladder cancer. We observed that from the point of cancer diagnosis forward into survivorship cancer patients (all sites) are at elevated risk of dying from CVDs compared to the general US population. In endometrial cancer, the first year after diagnosis poses a very high risk of dying from CVDs, supporting early involvement of cardiologists in such patients.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Additionally, extent of resection, tumor laterality, and IDH1 mutation status were also found to have sex-specific effects on overall survival. Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

ABSTRACT The adult zebrafish is an emerging vertebrate model for studying human cardiomyopathies; however, whether the simple zebrafish heart can model different subtypes of cardiomyopathies, such as dilated cardiomyopathy (DCM), remains elusive. Here, we generated and characterized an inherited DCM model in adult zebrafish and used this model to search for therapeutic strategies. We employed transcription activator-like effector nuclease (TALEN) genome editing technology to generate frame-shift mutants for the zebrafish ortholog of human BCL2-associated athanogene 3 (BAG3), an established DCM-causative gene. As in mammals, the zebrafish bag3 homozygous mutant (bag3e2/e2) exhibited aberrant proteostasis, as indicated by impaired autophagy flux and elevated ubiquitinated protein aggregation. Through comprehensive phenotyping analysis of the mutant, we identified phenotypic traits that resembled DCM phenotypes in mammals, including cardiac chamber enlargement, reduced ejection fraction characterized by increased end-systolic volume/body weight (ESV/BW), and reduced contractile myofibril activation kinetics. Nonbiased transcriptome analysis identified the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling in bag3e2/e2 mutant hearts. Further genetic studies showed that mtorxu015/+, an mTOR haploinsufficiency mutant, repaired abnormal proteostasis, improved cardiac function and rescued the survival of the bag3e2/e2 mutant. This study established the bag3e2/e2 mutant as a DCM model in adult zebrafish and suggested mtor as a candidate therapeutic target gene for BAG3 cardiomyopathy.

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in United States with a 5-year survival rate of only 8%. Inherited predisposition plays an important role in PDAC risk. Rare, moderately to highly penetrant mutations in hereditary cancer and pancreatitis genes, identified in families with a high incidence of disease, account for a small fraction of cases. At the other end of the spectrum, common risk variants of low penetrance have been discovered through genome-wide association studies (GWAS). Currently, over 20 common PDAC risk signals have been identified through GWAS in populations of European ancestry. However, these loci explain only a small fraction of genetic heritability for PDAC, and the causal genes for the large majority of these are unknown. Most susceptibility alleles discovered through GWAS are located in noncoding regions of the genome and are likely to function through allele specific regulation of gene expression. Transcriptome-wide association studies integrate expression quantitative trait loci (eQTL) with GWAS data to discover genes whose cis-regulated expression is associated with complex traits. To identify novel susceptibility loci and likely causal genes, we applied this approach to PDAC. Firstly, we used two reference datasets generated from histologically normal pancreatic tissue samples from individuals of European ancestry, the DCEG/LTG (n=95) and Genotype-Tissue Expression (GTEx v7, n=174), to build robust predictors for gene expression (n=2,872-5,906; r2&gt;0.01), using 5 different models (Top1, Lasso, Enet, Blup and Bslmm) in FUSION and PrediXcan. Gene expression predictors (n=2,043-21,422) were also generated by Enet in 48 different tissues (n=74-421 samples) from 608 individuals of European ancestry (GTEx). We then applied these predictor models to PDAC GWAS summary statistics from 9,040 PC cases and 12,496 controls. We discovered 24 genes whose genetically predicted expression is significantly associated with PDAC risk (FDR &lt; 0.05), including 13 candidate genes at 10 novel loci (CELA3B, SMC2, SMC2-AS1, RP11-80H5.9, SMUG1, BTBD6, RCCD1, PNMT, CDK12, PGAP3, SUPT4H1, RP11-888D10.3 and PGPEP1) and 11 at 5 known risk loci (TERT, CLPTM1L, ZDHHC11B, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, BCAR1 and TMEM170A). Pathway enrichment analysis for genes differentially expressed in the top vs. bottom quartile of CELA3B expression highlighted higher expression of inflammatory and immune response genes in both the DCEG/LTG and GTEx pancreatic transcriptome datasets, indicating that low expression of this gene may be associated with an inflammatory state in the pancreas. Our findings showcase the utility of integrating multiple datasets to generate hypotheses and provide novel clues for the genetic mechanisms underlying pancreatic cancer risk. Citation Format: Jun Zhong, Ashley Jermusyk, Lang Wu, Jason W. Hoskins, Irene Collins, Mingfeng Zhang, Song Lei, Charles C. Chung, Tongwu Zhang, Wenming Xiao, Rachael Stolzenberg-Solomon, Alison P. Klein, Brian M. Wolpin, Xiao-Ou Shu, Stephen J. Chanock, Sara Olson, Nilanjan Chatterjee, Jill Smith, Jianxin Shi, Peter Kraft, Gloria M. Petersen, Wei Zheng, Laufey T. Amundadottir. Large-scale transcriptome-wide association study (TWAS) identifies novel candidate susceptibility genes for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1591.

Although glioblastoma (GBM) is a fatal primary brain cancer with short median survival of 15 months, a small number of patients survive >5 years after diagnosis; they are known as extreme survivors (ES). Because of their rarity, very little is known about what differentiates these outliers from other patients with GBM. For the purpose of identifying unknown drivers of extreme survivorship in GBM, the ENDURES consortium (ENvironmental Dynamics Underlying Responsive Extreme Survivors of GBM) was developed. This consortium is a multicenter collaborative network of investigators focused on the integration of multiple types of clinical data and the creation of patient-specific models of tumor growth informed by radiographic and histologic parameters. Leveraging our combined resources, the goals of the ENDURES consortium are 2-fold: (1) to build a curated, searchable, multilayered repository housing clinical and outcome data on a large cohort of ES patients with GBM; and (2) to leverage the ENDURES repository for new insights into tumor behavior and novel targets for prolonging survival for all patients with GBM. In this article, the authors review the available literature and discuss what is already known about ES. The authors then describe the creation of their consortium and some preliminary results.

Abstract The presence of FMS-like receptor tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate primitive FLT3-ITD+ leukemia cells, which are potential sources of relapse. Thus, understanding the mechanisms underlying FLT3-ITD+ AML cell persistence is essential to devise future AML therapies. Here, we show that expression of protein arginine methyltransferase 1 (PRMT1), the primary type I arginine methyltransferase, is increased significantly in AML cells relative to normal hematopoietic cells. Genome-wide analysis, coimmunoprecipitation assay, and PRMT1-knockout mouse studies indicate that PRMT1 preferentially cooperates with FLT3-ITD, contributing to AML maintenance. Genetic or pharmacological inhibition of PRMT1 markedly blocked FLT3-ITD+ AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginine 972/973, and PRMT1 promoted leukemia cell growth in an FLT3 methylation–dependent manner. Moreover, the effects of FLT3-ITD methylation in AML cells were partially due to cross talk with FLT3-ITD phosphorylation at tyrosine 969. Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following kinase inhibition, indicating that methylation occurs independently of kinase activity. Finally, in patient-derived xenograft and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML cells relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes AML maintenance and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to eliminate FLT3-ITD+ AML cells.

Abstract Background: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Additionally, extent of resection, tumor laterality, and IDH1 mutation status were also found to have sex-specific effects on overall survival. Conclusion: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Abstract The types and magnitude of Ag-specific immune responses can be determined by the functional plasticity of dendritic cells (DCs). However, how DCs display functional plasticity and control host immune responses have not been fully understood. In this study, we report that ligation of DC–asialoglycoprotein receptor (DC-ASGPR), a C-type lectin receptor (CLR) expressed on human DCs, resulted in rapid activation of Syk, followed by PLCγ2 and PKCδ engagements. However, different from other Syk-coupled CLRs, including Dectin-1, signaling cascade through DC-ASGPR did not trigger NF-κB activation. Instead, it selectively activated MAPK ERK1/2 and JNK. Rapid and prolonged phosphorylation of ERK1/2 led to sequential activation of p90RSK and CREB, which consequently bound to IL10 promoter and initiated cytokine expression. In addition, DC-ASGPR ligation activated Akt, which differentially regulated the activities of GSK-3α/β and β-catenin and further contributed to IL-10 expression. Our observations demonstrate that DC-ASGPR induces IL-10 expression via an intrinsic signaling pathway, which provides a molecular explanation for DC-ASGPR–mediated programing of DCs to control host immune responses.

ABSTRACT Previously, we demonstrated that intratumoral delivery of adenoviral vector encoding single‐chain (sc) IL‐23 (Ad.scIL‐23) was able to induce systemic antitumor immunity. Here, we examined the role of IL‐23 in diabetes in nonobese diabetic mice. Intravenous delivery of Ad.scIL‐23 did not accelerate the onset of hyperglycemia but instead resulted in the development of psoriatic arthritis. Ad.scIL‐23–treated mice developed erythema, scales, and thickening of the skin, as well as intervertebral disc degeneration and extensive synovial hypertrophy and loss of articular cartilage in the knees. Immunological analysis revealed activation of conventional T helper type 17 cells and IL‐17–producing γδ T cells along with a significant depletion and suppression of T cells in the pancreatic lymph nodes. Furthermore, treatment with anti–IL‐17 antibody reduced joint and skin psoriatic arthritis pathologies. Thus, these Ad.scIL‐23–treated mice represent a physiologically relevant model of psoriatic arthritis for understanding disease progression and for testing therapeutic approaches.—Flores, R. R., Carbo, L., Kim, E., Van Meter, M., De Padilla, C. M. L., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, P. D. Adenoviral gene transfer of a single‐chain IL‐23 induces psoriatic arthritis–like symptoms in NOD mice. FASEB J. 33, 9505–9515 (2019). www.fasebj.org