SUMMARY Pancreatic cancer is a deadly disease characterized by late diagnosis and resistance to therapy. Much progress has been made in defining gene defects in pancreatic cancer, but a full accounting of its molecular pathogenesis awaits. Here, we show that expression of Ataxia-Telangiectasia Group D Complementing gene (ATDC), also called TRIM29, is elevated in most invasive pancreatic cancers and pancreatic cancer precursor lesions. ATDC promoted cancer cell proliferation in vitro and enhanced tumor growth and metastasis in vivo. ATDC expression correlated with elevated β-catenin levels in pancreatic cancer, and β-catenin function was required for ATDC’s oncogenic effects. ATDC was found to stabilize β-catenin via ATDC-induced effects on the disheveled-2 protein, a negative regulator of GSK3β in the Wnt/β-catenin signaling pathway. SIGNIFICANCE Pancreatic cancer is an aggressive malignancy, and an improved understanding of the molecular mechanisms governing its highly aggressive behavior is needed for more effective treatment, early detection and prevention. Defects in Wnt/β-catenin signaling are common in certain cancers, such as colorectal carcinoma, and recent evidence suggests Wnt/β-catenin signaling may contribute to pancreatic cancer. In this report, we show that ATDC is over-expressed in the majority of invasive pancreatic cancers and pancreatic cancer precursor lesions. ATDC contributes to pancreatic cancer via its ability to interact with and stabilize expression of disheveled-2, with resultant stabilization of β-catenin. Besides highlighting ATDC as a potential therapeutic target in pancreatic cancer, our studies have defined a novel mechanism for activating Wnt/β-catenin signaling in cancer.
Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of a prevalence of activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization of mesenchymal stem cells (MSC) within the human PDA microenvironment, highlighting the heterogeneity of the fibroblast population. Primary patient PDA samples and low-passage human pancreatic cancer–associated fibroblast cultures were found to contain a unique population of cancer-associated MSCs (CA-MSC). CA-MSCs markedly enhanced the growth, invasion, and metastatic potential of PDA cancer cells. CA-MSCs secreted the cytokine GM-CSF that was required for tumor cell proliferation, invasion, and transendothelial migration. Depletion of GM-CSF in CA-MSCs inhibited the ability of these cells to promote tumor cell growth and metastasis. Together, these data identify a population of MSCs within the tumor microenvironment that possesses a unique ability, through GM-CSF signaling, to promote PDA survival and metastasis. SIGNIFICANCE The role of stroma in pancreatic cancer is controversial. Here, we provide the first characterization of MSCs within the human PDA microenvironment and demonstrate that CA-MSCs promote tumorigenesis through the production of GM-CSF. These data identify a novel cytokine pathway that mediates mesenchymal–epithelial cross-talk and is amenable to therapeutic intervention.
Purpose: Mantle-cell lymphoma (MCL) is an incurable mature B-cell neoplasm with high initial response rates followed almost invariably by relapse. Prognosis for patients following relapse is poor, and treatment choices are limited. We evaluated the efficacy and safety of zanubrutinib, an investigational selective Bruton's tyrosine kinase (BTK) inhibitor. Patients and Methods: Patients with relapsed/refractory MCL were enrolled in this ongoing phase II, single-arm, open-label study, and treated with oral zanubrutinib 160 mg twice daily. The primary endpoint is overall response rate (ORR) assessed by an independent review committee (per Lugano 2014 classification); secondary endpoints include duration of response (DOR), time to response, progression-free survival (PFS), and safety. Results: Eighty-six patients (median age, 60.5 years) were enrolled after a median of 2 prior lines of therapy, received ≥1 dose of the study drug, and were evaluable for safety and efficacy. After a median follow-up of 18.4 months, 72 (84%) patients achieved an objective response, with 59 (68.6%) achieving a complete response (CR). Median DOR and PFS were 19.5 and 22.1 months, respectively; 12-month event-free estimates for DOR and PFS are 78% and 76%, respectively. Most common grade ≥3 adverse events (AE) were neutropenia (19.8%) and lung infection/ pneumonia (9.3%). Three patients experienced major bleeding events, and there were no reports of atrial fibrillation. Eight (9.3%) patients discontinued zanubrutinib for AEs. Conclusions: These results demonstrate high and durable ORR and CR rates in patients with relapsed/refractory MCL. Zanubrutinib was generally well tolerated; grade ≥3 BTK inhibitorassociated toxicities (hemorrhage, rash, hypertension, diarrhea, atrial fibrillation) were uncommon.
The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0439-6) contains supplementary material, which is available to authorized users.
Among the recognition molecules that determine a neuron's interaction with other cells, L1 and CD24 have been suggested to cooperate with each other in neurite outgrowth and signal transduction. Here we report that binding of CD24 to L1 depends on ␣2,3-sialic acid on CD24, which determines the CD24 induced and cell typespecific promotion or inhibition of neurite outgrowth. Using knockout mutants, we could show that the CD24-induced effects on neurite outgrowth are mediated via L1, and not GPI-linked CD24, by trans-interaction of L1 with sialylated CD24. This glycoform is excluded together with L1 from raft microdomains, suggesting that molecular compartmentation in the surface membrane could play a role in signal transduction.Path-finding of growth cones and neurite outgrowth toward targets are important events in the developing and regenerating nervous system and in synaptic remodeling during learning and memory. Axonal guidance depends on molecules at the cell surface and in the extracellular matrix. The different and often changing combinations of molecularly associated recognition molecules at the cell surface are important determinants of the ways by which the cell surface communicates with the cell interior, where cell surface signals are integrated to influence cell behavior.Two recognition molecules, L1 of the immunoglobulin superfamily and CD24, a highly glycosylated mucin type glycoprotein, interact with each other functionally (1, 2). L1 is a 200-kDa homophilic and heterophilic adhesion molecule expressed by many postmitotic neurons in the central nervous system (for reviews, see Refs. 3 and 4). It is one of the most potent promoters of neurite outgrowth in vitro known so far. Mutants of L1 in mice and men strongly underscore its importance during embryonic development in vivo (3,5,6).CD24 is linked to the surface membrane by a glycosyl phosphatidylinositol anchor and is, therefore, unable to directly interact with cytoplasmic proteins. It is also known as heatstable antigen or nectadrin with a peptide core of only 30 amino acids (for references, see Ref. 1). Similar to L1, it is highly expressed by neurons (7,8). The apparent molecular weight of CD24 varies considerably among cell types and also within each cell type, depending on its developmental stage due to differences in glycosylation pattern (for references, see Refs. 1 and 7). These observations suggest that post-translational modifications of CD24 play an important functional role. CD24 acts as a co-stimulator for various physiological functions. In the nervous system, CD24 has been reported to interact with L1 to stimulate cell adhesion and to increase intracellular Ca 2ϩ levels (1, 2). Interestingly, CD24 has been shown to inhibit neurite outgrowth of neonatal retinal ganglion cells and dorsal root ganglion neurons in culture (8) by yet unknown signal transduction mechanisms.Based on these observations on the functional interplay and molecular association between L1 and CD24, we decided to further study their functional interdependence. Her...
Amyotrophic lateral sclerosis (ALS) is caused by a progressive degeneration of motor neurons. The cause of sporadic ALS is not known, but 1-2% of all cases are familial and caused by mutations in the copper-zinc superoxide dismutase (SOD1) gene. Transgenic SOD1 mice serve as a transgenic mouse model for these cases. Glial cell-derived neurotrophic factor (GDNF) has a potent trophic effect on motor neurons. Clinical trials in which growth factors have been systemically administered to ALS patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. Gene transfer of therapeutic factors to motor neurons and/or their target cells, such as muscle, may overcome these problems. Previously, we and others have shown that intramuscularly administered adenovirus vector (AVR) results in foreign gene expression not only in muscle cells, but also in relevant motor neurons in the spinal cord, because of retrograde axonal transport. In this study we utilized an AVR to introduce GDNF into muscles of neonatal SOD1 mice. We showed that AVR-mediated GDNF expression delayed the onset of disease by 7 +/- 8 days (mean +/- SD), prolonged survival by 17 +/- 10 days, and delayed the decline in motor functions (as determined on a rotating rod) by 7-14 days. These results demonstrate that gene delivery to muscle and motor neurons has the potential to treat devastating neurodegenerative diseases such as ALS.
Prognosis is poor for patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after failure of or who are ineligible for autologous stem cell transplant. We evaluated the efficacy and safety of tislelizumab, an investigational anti-PD-1 monoclonal antibody, in phase 2, single-arm study in Chinese patients with R/R cHL. The primary endpoint was overall response rate as assessed by an independent review committee, according to the Lugano 2014 Classification. Seventy patients were enrolled in the study and received at least one dose of tislelizumab. After median follow-up of 9.8 months, 61 (87.1%) patients achieved an objective response, with 44 (62.9%) achieving a complete response (CR). The estimated 9month progression-free survival rate was 74.5%. Most common grade ≥3 adverse events (AEs) were upper respiratory tract infection and pneumonitis. Infusion-related reactions occurred in 27 (38.6%) patients, and 27 patients (38.6%) experienced an immune-related AE, the most common of which was thyroid dysfunction. Eleven (15.7%) patients experienced at least one treatment-emergent AE leading to dose interruption or delay. No deaths occurred due to AEs. Treatment of patients with R/R cHL with tislelizumab was generally well tolerated and resulted in high overall response and CR rates, potentially translating into more durable responses for these patients.
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