609 Combining bintrafusp alfa with abituzumab enhances suppression of the TGF-β signaling pathway

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor fused to a human IgG1 antibody blocking PD-L1. The TGF-βRII moiety of bintrafusp alfa functions as a "trap" to sequester active TGF-β but does not block TGF-β release from its latent form. Multiple mechanisms lead to the release of active TGF-β. Integrins control local activation of latent TGF-β stored in the extracellular matrix and cell-surface reservoirs in the tumor microenvironment (TME). Alpha v integrin mRNA expression is correlated with multiple TGF-β gene signatures. It has been shown that αvβ8 integrin mediates TGF-β activation without releasing it from the latent TGF-β complex, suggesting that the TGF-βRII moiety of bintrafusp alfa may be unable to sequester TGF-β activated by αvβ8 integrin. Therefore, we hypothesize that combining abituzumab, a pan–αv integrin antibody, with bintrafusp alfa may lead to enhanced suppression of TGF-β signaling.MethodsThe expression of αv and β6 integrin mRNA was determined by RNA sequencing of triple-negative breast cancer (TNBC) tumor samples from a phase 1 clinical trial of bintrafusp alfa and correlated with patient response to bintrafusp alfa. The combination of bintrafusp alfa and abituzumab was investigated in vitro and in vivo in a TGF-β–dependent human tumor model, Detroit 562. In this study, CellTiter-Glo 2.0 Assay measured cell proliferation in vitro and enzyme-linked immunosorbent assay measured the level of latency-associated protein (LAP). A TGF-β reporter cell line MDA-MB-231 measured the level of active TGF-β. Antitumor activity in vivo was evaluated via tumor growth of Detroit 562 xenograft model in SCID mice.ResultsIn TNBC, increased expression of αv and β6 integrin mRNA was associated with poor response to bintrafusp alfa, suggesting that TGF-β activated by αv integrin may not be blocked by bintrafusp alfa. In Detroit 562 cells, abituzumab increased LAP levels in the cell culture medium, confirming modulation of the TGF-β pathway. As a result, the amount of active TGF-β released into culture medium was reduced by abituzumab. In vitro, both abituzumab and bintrafusp alfa suppressed Detroit 562 cell proliferation, and the combination suppressed cell proliferation further. In vivo, the combination led to increased tumor growth inhibition of Detroit 562 xenograft tumors relative to either monotherapy, further supporting the potential of this combination.ConclusionsCollectively, these preclinical findings support clinical development of bintrafusp alfa and abituzumab combination therapy to maximally suppress TGF-β signaling in the TME.AcknowledgementsWe thank George Locke for his analysis of the RNAseq data.Ethics ApprovalThis study was approved by the Institutional Animal Care and Use Committee at EMD Serono, Inc.; approval number [17–008]

CAF-derived MFAP5 is a novel transcription regulator for immune checkpoint CD47 in ovarian cancer

https://openworks.mdanderson.org/sumexp23/1115/thumbnail.jp

Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer.

Peritoneal dissemination is the primary metastatic route of ovarian cancer (OvCa), and is often accompanied by the accumulation of ascitic fluid. The peritoneal cavity is lined by mesothelial cells (MCs), which can be converted into carcinoma-associated fibroblasts (CAFs) through mesothelial-to-mesenchymal transition (MMT). Here, we demonstrate that MCs isolated from ascitic fluid (AFMCs) of OvCa patients with peritoneal implants also undergo MMT and promote subcutaneous tumour growth in mice. RNA sequencing of AFMCs revealed that MMT-related pathways – including transforming growth factor (TGF)- signalling – are differentially regulated, and a gene signature was verified in peritoneal implants from OvCa patients. In a mouse model, pre-induction of MMT resulted in increased peritoneal tumour growth, whereas interfering with the TGF- receptor reduced metastasis. MC-derived CAFs showed activation of Smad-dependent TGF- signalling, which was disrupted in OvCa cells, despite their elevated TGF- production. Accordingly, targeting Smad-dependent signalling in the peritoneal pre-metastatic niche in mice reduced tumour colonization, suggesting that Smad-dependent MMT could be crucial in peritoneal carcinomatosis. Together, these results indicate that bidirectional communication between OvCa cells and MC-derived CAFs, via TGF--mediated MMT, seems to be crucial to form a suitable metastatic niche. We suggest MMT as a possible target for therapeutic intervention and a potential source of biomarkers for improving OvCa diagnosis and/or prognosis.post-print2310 K

Direct Manipulation of Particle Size and Morphology of Ordered Mesoporous Silica by Flow Synthesis

The precision by which the fluid mixing, flow pattern, and reaction can be manipulated in a flow-synthesis reactor enables the deliberate preparation of ordered mesoporous silicas (OMS) of controlled particle size (ca. 50 to 650 nm) and shapes (i.e., spheres and random), as well as complex microstructures (i.e., hollow spheres). Fluid mixing and flow pattern were generated using Tee- and slit interdigital micromixers under laminar and Taylor flow conditions, while hydrolysis reactions was governed by the alkoxide precursors (i.e. TEOS & TMOS) and temperature. The hollow OMS spheres can host molecules and clusters as demonstrated by the incorporation of ferrocene and iron nanoparticles

Flow-synthesis of mesoporous silicas and their use in the preparation of magnetic catalysts for Knoevenagel condensation reactions

Mesoporous silica MCM-41 was successfully prepared by flow synthesis in a microreactor at shorter reaction times (i.e., minutes versus day) at high yield (i.e., 60% calcined sample) to give particles of more uniform size and shape compared to MCM-41 prepared by conventional batch synthesis. Magnetic iron oxide nanoparticles were incorporated and organic amines (i.e., propylamine and propyl diethylene amine) were grafted to obtain magnetic mesoporous catalysts for the Knoevenagel condensation reactions of benzaldehyde with ethyl cyanoacetate, ethyl acetoacetate and diethyl malonate. The incorporation of magnetic nanoparticles and large organic amines can hinder reactants access to the catalyst resulting in lower reactivity. NH2-magMCM-41 showed superb catalyst activity and selectivity for the all three Knoevenagel condensation reactions studied. The catalyst can be easily dispersed into solution and rapidly removed by a magnet for recovery and reuse. (c) 2012 Elsevier B.V. All rights reserved

Targeting Stromal-Cancer Cell Crosstalk Networks in Ovarian Cancer Treatment

Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment

Maternal age of menarche and adiposity: evidence from Hong Kong’s “Children of 1997“ birth cohort

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.BACKGROUND:: Earlier age of menarche predicts chronic diseases. Earlier maternal age of menarche is also associated with higher body mass index (BMI) and height into childhood. METHODS:: We used generalized estimating equations in Hong Kong’s “Children of 1997“ birth cohort to examine the adjusted association of maternal age of menarche with BMI and height z-score, and whether associations varied by maternal birthplace. RESULTS:: Earlier maternal age of menarche was not associated with infant BMI but was associated subsequently with higher BMI in childhood and at puberty. Maternal age of menarche was negatively associated with height in children of Hong Kong-born mothers, but positively associated with infant length for children with mothers born in China (p-value for interaction 0.02). CONCLUSION:: These different patterns suggest drivers of adiposity and linear growth differ, and are more influential in some circumstances. Understanding these drivers may indicate setting-specific interventions to prevent childhood obesity.Link_to_subscribed_fulltex

Assessment of Sericin Biosorbent for Selective Dye Removal

The silk sericin is the main residue in silk production and it is found to be a low cost and efficient biosorbent. In this study, sericin was characterized with various techniques including SEM (scanning electron microscope), XRD, N-2 physisorption, FTIR (Fourier transformed infrared spectroscopy) and XPS (X-ray photoelectron spectroscopy). The nitrogen content of sericin was ca. 8.5 mmol.g(-1) according to elemental analysis. Dye adsorption by sericin biosorbent was investigated with the acid yellow (AY), methylene blue (MB) and copper (II) phthalocyanine-3,4'4 " 4 "'-tetrasulfonic acid (CuPc) dyes from water. Sericin displayed large capacity for AY and CuPc adsorption with adsorption capacities of respectively 3.1 and 0.35 mmol.g(-1), but it did not adsorbed methylene blue dye. This selectivity is due to the basicity of amide groups in sericin biosorbents