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Effect of ofatumumab on pregnancy, parturition, and lactation in cynomolgus monkeys.
No full textKnowledge of the impacts of the anti-CD20 monoclonal antibody ofatumumab on the developing immune system is limited. This study examined the effects of intravenous ofatumumab on pregnancy, parturition, and lactation, and on pre- and postnatal survival and development in cynomolgus monkeys, an established model for developmental toxicity assessment. Pregnant cynomolgus monkeys (n = 42) were randomized to receive vehicle only (control group; n = 14), low-dose ofatumumab (n = 14), or high-dose ofatumumab (n = 14). Survival, clinical outcomes, and clinical pathology investigations were evaluated regularly until lactation day (maternal animals) and postnatal day 180±1 (infants). Anatomic pathology was investigated in euthanized infants and unscheduled terminations of maternal animals and infants. Ofatumumab treatment was not associated with maternal toxicity or embryotoxicity and had no effect on the growth and development of offspring. As expected, B-cell depletion occurred in maternal animals and their offspring, with a reduced humoral immune response in infants of mothers on high-dose ofatumumab. Both effects were reversible. In the high-dose group, perinatal deaths of 3 infants were attributed to infections, potentially secondary to pharmacologically induced immunosuppression. The no-observed adverse-effect level for initial/maintenance ofatumumab doses was 100/20 mg, and 10/3 mg/kg for pharmacological effects in infant animals, which are associated with exposures significantly higher than those following therapeutic doses in humans. In this study with cynomolgus monkeys, ofatumumab treatment was not associated with maternal toxicity or embryotoxicity and had no effect on the growth and development of offspring
Explainable Machine Learning for Property Predictions in Compound Optimization.
No full textThe prediction of compound properties from chemical structure is a main task for machine learning (ML) in medicinal chemistry. ML is often applied to large data sets in applications such as compound screening, virtual library enumeration, or generative chemistry. Albeit desirable, a detailed understanding of ML model decisions is typically not required in these cases. By contrast, compound optimization efforts rely on small data sets to identify structural modifications leading to desired property profiles. In this situation, if ML is applied, one usually is reluctant to make decisions based on predictions that cannot be rationalized. Only few ML methods are interpretable. However, to yield insights into complex ML model decisions, explanatory approaches can be applied. Herein, methodologies for better understanding of ML models or explaining individual predictions are reviewed and current challenges in integrating ML into medicinal chemistry programs as well as future opportunities are discussed
Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression
No full textHeterogeneity within a tumour increases its ability to adapt to constantly changing constraints, but adversely affects a patient's prognosis, therapy response and clinical outcome. Intratumoural heterogeneity results from a combination of extrinsic factors from the tumour microenvironment and intrinsic parameters from the cancer cells themselves, including their genetic, epigenetic and transcriptomic traits, their ability to proliferate, migrate and invade, and their stemness and plasticity attributes. Cell plasticity constitutes the ability of cancer cells to rapidly reprogramme their gene expression repertoire, to change their behaviour and identities, and to adapt to microenvironmental cues. These features also directly contribute to tumour heterogeneity and are critical for malignant tumour progression. In this article, we use breast cancer as an example of the origins of tumour heterogeneity (in particular, the mutational spectrum and clonal evolution of progressing tumours) and of tumour cell plasticity (in particular, that shown by tumour cells undergoing epithelial-to-mesenchymal transition), as well as considering interclonal cooperativity and cell plasticity as sources of cancer cell heterogeneity. We review current knowledge on the functional contribution of cell plasticity and tumour heterogeneity to malignant tumour progression, metastasis formation and therapy resistance
Parsing β-catenin's cell adhesion and Wnt signaling functions in malignant mammary tumor progression
No full textDuring malignant progression, epithelial cancer cells dissolve their cell-cell adhesion and gain invasive features. By virtue of its dual function, β-catenin contributes to cadherin-mediated cell-cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of β-catenin's transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)-PyMT mouse model of metastatic breast cancer, we compared the complete elimination of β-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin's transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial-mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by β-catenin's transcriptional activities upon stimulation with Wnt3a or during TGF-β-induced EMT. Our results uncouple the signaling from the adhesion function of β-catenin and underline the importance of Wnt/β-catenin-dependent transcription in malignant tumor progression of breast cancer
PAX8 and MECOM are interaction partners driving Ovarian Carcinogenesis
No full textThe transcription factor PAX8 is critical for the development of the thyroid and urogenital system. Comprehensive genomic screens furthermore indicate an additional oncogenic role for PAX8 in renal and ovarian carcinogenesis. While a plethora of PAX8-regulated genes in different contexts have been proposed, we still lack a mechanistic understanding of how PAX8 engages molecular complexes to drive disease-relevant oncogenic transcriptional programs. Here we show that protein isoforms originating from the MECOM locus form a complex with PAX8. This includes PRDM3 (also called MDS1-EVI1) for which we map its interaction with PAX8 in vitro and in vivo. We show that PAX8 binds a large number of genomic sites and forms transcriptional hubs. At a subset of these, PAX8 together with PRDM3 regulate a specific gene expression module involved in adhesion and extracellular matrix. This gene module correlates with PAX8 and MECOM expression in large scale profiling of cell lines, PTXs and clinical cases and stratifies gynecological cancer cases with worse prognosis. PRDM3 is amplified in Ovarian Cancers and we show that the MECOM locus and PAX8 sustain in-vivo ovarian cancer growth, further supporting that the identified function of the MECOM locus underlies PAX8-driven oncogenic functions in ovarian cancer
Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8
No full textBromodomain-containing proteins frequently reside in multisubunit chromatin complexes with tissue or cell state specific compositions. Recent studies have revealed tumor specific dependencies on the BAF complex bromodomain subunit BRD9 that are a result of recurrent mutations afflicting the structure and composition of associated complex members. To enable study of ligand engaged complex assemblies, we established a native affinity matrix approach using a functionalized derivative of the BRD9 ligand BI-9564. Unexpectedly, in addition to known interactions with the BRD9 and associated BAF complex proteins, we identify a previously unreported interaction with members of the NuA4 complex through the bromdomain subunit BRD8. We apply this finding, alongside homology-model guided design, to develop chemical biology approaches for the study of BRD8 inhibition, and to arrive at first in class selective and cellularly active probes for BRD8. These tools will empower further pharmacological study of BRD9 and BRD8 within respective BAF and NuA4 complexes
Mechanisms driving neutrophil-induced t-cell immunoparalysis in ovarian cancer
No full textT-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in theTME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumorassociated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy
Presenting secondary endpoints in plain language clinical trial result summaries: Considerations for emerging practice
No full textBackground: The European Union Clinical Trials Regulation 536/2014 (EU CTR) requires sponsors to submit summaries of
clinical trial results in plain/lay language (Plain Language Trial Summaries [PLTS]). A multidisciplinary working group developed recommendations for defining, selecting, and summarising patient-relevant secondary endpoints in the PLTS.
Considerations: For sponsors who elect to include more than the primary endpoint, emerging practice is to include patient relevant secondary endpoints, defined as those that were prespecified as secondary endpoints in the protocol, their analysis being described in the protocol or statistical analysis plan, and represent something of particular importance or value to patients. The summarisation of patient-relevant secondary endpoints should reflect the statistical rigour applied to the analysis. Patient-relevant secondary endpoints should be clearly distinguished from primary endpoints in the PLTS, and they should refer to information that exists in the public domain.
Conclusions: For sponsors who elect to include patient-relevant secondary endpoints in the PLTS, emerging practice is to apply a systematic approach for selection and summarisation so that meaningful information is provided to patients in a fair and balanced way
Phase I study of single-agent WNT974 a first-in-class Porcupine inhibitor, in patients with advanced solid tumors
No full textThis Phase I study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumors. Patients (n=94) received oral WNT974 at doses of 5–30 mg once daily (QD), plus additional dosing schedules. Maximum tolerated dose was not established; the recommended dose for expansion was 10 mg QD. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by RECIST v1.1 criteria; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n=52) and 74% of paired tumor biopsies (n=35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumor samples (n=8), suggesting WNT974 may influence immune cell recruitment to tumors, and may enhance checkpoint inhibitor activity
Important considerations related to permeability of peptides
No full textThis review on intracellular delivery and oral bioavailability of peptides reflects a number of principal investigations at Novartis. Our studies were aiming at either to understand features enabling peptides to interfere with intracellular protein-protein interactions, or to achieve a more patient-friendly delivery by the oral route. In the light of these objectives, we have also spent some effort on assay development to come up with alternative methods for monitoring cellular peptide uptake. This summary of our insights is thought to help in the assessment and development of peptide therapeutics requiring membrane transitio