Faculty Bibliography

Background: In preclinical studies, the combination of amivantamab (EGFR-MET bispecific antibody) with lazertinib demonstrates synergistic inhibition of tumor growth. We present the safety and early efficacy results of patients receiving amivantamab in combination with lazertinib in the phase 1 CHRYSALIS study (NCT02609776).
Method(s): Patients with EGFR Exon 19 deletion or L858R mutation non-small cell lung cancer (NSCLC) were enrolled in this 2-part study. To identify the recommended phase 2 combination dose (RP2CD), Part 1 enrolled patients without restriction on prior therapy to evaluate escalating dose cohorts of amivantamab (700-1050 mg, iv once weekly for 28 days; biweekly thereafter) in combination with standard monotherapy dosing of lazertinib (240 mg oral daily). The ongoing Part 2 dose expansion Cohort E is evaluating preliminary efficacy, without biomarker selection, in patients progressing on osimertinib. Response was assessed by investigator per RECIST v1.1.
Result(s): As of 17 March 2020, 71 patients received the combination: median age was 61 y (36-79), median prior lines was 1 (0-9). In Part 1, the RP2CD was the maximally assessed doses of 1050 mg (1400 mg, >=80 kg) amivantamab + 240 mg lazertinib. Interim safety profile includes rash (78%), infusion related reaction (61%), paronychia (42%), stomatitis (31%), pruritus (24%), and diarrhea (14%). Majority of treatment-related AEs were grade 1-2, with grade >=3 reported in 7%. As of 30 April 2020, in 23 Part 1 patients with measurable disease, the overall response rate (ORR) was 43.5% (95% CI, 23.2-65.5) with 10 partial responses (PRs), and 9 patients with stable disease (SD); median treatment duration was 8.2 months (0.5-10.7), with 13 patients still ongoing. In the post-osimertinib expansion Cohort E, early antitumor activity is being observed in 14/20 response-evaluable patients with 1 complete response, 7 PRs (2 pending confirmation), and 6 SD with tumor shrinkage.
Conclusion(s): Amivantamab can be combined safely with lazertinib at their respective full monotherapy doses. Encouraging preliminary activity was observed in osimertinib-relapsed disease: updated data will be presented. Clinical trial identification: NCT02609776; submitted November 18, 2015. Editorial acknowledgement: Medical writing support was provided by Tracy T. Cao, PhD (Janssen Global Services, LLC) and funded by Janssen Global Services, LLC. Legal entity responsible for the study: Janssen R&D.
Funding(s): Janssen R&D. Disclosure: B.C. Cho: Advisory/Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Yuhan, Pfizer, Lilly, Janssen, Takeda, MSD, Ono Pharmaceuticals; Speaker Bureau/Expert testimony: Novartis; Licensing/Royalties: Champions Oncology; Shareholder/Stockholder/Stock options: Theravance, Gencurix, Bridgebio Therapeutics, Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Research grant/Funding (self): Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD. K.H. Lee: Advisory/Consultancy: Bristol-Myers Squibb, MSD, AstraZeneca; Honoraria (self): Bristol-Myers Squibb, MSD, AstraZeneca. D-W. Kim: Travel/Accommodation/Expenses: Daiichi Sankyo, Amgen; Research grant/Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim. J-Y. Han: Advisory/Consultancy: MSD Oncology, AstraZeneca, Bristol-Myers Squibb, Lilly, Novartis, Takeda, Pfizer; Honoraria (self): Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda; Research grant/Funding (self): Roche, Pfizer, Ono Pharmaceutical, Takeda. A. Spira: Advisory/Consultancy, AstraZeneca/MedImmune consulting applies to my institution: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune; Shareholder/Stockholder/Stock options: Lilly; Honoraria (self): CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen; Research grant/Funding (institution): Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therap; Research grant/Funding (self): LAM Therapeutics. E.B. Haura: Advisory/Consultancy: Janssen; Travel/Accommodation/Expenses: Bristol-Myers Squibb, Roche, Janssen; Research grant/Funding (institution): Janssen, Novartis, Revolution Medicines, AstraZeneca, Genentech; Research grant/Funding (self): FORMA Therapeutics, Incyte. J.K. Sabari: Advisory/Consultancy: AstraZeneca. R.E. Sanborn: Advisory/Consultancy: Amgen, Seattle Genetics, Peregrine Pharmaceuticals, ARIAD, Genentech/Roche, AstraZeneca, Celldex, AbbVie, Takeda; Travel/Accommodation/Expenses: Five Prime Therapeutics, Janssen, AstraZeneca; Honoraria (self): AstraZeneca; Research grant/Funding (institution): Bristol-Myers Squibb, MedImmune; Research grant/Funding (self): Merck. J.M. Bauml: Advisory/Consultancy: Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron; Research grant/Funding (institution): Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen. J.E. Gomez: Speaker Bureau/Expert testimony: Bristol-Myers Squibb, Atara, AstraZeneca. P. Lorenzini, J.R. Infante, J. Xie, N. Haddish-Berhane, M. Thayu, R.E. Knoblauch: Full/Part-time employment: Janssen; Shareholder/Stockholder/Stock options: Johnson & Johnson. K. Park: Advisory/Consultancy: AstraZeneca, Boehringer Ingelheim, Lilly, Hanmi, Novartis, Ono Pharmaceutical, Roche, Bristol-Myers Squibb, MSD, Blueprint Medicines, Amgen, Merck KGaA, Loxo, AbbVie, Daiichi Sankyo; Speaker Bureau/Expert testimony: Boehringer Ingelheim, AZD; Research grant/Funding (self): AstraZeneca, MSD Oncology. All other authors have declared no conflicts of interest.
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BACKGROUND:The discovery that much of the non-protein-coding genome is transcribed and plays a diverse functional role in fundamental cellular processes has led to an explosion in the development of tools and technologies to investigate the role of these noncoding RNAs in cardiovascular health. Furthermore, identifying noncoding RNAs for targeted therapeutics to treat cardiovascular disease is an emerging area of research. The purpose of this statement is to review existing literature, offer guidance on tools and technologies currently available to study noncoding RNAs, and identify areas of unmet need. METHODS:The writing group used systematic literature reviews (including MEDLINE, Web of Science through 2018), expert opinion/statements, analyses of databases and computational tools/algorithms, and review of current clinical trials to provide a broad consensus on the current state of the art in noncoding RNA in cardiovascular disease. RESULTS:Significant progress has been made since the initial studies focusing on the role of miRNAs (microRNAs) in cardiovascular development and disease. Notably, recent progress on understanding the role of novel types of noncoding small RNAs such as snoRNAs (small nucleolar RNAs), tRNA (transfer RNA) fragments, and Y-RNAs in cellular processes has revealed a noncanonical function for many of these molecules. Similarly, the identification of long noncoding RNAs that appear to play an important role in cardiovascular disease processes, coupled with the development of tools to characterize their interacting partners, has led to significant mechanistic insight. Finally, recent work has characterized the unique role of extracellular RNAs in mediating intercellular communication and their potential role as biomarkers. CONCLUSIONS:The rapid expansion of tools and pipelines for isolating, measuring, and annotating these entities suggests that caution in interpreting results is warranted until these methodologies are rigorously validated. Most investigators have focused on investigating the functional role of single RNA entities, but studies suggest complex interaction between different RNA molecules. The use of network approaches and advanced computational tools to understand the interaction of different noncoding RNA species to mediate a particular phenotype may be required to fully comprehend the function of noncoding RNAs in mediating disease phenotypes.

Animal development entails the organization of specific cell types in space and time, and spatial patterns must form in a robust manner. In the zebrafish spinal cord, neural progenitors form stereotypic patterns despite noisy morphogen signaling and large-scale cellular rearrangements during morphogenesis and growth. By directly measuring adhesion forces and preferences for three types of endogenous neural progenitors, we provide evidence for the differential adhesion model in which differences in intercellular adhesion mediate cell sorting. Cell type-specific combinatorial expression of different classes of cadherins (N-cadherin, cadherin 11, and protocadherin 19) results in homotypic preference ex vivo and patterning robustness in vivo. Furthermore, the differential adhesion code is regulated by the sonic hedgehog morphogen gradient. We propose that robust patterning during tissue morphogenesis results from interplay between adhesion-based self-organization and morphogen-directed patterning.

Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. We show that one of these single nucleotide polymorphisms is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T cell accumulation in adipose tissue. These findings demonstrate that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.

Individual cells detach from cohesive ensembles during development and can inappropriately separate in disease. Although much is known about how cells separate from epithelia, it remains unclear how cells disperse from clusters lacking apical-basal polarity, a hallmark of advanced epithelial cancers. Here, using live imaging of the developmental migration program of Drosophila primordial germ cells (PGCs), we show that cluster dispersal is accomplished by stabilizing and orienting migratory forces. PGCs utilize a G protein coupled receptor (GPCR), Tre1, to guide front-back migratory polarity radially from the cluster toward the endoderm. Posteriorly positioned myosin-dependent contractile forces pull on cell-cell contacts until cells release. Tre1 mutant cells migrate randomly with transient enrichment of the force machinery but fail to separate, indicating a temporal contractile force threshold for detachment. E-cadherin is retained on the cell surface during cell separation and augmenting cell-cell adhesion does not impede detachment. Notably, coordinated migration improves cluster dispersal efficiency by stabilizing cell-cell interfaces and facilitating symmetric pulling. We demonstrate that guidance of inherent migratory forces is sufficient to disperse cell clusters under physiological settings and present a paradigm for how such events could occur across development and disease.

Methylation of histone 3 at lysine 9 (H3K9) constitutes a roadblock for cellular reprogramming. Interference with methyltransferases or activation of demethylases by the cofactor ascorbic acid (AA) facilitates the derivation of induced pluripotent stem cells (iPSCs), but possible interactions between specific methyltransferases and AA treatment remain insufficiently explored. We show that chemical inhibition of the methyltransferases EHMT1 and EHMT2 counteracts iPSC formation in an enhanced reprogramming system in the presence of AA, an effect that is dependent on EHMT1. EHMT inhibition during enhanced reprogramming is associated with rapid loss of H3K9 dimethylation, inefficient downregulation of somatic genes, and failed mesenchymal-to-epithelial transition. Furthermore, transient EHMT inhibition during reprogramming yields iPSCs that fail to efficiently give rise to viable mice upon blastocyst injection. Our observations establish novel functions of H3K9 methyltransferases and suggest that a functional balance between AA-stimulated enzymes and EHMTs supports efficient and less error-prone iPSC reprogramming to pluripotency.

The severe acute respiratory syndrome coronavirus-2 emerged as a serious human pathogen in late 2019, causing the disease coronavirus disease 2019 (COVID-19). The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Airway, lung parenchymal, pulmonary vascular, and respiratory neuromuscular disorders all feature in COVID-19. This article reviews what is known about the effects of severe acute respiratory syndrome coronavirus-2 infection on different parts of the respiratory system, clues to understanding the underlying biology of respiratory disease, and highlights current and future translation and clinical research questions.