tbuckley/cabot-search huggingface dataset:
A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non–Small Cell Lung Cancer
Authors: Jieun Son, Jaebong Jang, Tyler S. Beyett, Yoonji Eum, Heidi M. Haikala, Alyssa Verano, Mika Lin, John M. Hatcher, Nicholas P. Kwiatkowski, Pinar Ö. Eser, Michael J. Poitras, Stephen Wang, Man Xu, Prafulla C. Gokhale, Michael D. Cameron, Michael J. Eck, Nathanael S. Gray, Pasi A. Jänne
Journal: Cancer Research (2022)

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non-small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08-178-01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08-178-01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08-178-01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08-178-01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08-178-01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification.This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.
Abstract 10488: Overexpression of MFN2 Alleviates Sorafenib-Induced Cardiomyocyte Necroptosis via the MAM-CaMKIIδ Pathway <i>in vitro</i> and <i>in vivo</i>
Authors: Ziping Song, haixu song, Dan Liu, Xiaoxiang Tian, Chenghui Yan, Han Yaling
Journal: Circulation (2021)

Background: The continued success of oncological therapeutics is dependent on the mitigation of treatment-related adverse events, particularly cardiovascular toxicities. As such, there is an important need to understand the basic mechanisms of drug toxicities and to explore the differences in the fundamental signaling pathways between cancer cells and non-cancer cells for the maintenance of function and survival of these cells. Our aim in this study was to elucidate the underlying mechanisms of sorafenib (Sor)-induced cardiomyocyte damage. Methods: Primary mouse cardiomyocytes were prepared and treated with Sor and various other treatments. Cardiomyocyte necroptosis was detected by flow cytometry, western blotting, and CCK8 assays. Mitochondrial Ca 2+ uptake was detected by Rhod-2 probes using confocal imaging. Morphological changes in mitochondria and mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) were imaged using transmission electron microscopy (TEM) and confocal microscopy. Results: We reported that RIP3/MLKL cascade activation, mitochondrial Ca 2+ overload, and the subsequent increase in calmodulin-dependent protein kinase II delta (CaMKIIδ) contributed to Sor-induced cardiac necroptosis. Excess MAM formation and close ER-mitochondria contact were key in the pathogenesis of Sor-induced Ca 2+ overload. Furthermore, we found that reduced mitofusin-2 (MFN2) levels corresponded to repressed MAM biogenesis and increased mitochondria-MAM tethering in cardiomyocytes. Sor-induced Mammalian Target of Rapamycin (mTOR) inactivation, followed by the activation and nuclear translocation of Transcription Factor EB (TFEB), contributed to mitophagy and MFN2 degradation. In an in vivo model, we reported that an increase in MFN2 expression specifically improved Sor-induced cardiomyocyte necroptosis by repressing the MAM-CaMKIIδ-MCU pathway. Conclusions: Sorafenib mediated cardiomyocyte necroptosis through the mTOR-MFN2-MAM-Ca 2+ -RIP3-CaMKIIδ pathway in vitro and in vivo . The overexpression of MFN2 could rescue Sor-induced cardiomyocyte necroptosis without disturbing the anti-tumor effects.
Aberrant Transcript Usage Is Associated with Homologous Recombination Deficiency and Predicts Therapeutic Response
Authors: Hyeon Gu Kang, Haeun Hwangbo, Myung Ji Kim, Sinae Kim, Eun Ji Lee, Min Ji Park, Jae-Weon Kim, Byoung-Gie Kim, Eun-Hae Cho, Suhwan Chang, Jung-Yun Lee, Jung Kyoon Choi
Journal: Cancer Research (2021)

BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (aTU) of minor isoforms. Specifically, increased TU of nonfunctional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aTU with impaired HR activity. Machine learning-based tHRD detection by the transcript usage (TU) pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and patients with cancer to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib-treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors. SIGNIFICANCE: A novel but widespread transcriptional mechanism by which homologous recombination deficiency arises independently of BRCA1/2 mutations can be utilized as a companion diagnostic for PARP inhibitors.
Marrow ring sideroblasts are highly predictive for TP53 mutation in MDS with excess blasts
Authors: David M. Swoboda, Rashmi Kanagal-Shamanna, Andrew M. Brunner, Thomas Cluzeau, Onyee Chan, Najla Al Ali, Guillermo Montalban-Bravo, Quinto J. Gesiotto, Alexander Gavralidis, Anthony M. Hunter, Jung-Hoon Lee, Andrew T. Kuykendall, Chetasi Talati, Kendra L. Sweet, Jeffrey E. Lancet, Eric Padron, Mohammad Hussaini, Jinming Song, Guillermo Garcia-Manero, Rami S. Komrokji, David A. Sallman
Journal: Leukemia (2022)
Weekly Cisplatin Plus Radiation for Postoperative Head and Neck Cancer (JCOG1008): A Multicenter, Noninferiority, Phase II/III Randomized Controlled Trial
Authors: Naomi Kiyota, Makoto Tahara, Junki Mizusawa, Takeshi Kodaira, Hirofumi Fujii, Tomoko Yamazaki, Hiroki Mitani, Shigemichi Iwae, Yasushi Fujimoto, Yusuke Onozawa, Nobuhiro Hanai, Takenori Ogawa, Hiroki Hara, Nobuya Monden, Eiji Shimura, Shujiro Minami, Takashi Fujii, Kaoru Tanaka, Akihiro Homma, Seiichi Yoshimoto, Nobuhiko Oridate, Koichi Omori, Tsutomu Ueda, Kenji Okami, Ichiro Ota, Kiyoto Shiga, Masashi Sugasawa, Takahiro Asakage, Yuki Saito, Shigeyuki Murono, Yasumasa Nishimura, Kenichi Nakamura, Ryuichi Hayashi
Journal: Journal of Clinical Oncology (2022)

PURPOSE The standard treatment for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (100 mg/m 2 ). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m 2 ) yields comparable efficacy with 3-weekly cisplatin in postoperative high-risk LA-SCCHN is unknown. PATIENTS AND METHODS In this multi-institutional open-label phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin (100 mg/m 2 ) or with weekly cisplatin (40 mg/m 2 ) to confirm the noninferiority of weekly cisplatin. The primary end point of phase II was the proportion of treatment completion, and that of phase III was overall survival. A noninferiority margin of hazard ratio was set at 1.32. RESULTS Between October 2012 and December 2018, a total of 261 patients were enrolled (3-weekly cisplatin, 132 patients; weekly cisplatin, 129 patients). At the planned third interim analysis in the phase III part, after a median follow-up of 2.2 (interquartile range 1.19-3.56) years, chemoradiotherapy with weekly cisplatin was noninferior to 3-weekly cisplatin in terms of overall survival, with a hazard ratio of 0.69 (99.1% CI, 0.374 to 1.273 [&lt; 1.32], one-sided P for noninferiority = .0027 &lt; .0043). Grade 3 or more neutropenia and infection were less frequent in the weekly arm (3-weekly v weekly, 49% v 35% and 12% v 7%, respectively), as were renal impairment and hearing impairment. No treatment-related death was reported in the 3-weekly arm, and two (1.6%) in the weekly arm. CONCLUSION Chemoradiotherapy with weekly cisplatin is noninferior to 3-weekly cisplatin for patients with postoperative high-risk LA-SCCHN. These findings suggest that chemoradiotherapy with weekly cisplatin can be a possible treatment option for these patients.
Abstract P211: Effect Of An Mobile Health Weight Loss Intervention On Healthy Eating Index Diet Quality: The Smarter Randomized Controlled Trial
Authors: Jessica Cheng, Susan M Sereika, Tina Costacou, Margaret B Conroy, Bambang Parmanto, Bonny Rockette-Wagner, Andrea Kriska, Lora E Burke
Journal: Circulation (2022)

Introduction: Dietary modification is key to standard behavioral treatment for weight loss. However, few studies assess whether diet quality—the overall healthfulness of the diet—is improved over the course of the intervention. As diet quality is relevant to health separate from its effect on weight, it may be an important endpoint to assess. The purpose of this secondary analysis of a randomized mobile health weight loss trial was to assess whether self-monitoring with automated, personalized feedback (SM+FB) compared to self-monitoring alone (SM) resulted in improved diet quality. Methods: Adults (N=502) with overweight/obesity (n=251 in SM+FB; n=251 SM) were provided calorie, fat gram, and physical activity goals and instructed to weigh daily, wear a Fitbit activity tracker, and self-monitor diet. Feedback messages were sent up to three times daily to SM+FB participants and were based on participant reported intake of calories, fat, and sugar but did not specifically target diet quality. Diet data were collected from two dietary recalls at baseline, 6 months, and 12 months using the Automated Self-Administered system (ASA-24). The Simple Scoring method was used to calculate Healthy Eating Index 2015 (HEI-2015) total scores as it aligns with the Dietary Guidelines for Americans. Change in diet quality was assessed using two-way repeated measures analysis of variance. Missing dietary data was imputed using last observation carried forward. Analyses used intention to treat. Results: The overall sample was mostly female (79%), white (82.5%), and middle-aged (mean=45.0 years, SD=14.4 years). Baseline HEI-2015 total scores were similar between SM (mean=54.44, SE=0.78) and SM+FB (mean=55.49, SE=0.82) and did not improve for either group over 6 months (SM: mean=55.64, SE=0.77; SM+FB: mean=56.89, SE=0.88) or 12 months (SM: mean=56.21, SE=0.81; SM+FB: mean=56.10, SE=0.88). Group, time, and group by time interaction effects were all non-significant (p&gt;0.003) after Bonferroni adjustment. Discussion: Given that the HEI-2015 total score ranges from 0 to 100 with 74 meeting Healthy People 2020 goals, the diet quality of participants was less than ideal (grade: F) at baseline. The small improvements over time were likely not clinically significant. Future mHealth interventions might consider ways to increase user engagement, customization of additional features beyond feedback, and the addition of more targeted nutritional education in order to improve diet quality.
Intense 68Ga-PSMA Uptake in Neurofibroma Mimicking Cutaneous Metastases in a Patient With Prostate Cancer
Authors: Özge Erol Fenercioğlu, Ediz Beyhan, Cem Leblebici, Esra Arslan, Tevfik Fikret Çermik
Journal: Clinical Nuclear Medicine (2022)

Prostate cancer is the most common cancer in men. 68 Ga-PSMA PET/CT is frequently used in staging and restaging prostate cancer; it is important to keep in mind the causes of false-positives when evaluating imaging. We present findings of 68 Ga-PSMA PET/CT and histopathological features of a 68-year-old prostate cancer man with neurofibroma. 68 Ga-PSMA PET/CT showed intense 68 Ga-PSMA uptake in neurofibroma.
β-Catenin signaling in hepatocellular carcinoma
Authors: Chuanrui Xu, Zhong Xu, Yi Zhang, Matthias Evert, Diego F. Calvisi, Xin Chen
Journal: Journal of Clinical Investigation (2022)

Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.
Circulating Immune Bioenergetic, Metabolic, and Genetic Signatures Predict Melanoma Patients' Response to Anti–PD-1 Immune Checkpoint Blockade
Authors: Pierre L. Triozzi, Elizabeth R. Stirling, Qianqian Song, Brian Westwood, Mitra Kooshki, M. Elizabeth Forbes, Beth C. Holbrook, Katherine L. Cook, Martha A. Alexander-Miller, Lance D. Miller, Wei Zhang, David R. Soto-Pantoja
Journal: Clinical Cancer Research (2022)

Immunotherapy with checkpoint inhibitors is improving the outcomes of several cancers. However, only a subset of patients respond. Therefore, predictive biomarkers are critically needed to guide treatment decisions and develop approaches to the treatment of therapeutic resistance.We compared bioenergetics of circulating immune cells and metabolomic profiles of plasma obtained at baseline from patients with melanoma treated with anti-PD-1 therapy. We also performed single-cell RNA sequencing (scRNAseq) to correlate transcriptional changes associated with metabolic changes observed in peripheral blood mononuclear cells (PBMC) and patient plasma.Pretreatment PBMC from responders had a higher reserve respiratory capacity and higher basal glycolytic activity compared with nonresponders. Metabolomic analysis revealed that responder and nonresponder patient samples cluster differently, suggesting differences in metabolic signatures at baseline. Differential levels of specific lipid, amino acid, and glycolytic pathway metabolites were observed by response. Further, scRNAseq analysis revealed upregulation of T-cell genes regulating glycolysis. Our analysis showed that SLC2A14 (Glut-14; a glucose transporter) was the most significant gene upregulated in responder patients' T-cell population. Flow cytometry analysis confirmed significantly elevated cell surface expression of the Glut-14 in CD3+, CD8+, and CD4+ circulating populations in responder patients. Moreover, LDHC was also upregulated in the responder population.Our results suggest a glycolytic signature characterizes checkpoint inhibitor responders; consistently, both ECAR and lactate-to-pyruvate ratio were significantly associated with overall survival. Together, these findings support the use of blood bioenergetics and metabolomics as predictive biomarkers of patient response to immune checkpoint inhibitor therapy.
Antisense RNAs Influence Promoter Usage of Their Counterpart Sense Genes in Cancer
Authors: Fernando Bellido Molias, Andre Sim, Ka Wai Leong, Omer An, Yangyang Song, Vanessa Hui En Ng, Max Wei Jie Lim, Chen Ying, Jasmin Xin Jia Teo, Jonathan Göke, Leilei Chen
Journal: Cancer Research (2021)

Abstract Multiple noncoding natural antisense transcripts (ncNAT) are known to modulate key biological events such as cell growth or differentiation. However, the actual impact of ncNATs on cancer progression remains largely unknown. In this study, we identified a complete list of differentially expressed ncNATs in hepatocellular carcinoma. Among them, a previously undescribed ncNAT HNF4A-AS1L suppressed cancer cell growth by regulating its sense gene HNF4A, a well-known cancer driver, through a promoter-specific mechanism. HNF4A-AS1L selectively activated the HNF4A P1 promoter via HNF1A, which upregulated expression of tumor suppressor P1-driven isoforms, while having no effect on the oncogenic P2 promoter. RNA-seq data from 23 tissue and cancer types identified approximately 100 ncNATs whose expression correlated specifically with the activity of one promoter of their associated sense gene. Silencing of two of these ncNATs ENSG00000259357 and ENSG00000255031 (antisense to CERS2 and CHKA, respectively) altered the promoter usage of CERS2 and CHKA. Altogether, these results demonstrate that promoter-specific regulation is a mechanism used by ncNATs for context-specific control of alternative isoform expression of their counterpart sense genes. Significance: This study characterizes a previously unexplored role of ncNATs in regulation of isoform expression of associated sense genes, highlighting a mechanism of alternative promoter usage in cancer.
Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor– and ErbB2-positive Breast Cancer
Authors: Lucia Viganò, Alberta Locatelli, Adele Ulisse, Barbara Galbardi, Matteo Dugo, Diego Tosi, Carlo Tacchetti, Tiziana Daniele, Balázs Győrffy, Lorenzo Sica, Marina Macchini, Milvia Zambetti, Stefania Zambelli, Giampaolo Bianchini, Luca Gianni
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of ER-positive (ER+)/HER2-positive (HER2+) breast cancer and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this cross-talk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6-inhibition (palbociclib; PFHPert). Experimental Design: Cytotoxic drug effects, interactions, and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-negative (ER−)/HER2+ breast cancer cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ breast cancer treated with neoadjuvant PFHPert in NA-PHER2 trial (NCT02530424). Results: In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week 2 and surgery were significantly associated to upregulation of senescence-related genes (P = 7.7E-4 and P = 1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (P = 0.019). Conclusions: Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by cotargeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.
Metastasis From Clear Cell Renal Cell Carcinoma Mimicking Well-Differentiated Pancreatic Neuroendocrine Tumor at 18F-FDG and 68Ga-DOTATOC PET/CT
Authors: Priscilla Guglielmo, Fiammetta Pesella, Alida Sartorello, Badr El Khouzai, Sara Berti, Simona Muccioli, Michele Gregianin
Journal: Clinical Nuclear Medicine (2022)

Abstract Dual-tracer PET/CT with both 18 F-FDG and 68 Ga-DOTA–conjugated peptides is currently used in clinical routine for characterizing pNET (pancreatic masses suspicious for neuroendocrine tumor). We describe here the case of a 81-year-old man with a pancreatic lesion showing high 68 Ga-DOTATOC uptake and mild 18 F-FDG avidity, thus suggesting a well-differentiated pNET, which resulted at endoscopic ultrasound-guided fine-needle aspiration to be a clear cell renal cell carcinoma metastasis. In fact, the patient had right nephrectomy for clear cell renal cell carcinoma 27 years earlier. This case puts light on the role of PET/CT with 68 Ga-DOTATOC in imaging RCC, a field which deserves to be further explored.
Risks and Benefits of Janus Kinase Inhibitors in Rheumatoid Arthritis — Past, Present, and Future
Authors: Jasvinder A Singh
Journal: New England Journal of Medicine (2022)

The Food and Drug Administration (FDA) mandated a safety study to be performed because of possible safety signals detected for the Janus kinase (JAK) inhibitor tofacitinib. As Ytterberg et al. report in this issue of the Journal, the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance was a 4-year randomized, open-label, noninferiority, postauthorization, safety end-point trial, in which patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor were randomly assigned in a 1:1:1 ratio to receive oral tofacitinib at a dose of 5 or 10 mg . . .
39P Determination of essential biomarkers in lung cancer: A real-world data study in Spain
Authors: V. Calvo de Juan, M. Cobo Dols, D. Rodriguez-Abreu, E. Carcereny, A. Cantero, R. Bernabé Caro, G. Benitez Lopez, R. Lopez Castro, B. Massuti Sureda, E. del Barco, M.R. Garcia Campelo, M. Guirado, C.J.C. Camps Herrero, A.L.O. Ortega Granados, J.L. Gonzalez-Larriba, A. Sanchez Hernandez, C. Gonzalez Ojea, M.A. Sala Gonzalez, O.J. Juan Vidal, M. Provencio Pulla
Journal: Annals of Oncology (2022)