bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Frequency Performance Characteristics of the Double-Gate Schottky Barrier Tunnel Field Effect Transistor in Analog and Radio-Frequency Applications
Authors: Shalini V. , Kumar Prashanth
Published: August 2023

In this paper, a novel structure of Double Gate Schottky Barrier Tunnel Field Effect Transistor (DG-SBTFET) has been designed and simulated. The DG-SBTFET has two sources (NiSi) and two gate metals with an HfO2. Silvaco-TCAD simulator has been used for investigating the analog and radio frequency performance of the DG-SBTFET. The proposed device (DG-SBTFET) is compared with the conventional devices in terms of electrical parameters including ION current, ION/IOFF ratio, RF performance including transconductances (gm), cut-off frequency (f

T
), transit time (r), gain bandwidth product (GBP), transconductance generation factor (TGF), and transconductance frequency product (TFP). Further, we simulate the linearity characteristics of the DG-SBTFET device is compared it with other conventional devices, including the second-order voltage intercept point (VIP2), third-order voltage intercept point (VIP3), and third-order input intercept point (IIP3). Hence, the proposed device (DG- SBTFET) is suitable for low-power and high-frequency applications.
Electrochemical Deposition of Reduced Graphene Oxide Decorated with Silver and Nickel Oxide Nanoparticles for Quantification of Ascorbic Acid in Bottled Fruit Juice and Vitamin C Tablet
Authors: Wondimu Tadele Hunde , Desissa Temesgen Debelo , Duma Alemayehu Dubale , Bakare Fetene Fufa , Kabtamu Daniel Manaye , Andoshe Dinsefa Mensur , Zelekew Osman Ahmed , Woldeyonnis Bruk Sisay , Bayeh Anteneh Wodaje , Gemeda Kena Dechasa , Bayana Kenate Sambaba
Published: August 2023

Because of its simplicity of evaluation, ability to detect the lowest quantities, and convenience of operation, electrochemical determination of ascorbic acid is gaining popularity. The high sensitivity, selectivity, and low cost, nanosensors have gained enourmous attention in recent years for the detection of active pharmacological compounds and food pollutants. Ni and Ni-containing compounds have a favorable affinity for a number of organic functional groups such as -thio, -hydroxyl, -carboxyl, and -amine. However, its poor conductivity hinders its electrochemical performance. Hence, the procedures for improving the conductivity of metal oxides that are incredibly good studies query to meet the desired level of detection. We devised a straightforward method for concurrently synthesizing silver and nickel oxide nanoparticles on reduced graphene oxide using electrochemical deposition method on a glassy carbon electrode (GCE). The electrodeposited materials were scratched from GCE and characterized for Raman, SEM/EDS, EIS, and XPS. The materials produced after deposition were examined also for Ascorbic Acid (AA) detection in bottled fruit juice and Vitamin C tablets yielded 0.457 μM limits of quantification and 100.61% and 99.40% average recoveries, respectively.
Volumetric graft changes after liver transplantation: evidence of adaptation to recipient body size
Authors: Arslan Alin , Romano Antonio , Wang Qiang , Wang Benny , Brismar Torkel B. , Nowak Greg
Published: August 2023

This is the first and largest human study to verify the hypothesis that whole liver grafts adjust their size to match recipient body size 1 year after transplantation—a phenomenon that has previously only been observed in experimental animal studies and human case reports. The direction of volumetric changes is driven by the disparity between graft size relative to recipient body surface area and weight, as well as the intraoperative portal- and arterial graft perfusion.
P2X7 signaling influences the production of pro-resolving and pro-inflammatory lipid mediators in alveolar macrophages derived from individuals with asthma
Authors: Townsend Elizabeth A. , Guadarrama Arturo , Shi Lei , Roti Roti Elon , Denlinger Loren C.
Published: August 2023

Alveolar macrophages obtained from individuals with asthma produce soluble lipid mediators in response to P2X7 purinergic receptor signaling. Proinflammatory mediators may contribute to asthma exacerbations but proresolving mediators may help with resolution of asthma loss of control. These specialized proresolving lipid mediators may serve as future potential therapeutics for asthma exacerbation resolution and recovery.
Secuelas COVID en Chile: ¿Es el mismo mercado laboral?
Authors: González Pablo
Published: August 2023

El PIB se recuperó de la pandemia, aunque está en la parte recesiva del ciclo. Desempleo alto, el empleo aún parece estar lento. Pero hay algunos cambios postpandemia. Los inactivos habituales han crecido. Continuar leyendo...
Table S6 from Elevated Mast Cell Abundance Is Associated with Enrichment of CCR2+ Cytotoxic T Cells and Favorable Prognosis in Lung Adenocarcinoma
Authors: Fan Fanfan , Gao Jian , Zhao Yue , Wang Jun , Meng Lu , Ma Jiaqiang , Li Teng , Han Han , Lai Jinglei , Gao Zhendong , Li Xiongfei , Guo Ran , Cao Zhiwei , Zhang Yang , Zhang Xiaoming , Chen Haiquan
Published: August 2023

Table S6
Table S3 from Elevated Mast Cell Abundance Is Associated with Enrichment of CCR2+ Cytotoxic T Cells and Favorable Prognosis in Lung Adenocarcinoma
Authors: Fan Fanfan , Gao Jian , Zhao Yue , Wang Jun , Meng Lu , Ma Jiaqiang , Li Teng , Han Han , Lai Jinglei , Gao Zhendong , Li Xiongfei , Guo Ran , Cao Zhiwei , Zhang Yang , Zhang Xiaoming , Chen Haiquan
Published: August 2023

Table S3
Supplementary Data 4 from Targeting KDM2A Enhances T-cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma
Authors: Chen Chen , Shin June Ho , Fang Zhuoqing , Brennan Kevin , Horowitz Nina B. , Pfaff Kathleen L. , Welsh Emma L. , Rodig Scott J. , Gevaert Olivier , Gozani Or , Uppaluri Ravindra , Sunwoo John B.
Published: August 2023

raw cell counts from organoid staining
Supplementary Data 2 from Targeting KDM2A Enhances T-cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma
Authors: Chen Chen , Shin June Ho , Fang Zhuoqing , Brennan Kevin , Horowitz Nina B. , Pfaff Kathleen L. , Welsh Emma L. , Rodig Scott J. , Gevaert Olivier , Gozani Or , Uppaluri Ravindra , Sunwoo John B.
Published: August 2023

Western blots
Supplementary Data 1 from Targeting KDM2A Enhances T-cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma
Authors: Chen Chen , Shin June Ho , Fang Zhuoqing , Brennan Kevin , Horowitz Nina B. , Pfaff Kathleen L. , Welsh Emma L. , Rodig Scott J. , Gevaert Olivier , Gozani Or , Uppaluri Ravindra , Sunwoo John B.
Published: August 2023

qRT-PCR-raw data_organized
Supplementary Table S8 from The EstroGene Database Reveals Diverse Temporal, Context-Dependent, and Bidirectional Estrogen Receptor Regulomes in Breast Cancer
Authors: Li Zheqi , Li Tianqin , Yates Megan E. , Wu Yang , Ferber Amanda , Chen Lyuqin , Brown Daniel D. , Carroll Jason S. , Sikora Matthew J. , Tseng George C. , Oesterreich Steffi , Lee Adrian V.
Published: August 2023

High confident E2-regulated genes and BETA score
Supplementary Table S7 from The EstroGene Database Reveals Diverse Temporal, Context-Dependent, and Bidirectional Estrogen Receptor Regulomes in Breast Cancer
Authors: Li Zheqi , Li Tianqin , Yates Megan E. , Wu Yang , Ferber Amanda , Chen Lyuqin , Brown Daniel D. , Carroll Jason S. , Sikora Matthew J. , Tseng George C. , Oesterreich Steffi , Lee Adrian V.
Published: August 2023

ChIP-seq data processing QC parameters
Supplementary Table S6 from The EstroGene Database Reveals Diverse Temporal, Context-Dependent, and Bidirectional Estrogen Receptor Regulomes in Breast Cancer
Authors: Li Zheqi , Li Tianqin , Yates Megan E. , Wu Yang , Ferber Amanda , Chen Lyuqin , Brown Daniel D. , Carroll Jason S. , Sikora Matthew J. , Tseng George C. , Oesterreich Steffi , Lee Adrian V.
Published: August 2023

E2-induced DEGs from inter-dataset concordance analysis
Supplementary Table S3 from The EstroGene Database Reveals Diverse Temporal, Context-Dependent, and Bidirectional Estrogen Receptor Regulomes in Breast Cancer
Authors: Li Zheqi , Li Tianqin , Yates Megan E. , Wu Yang , Ferber Amanda , Chen Lyuqin , Brown Daniel D. , Carroll Jason S. , Sikora Matthew J. , Tseng George C. , Oesterreich Steffi , Lee Adrian V.
Published: August 2023

Metadata of four RNA-seq experiments for inter-data set concordance analysis
Supplementary Table 1. from The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer
Authors: Lundberg Arian , Zhang Meng , Aggarwal Rahul , Li Haolong , Zhang Li , Foye Adam , Sjöström Martin , Chou Jonathan , Chang Kevin , Moreno-Rodriguez Thaidy , Shrestha Raunak , Baskin Avi , Zhu Xiaolin , Weinstein Alana S. , Younger Noah , Alumkal Joshi J. , Beer Tomasz M. , Chi Kim N. , Evans Christopher P. , Gleave Martin , Lara Primo N. , Reiter Rob E. , Rettig Matthew B. , Witte Owen N. , Wyatt Alexander W. , Feng Felix Y. , Small Eric J. , Quigley David A.
Published: August 2023

Clinical characteristics of samples in WCDT cohort
Data from Targeting KDM2A Enhances T-cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma
Authors: Chen Chen , Shin June Ho , Fang Zhuoqing , Brennan Kevin , Horowitz Nina B. , Pfaff Kathleen L. , Welsh Emma L. , Rodig Scott J. , Gevaert Olivier , Gozani Or , Uppaluri Ravindra , Sunwoo John B.
Published: August 2023

Abstract
In head and neck squamous cell carcinoma (HNSCC), a significant proportion of tumors have inactivating mutations in the histone methyltransferase NSD1. In these tumors, NSD1 inactivation is a driver of T-cell exclusion from the tumor microenvironment (TME). A better understanding of the NSD1-mediated mechanism regulating infiltration of T cells into the TME could help identify approaches to overcome immunosuppression. Here, we demonstrated that NSD1 inactivation results in lower levels of H3K36 dimethylation and higher levels of H3K27 trimethylation, the latter being a known repressive histone mark enriched on the promoters of key T-cell chemokines CXCL9 and CXCL10. HNSCC with NSD1 mutations had lower levels of these chemokines and lacked responses to PD-1 immune checkpoint blockade. Inhibition of KDM2A, the primary lysine demethylase that is selective for H3K36, reversed the altered histone marks induced by NSD1 loss and restored T-cell infiltration into the TME. Importantly, KDM2A suppression decreased growth of NSD1-deficient tumors in immunocompetent, but not in immunodeficient, mice. Together, these data indicate that KDM2A is an immunotherapeutic target for overcoming immune exclusion in HNSCC.
Significance:
The altered epigenetic landscape of NSD1-deficient tumors confers sensitivity to inhibition of the histone-modifying enzyme KDM2A as an immunotherapeutic strategy to stimulate T-cell infiltration and suppress tumor growth.
Data from Tumor-Derived Small Extracellular Vesicles Inhibit the Efficacy of CAR T Cells against Solid Tumors
Authors: Zhong Wenqun , Xiao Zebin , Qin Zhiyuan , Yang Jingbo , Wen Yi , Yu Ziyan , Li Yumei , Sheppard Neil C. , Fuchs Serge Y. , Xu Xiaowei , Herlyn Meenhard , June Carl H. , Puré Ellen , Guo Wei
Published: August 2023

Abstract
Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable success in the treatment of hematologic malignancies. Unfortunately, it has limited efficacy against solid tumors, even when the targeted antigens are well expressed. A better understanding of the underlying mechanisms of CAR T-cell therapy resistance in solid tumors is necessary to develop strategies to improve efficacy. Here we report that solid tumors release small extracellular vesicles (sEV) that carry both targeted tumor antigens and the immune checkpoint protein PD-L1. These sEVs acted as cell-free functional units to preferentially interact with cognate CAR T cells and efficiently inhibited their proliferation, migration, and function. In syngeneic mouse tumor models, blocking tumor sEV secretion not only boosted the infiltration and antitumor activity of CAR T cells but also improved endogenous antitumor immunity. These results suggest that solid tumors use sEVs as an active defense mechanism to resist CAR T cells and implicate tumor sEVs as a potential therapeutic target to optimize CAR T-cell therapy against solid tumors.
Significance:
Small extracellular vesicles secreted by solid tumors inhibit CAR T cells, which provide a molecular explanation for CAR T-cell resistance and suggests that strategies targeting exosome secretion may enhance CAR T-cell efficacy.

See related commentary by Ortiz-Espinosa and Srivastava, p. 2637
Data from Elevated Mast Cell Abundance Is Associated with Enrichment of CCR2+ Cytotoxic T Cells and Favorable Prognosis in Lung Adenocarcinoma
Authors: Fan Fanfan , Gao Jian , Zhao Yue , Wang Jun , Meng Lu , Ma Jiaqiang , Li Teng , Han Han , Lai Jinglei , Gao Zhendong , Li Xiongfei , Guo Ran , Cao Zhiwei , Zhang Yang , Zhang Xiaoming , Chen Haiquan
Published: August 2023

Abstract
Mast cells constitute indispensable immunoregulatory sentinel cells in the tumor microenvironment. A better understanding of the regulation and functions of mast cells in lung adenocarcinoma (LUAD) could uncover therapeutic approaches to reprogram the immunosuppressive tumor microenvironment. Here, we performed flow cytometry and single-cell RNA sequencing (scRNA-seq) of patient LUAD samples to comprehensively characterize LUAD-infiltrating mast cells. Mast cells exhibited functional heterogeneity and were enriched in LUAD with ground-glass opacity features (gLUAD). The mast cells in gLUAD exhibited proinflammatory and chemotactic properties while those in radiologically solid LUAD (sLUAD) were associated with tumor angiogenesis. Mast cells were an important source of CCL2 and correlated with the recruitment of CCR2+ CTL, a specific subcluster of preexhausted T cells with tissue-resident memory phenotype and enhanced cytotoxicity. Increased infiltration of mast cells and CCR2+ CTLs and their colocalization showed a strong association with favorable prognosis after surgery but were not associated with improved survival after chemotherapy. Collectively, these findings reveal a key role of mast cells in LUAD and their potential cross-talk with CTLs, suggesting that targeting mast cells may be an immunotherapeutic strategy for LUAD.
Significance:
Comprehensive characterization of mast cells in lung adenocarcinoma elucidates their heterogeneity and identifies interplay between mast cells and CCR2+ T cells that is associated with a favorable prognosis.
Data from The EstroGene Database Reveals Diverse Temporal, Context-Dependent, and Bidirectional Estrogen Receptor Regulomes in Breast Cancer
Authors: Li Zheqi , Li Tianqin , Yates Megan E. , Wu Yang , Ferber Amanda , Chen Lyuqin , Brown Daniel D. , Carroll Jason S. , Sikora Matthew J. , Tseng George C. , Oesterreich Steffi , Lee Adrian V.
Published: August 2023

Abstract
As one of the most successful cancer therapeutic targets, estrogen receptor-α (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, we established the EstroGene database through unified processing of data from 246 experiments including 136 transcriptomic, cistromic, and epigenetic datasets focusing on estradiol (E2)-triggered ER activation across 19 breast cancer cell lines. A user-friendly browser (https://estrogene.org/) was generated for multiomic data visualization involving gene inquiry under user-defined experimental conditions and statistical thresholds. Notably, annotation of metadata associated with public datasets revealed a considerable lack of experimental details. Comparison of independent RNA-seq or ER ChIP-seq data with the same design showed large variability and only strong effects could be consistently detected. Temporal estrogen response metasignatures were defined, and the association of E2 response rate with temporal transcriptional factors, chromatin accessibility, and heterogeneity of ER expression was evaluated. Unexpectedly, harmonizing 146 E2-induced transcriptomic datasets uncovered a subset of genes harboring bidirectional E2 regulation, which was linked to unique transcriptional factors and highly associated with immune surveillance in the clinical setting. Furthermore, the context dependent E2 response programs were characterized in MCF7 and T47D cell lines, the two most frequently used models in the EstroGene database. Collectively, the EstroGene database provides an informative and practical resource to the cancer research community to uniformly evaluate key reproducible features of ER regulomes and unravels modes of ER signaling.
Significance:
A resource database integrating 246 publicly available ER profiling datasets facilitates meta-analyses and identifies estrogen response temporal signatures, a bidirectional program, and model-specific biases.
Figure S6 from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon
Published: August 2023

Supplementary Figure 6. Analysis of BBT-176 using in vivo models. A, Body weight changes in Ba/F3 EGFR 19Del/C797S, EGFR 19Del/T790M/C797S and patient-derived xenograft models. The patient-derived xenograft was derived from a patient with poorly-differentiated adenocarcinoma harboring an EGFR 19Del/T790M/C797S mutation. B, BBT-176 activity in a LU1235 EGFR 19Del patient-derived xenograft model. Abbreviations: PDX, patient-derived xenograft; PO, orally; QD, once daily.
Figure S4 from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon
Published: August 2023

Supplementary Figure 4. Western blot of Ba/F3 cells with the EGFR 19Del/T790M/C797S mutation after BBT-176 treatment, alone and combined with cetuximab.
Figure S3 from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon
Published: August 2023

Supplementary Figure 3. Activity of osimertinib in EGFR 19Del-derived BBT-176-resistant clones. Abbreviation: BR(1/2), BBT-176-resistant (clone 1/2).
Supplementary Table S2 from Osimertinib and Selpercatinib Efficacy, Safety, and Resistance in a Multicenter, Prospectively Treated Cohort of EGFR-Mutant and RET Fusion-Positive Lung Cancers
Authors: Rotow Julia , Patel Jyoti D. , Hanley Matthew P. , Yu Helena , Awad Mark , Goldman Jonathan W. , Nechushtan Hovav , Scheffler Matthias , Kuo Chih-Hsi S. , Rajappa Senthil , Harada Guilherme , Clifford Sarah , Santucci Alison , Silva Laura , Tupper Rebecca , Oxnard Geoffrey R. , Kherani Jennifer , Drilon Alexander
Published: August 2023

Prior tyrosine kinase inhibitor (TKI) therapy details
Supplementary Table S1: Pooled analyses of oncology clinical trial data 2018-2021 from FDA Oncology Center of Excellence Crowdsourcing Initiative: Outreach to the Scientific Community to Identify Research Questions for Pooled Analyses of Oncology Clinical Trial Data
Authors: Schneider Julie A. , Eckstein Julia , Goldberg Kirsten B. , Ascione Mark C. , Bailey Thamar , Taylor Kimberly , Coffey Aisha M. , Satchi Darshini , Philips Howard , Sridhara Rajeshwari , Nair Abhilasha , Pazdur Richard , Theoret Marc R.
Published: August 2023

Pooled analyses of oncology clinical trial data 2018-2021
Supplementary Figure S6 from Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
Authors: Pikkusaari Sanna , Tumiati Manuela , Virtanen Anni , Oikkonen Jaana , Li Yilin , Perez-Villatoro Fernando , Muranen Taru , Salko Matilda , Huhtinen Kaisa , Kanerva Anna , Koskela Heidi , Tapper Johanna , Koivisto-Korander Riitta , Joutsiniemi Titta , Haltia Ulla-Maija , Lassus Heini , Hautaniemi Sampsa , Färkkilä Anniina , Hynninen Johanna , Hietanen Sakari , Carpén Olli , Kauppi Liisa
Published: August 2023

Comparison of surgery outcome between fHRD and fHRP groups.
Supplementary Table S7 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Supplementary Table S7. Distribution of clinical and biomarker-related characteristics between Methylation Hypoxia High vs Low in the TCGA-pancancer cohort
Supplementary Figure S3 from Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
Authors: Pikkusaari Sanna , Tumiati Manuela , Virtanen Anni , Oikkonen Jaana , Li Yilin , Perez-Villatoro Fernando , Muranen Taru , Salko Matilda , Huhtinen Kaisa , Kanerva Anna , Koskela Heidi , Tapper Johanna , Koivisto-Korander Riitta , Joutsiniemi Titta , Haltia Ulla-Maija , Lassus Heini , Hautaniemi Sampsa , Färkkilä Anniina , Hynninen Johanna , Hietanen Sakari , Carpén Olli , Kauppi Liisa
Published: August 2023

Binned distributions of fHR scores in the discovery cohorts.
Supplementary Table S3 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Supplementary Table S3. Distribution of clinical and biomarker-related characteristics between Methylation Hypoxia High vs Low in the training cohort (TCGA-HNSCC)
Supplementary Table S2 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Supplementary Table S2. Treatment Information for the validation cohort (n=88, DKTK-ROG)
Figure 3 from Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
Authors: Pikkusaari Sanna , Tumiati Manuela , Virtanen Anni , Oikkonen Jaana , Li Yilin , Perez-Villatoro Fernando , Muranen Taru , Salko Matilda , Huhtinen Kaisa , Kanerva Anna , Koskela Heidi , Tapper Johanna , Koivisto-Korander Riitta , Joutsiniemi Titta , Haltia Ulla-Maija , Lassus Heini , Hautaniemi Sampsa , Färkkilä Anniina , Hynninen Johanna , Hietanen Sakari , Carpén Olli , Kauppi Liisa
Published: August 2023

Kaplan–Meier survival analysis. fHRD status significantly predicts longer PFS and OS in chemo-naïve (A and C) and IDS (B and D) cohorts (Log-rank, Mantel–Cox test). Patients treated with PARPi in the first-line setting or with unknown PARPi treatment status were excluded from the PFS analysis (A and B). In addition to first-line and unknown PARPi treatment statuses, patients treated with PARPi at recurrence were excluded from OS analyses (C and D).
Supplementary Methods S1 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Supplementary Methods, Results, Table of Contents
Figure 1 from Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
Authors: Pikkusaari Sanna , Tumiati Manuela , Virtanen Anni , Oikkonen Jaana , Li Yilin , Perez-Villatoro Fernando , Muranen Taru , Salko Matilda , Huhtinen Kaisa , Kanerva Anna , Koskela Heidi , Tapper Johanna , Koivisto-Korander Riitta , Joutsiniemi Titta , Haltia Ulla-Maija , Lassus Heini , Hautaniemi Sampsa , Färkkilä Anniina , Hynninen Johanna , Hietanen Sakari , Carpén Olli , Kauppi Liisa
Published: August 2023

RAD51-based assay to determine fHR capacity from chemo-naïve and NACT-treated clinical HGSC specimens. A, Diagram showing the sample collection. Chemo-naïve samples were obtained from PDS or DL. NACT-treated specimens were obtained from IDS. B, Workflow of the fHR assay. Example images of geminin (green) and RAD51 (red) double stained fHRD and fHRP samples with ImageJ analysis illustration. Number of RAD51 and geminin double positive nuclei divided by the number of geminin-positive nuclei provides the fHR score. C and D, Distribution of fHR scores in chemo-naïve samples (C), as well as in the IDS (NACT-treated) samples (D), shown separately for discovery and validation cohorts. Dashed line indicates the proposed fHRD versus fHRP cutoffs. Colored squares depict HRD estimates from genomics-based assays, with blue shades corresponding to HRD and red shades to HRP. “Non-matched treatment stage” refers to cases where the genomics-based estimate of the patient was obtained from a different surgery sample (PDS/DL vs. IDS) than the fHR score. Deleterious mutations in HR genes identified from WGS/WES data are indicated for each patient. For the IDS validation cohort, only BRCA1/2 mutational testing results from the clinic were available. Asterisks indicate patients who received bevacizumab as part of their subsequent maintenance treatment. E, Comparison of fHR scores from chemo-naïve and IDS (NACT-treated) samples, obtained from the same patient (n = 13 patients). Abbreviations: ND, no data. (A, Created with BioRender.com.)
Supplementary Figure S3 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Supplementary Figure S3. (Top) Hypoxia-M V2 is associated with decreased OS in the TCGApancancer cohort (p<0.002) (Bottom) Hypoxia-M V2 is an independent prognosticator of OS (HR=1.81, p<0.03) after adjusting for demographic and clinical factors.
Supplementary Table 1 from The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma
Authors: Shi Linyong , Chen Hanning , Chen Kunxiang , Zhong Chengzong , Song Chong , Huang Yifeng , Wang Tong , Chen Lei , Li Chiyang , Huang Annie , Qi Songtao , Li Hong , Lu Yuntao
Published: August 2023

Supplementary Table 1
Supplementary Fig. 4 from Discovery and Targeting of a Noncanonical Mechanism of Sarcoma Resistance to ADI-PEG20 Mediated by the Microenvironment
Authors: Rogers Leonard C. , Kremer Jeff C. , Brashears Caitlyn B. , Lin Zongtao , Hu Zhixian , Bastos Alliny C.S. , Baker Adriana , Fettig Nicole , Zhou Dong , Shoghi Kooresh I. , Dehner Carina A. , Chrisinger John S.A. , Bomalaski John S. , Garcia Benjamin A. , Oyama Toshinao , White Eileen P. , Van Tine Brian A.
Published: August 2023

Supplemental Figure 4. Validation of gene knockouts and ASS1 expression in MEFs.
Supplementary Table S5 from Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer
Authors: Tomasich Erwin , Steindl Ariane , Paiato Christina , Hatziioannou Teresa , Kleinberger Markus , Berchtold Luzia , Puhr Rainer , Hainfellner Johannes A. , Müllauer Leonhard , Widhalm Georg , Eckert Franziska , Bartsch Rupert , Heller Gerwin , Preusser Matthias , Berghoff Anna Sophie
Published: August 2023

Differentially methylated CpG sites in HER3+ vs HER3- breast cancer samples (TNBC cohort)
Supplementary Figure S4 from Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer
Authors: Tomasich Erwin , Steindl Ariane , Paiato Christina , Hatziioannou Teresa , Kleinberger Markus , Berchtold Luzia , Puhr Rainer , Hainfellner Johannes A. , Müllauer Leonhard , Widhalm Georg , Eckert Franziska , Bartsch Rupert , Heller Gerwin , Preusser Matthias , Berghoff Anna Sophie
Published: August 2023

Selected CpG sites covering the genomic locus of HER3 (ERBB3) were evaluated for their methylation state (A).
Supplementary Figure S1 from Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer
Authors: Tomasich Erwin , Steindl Ariane , Paiato Christina , Hatziioannou Teresa , Kleinberger Markus , Berchtold Luzia , Puhr Rainer , Hainfellner Johannes A. , Müllauer Leonhard , Widhalm Georg , Eckert Franziska , Bartsch Rupert , Heller Gerwin , Preusser Matthias , Berghoff Anna Sophie
Published: August 2023

Further evaluation of HER3 expression in BM of breast and lung cancer.
Figure S6 from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: August 2023

Supplementary Figure S6. Distribution of HER2 gene ratio in relation to PIK3CA mutation status and HER2-enriched subtype.
Supplementary Data 1 from Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors
Authors: Sousa Luana Guimaraes , McGrail Daniel J. , Lazar Neto Felippe , Li Kaiyi , Marques-Piubelli Mario L. , Ferri-Borgogno Sammy , Dai Hui , Mitani Yoshitsugu , Spardy Burr Nicole , Cooper Zachary A. , Kinneer Krista , Cortez Maria Angelica , Lin Shiaw-Yih , Bell Diana , El Naggar Adel , Burks Jared , Ferrarotto Renata
Published: August 2023

Supplementary material including methods, supplementary table 1, supplementary table 2, and supplementary table 3
Figure S4 from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: August 2023

Supplementary Figure S4. Decision tree algorithm to construct the multiparameter classifier of response in TBCRC023.
Figure S3 from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: August 2023

Supplementary Figure S3. Distribution of intrinsic subtypes in (A) TBCRC023 and (B) PAMELA cohort.
Supplementary Fig. 4 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling
Authors: Ghukasyan Razmik , Liang Keke , Chau Kevin , Li Luyi , Chan Charlotte , Abt Evan R. , Le Thuc , Park Joon Y. , Wu Nanping , Premji Alykhan , Damoiseaux Robert , Luu Tony , Labora Amanda , Rashid Khalid , Link Jason M. , Radu Caius G. , Donahue Timothy R.
Published: August 2023

Supplementary Fig. 4 Immunoblot analysis demonstrating the effect of ± 100 U/ml exogenous IFN on CFPAC-1 and SUIT2 parental cells compared to their respective IFNAR-deficient isogenic cell lines. (B) Immunoblot analysis of CFPAC-1 parental and IFNAR1-KO cells exposed to ± 1 µM diABZI ± 100 nM trametinib for 24 h (C)Immunoblot analysis of the effects of ± 100 U/ml exogenous IFN ± 1 µM diABZI for 24 h.
Supplementary Data 1 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling
Authors: Ghukasyan Razmik , Liang Keke , Chau Kevin , Li Luyi , Chan Charlotte , Abt Evan R. , Le Thuc , Park Joon Y. , Wu Nanping , Premji Alykhan , Damoiseaux Robert , Luu Tony , Labora Amanda , Rashid Khalid , Link Jason M. , Radu Caius G. , Donahue Timothy R.
Published: August 2023

Supplementary Resources and Table
Supplementary Data 1 from Clinical Activity of Combined Telomerase Vaccination and Pembrolizumab in Advanced Melanoma: Results from a Phase I Trial
Authors: Ellingsen Espen B. , O'Day Steven , Mezheyeuski Artur , Gromadka Agnieszka , Clancy Trevor , Kristedja Timothy S. , Milhem Mohammed , Zakharia Yousef
Published: August 2023

Table S1
Data from FDA Oncology Center of Excellence Crowdsourcing Initiative: Outreach to the Scientific Community to Identify Research Questions for Pooled Analyses of Oncology Clinical Trial Data
Authors: Schneider Julie A. , Eckstein Julia , Goldberg Kirsten B. , Ascione Mark C. , Bailey Thamar , Taylor Kimberly , Coffey Aisha M. , Satchi Darshini , Philips Howard , Sridhara Rajeshwari , Nair Abhilasha , Pazdur Richard , Theoret Marc R.
Published: August 2023

Abstract
The FDA Oncology Center of Excellence recently launched a crowdsourcing pilot to request ideas from the scientific community for research questions that FDA could address with pooled analyses of clinical trial data submitted to the agency for regulatory purposes. This effort builds on FDA's track record of publishing pooled analyses to explore scientific questions that cannot be addressed in a single trial due to limited sample size. The research crowdsourcing pilot tested a new approach for obtaining external input on regulatory science activities, because FDA is generally unable to share patient-level data outside of the agency due to federal disclosure laws and regulations protecting different types of data submitted in regulatory applications. We received 29 submissions over the 28-day crowdsourcing campaign, including one research idea that we are exploring for possible follow-up. Based on our experience with this pilot, we learned that crowdsourcing is a promising new approach to gather external input and feedback. We identified opportunities to build understanding in the external oncology community about the types of data typically included in regulatory applications and expand the dissemination of published FDA pooled analyses to help inform future drug development and clinical practice.
Data from Clinical Relevance of BRCA1 Promoter Methylation Testing in Patients with Ovarian Cancer
Authors: Blanc-Durand Félix , Tang Roseline , Pommier Margaux , Nashvi Marzieh , Cotteret Sophie , Genestie Catherine , Le Formal Audrey , Pautier Patricia , Michels Judith , Kfoury Maria , Hervé Robert , Mengue Sylvie , Wafo Estelle , Elies Antoine , Miailhe Gregoire , Uzan Jennifer , Rouleau Etienne , Leary Alexandra
Published: August 2023

AbstractPurpose:
Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance.
Experimental Design:
This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing.
Results:
Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P < 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum.
Conclusions:
Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction.

See related commentary by Garg and Oza, p. 2957
Data from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: August 2023

AbstractPurpose:
Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-“addicted” tumors who may benefit from a chemotherapy-sparing strategy.
Experimental Design:
Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor–positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA.
Results:
In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation.
Conclusions:
Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.
Data from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling
Authors: Ghukasyan Razmik , Liang Keke , Chau Kevin , Li Luyi , Chan Charlotte , Abt Evan R. , Le Thuc , Park Joon Y. , Wu Nanping , Premji Alykhan , Damoiseaux Robert , Luu Tony , Labora Amanda , Rashid Khalid , Link Jason M. , Radu Caius G. , Donahue Timothy R.
Published: August 2023

AbstractPurpose:
Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell–intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity.
Experimental Design:
We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo.
Results:
We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation.
Conclusions:
Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.
Data from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon
Published: August 2023

AbstractPurpose:
Resistance to third-generation EGFR inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting the C797S mutation.
Patients and Methods:
Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells, and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the anticancer efficacy of BBT-176 both in vitro and in vivo. Patient case data are also available from an ongoing phase I clinical trial (NCT04820023).
Results:
The half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S proteins were measured at 4.36, 1.79, and 5.35 nmol/L, respectively (vs. 304.39, 124.82, and 573.72 nmol/L, for osimertinib). IC50 values of BBT–176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183, and 202 nmol/L, respectively (vs. 869, 1,134, 2,799, and 2,685 nmol/L for osimertinib). N-ethyl-N-nitrosourea mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT-176 effectively suppressed the growth of BBT-176–resistant clones. BBT-176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiologic improvements.
Conclusions:
BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKI, with early clinical efficacy and safety.
Data from The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma
Authors: Shi Linyong , Chen Hanning , Chen Kunxiang , Zhong Chengzong , Song Chong , Huang Yifeng , Wang Tong , Chen Lei , Li Chiyang , Huang Annie , Qi Songtao , Li Hong , Lu Yuntao
Published: August 2023

AbstractPurpose:
Temozolomide resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of temozolomide with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance.
Experimental Design:
Haloperidol/temozolomide synergism was assessed in GBM cell lines with different dopamine D2 receptor (DRD2) expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum (ER) stress and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) were used to validate the specific mechanisms by which haloperidol and temozolomide induce ferroptosis in GBM cells.
Results:
In the present work, we demonstrate that the DRD2 level is increased by temozolomide in a time-dependent manner and is inversely correlated with temozolomide sensitivity in GBM. The DRD2 antagonist haloperidol, a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances temozolomide efficacy in vivo and in vitro. Mechanistically, haloperidol suppressed the effect of temozolomide on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered ER stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis.
Conclusions:
Our results provide experimental evidence for repurposing haloperidol as an effective adjunct therapy to inhibit adaptive temozolomide resistance to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application.