bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidation of Mass Transport Phenomena in Highly Concentrated Electrolytes during Current Cycling Using In-Situ Interferometry and Finite Difference Method
Authors: Kamesui Go , Nishikawa Kei , Ueda Mikito , Matsushima Hisayoshi
Published: April 2024

Understanding electrolyte mass transfer during charge–discharge reactions is essential for developing next-generation storage batteries with high energy densities. In this study, we investigated Li+ transport in a highly concentrated electrolyte (HCE) consisting of an equimolar mixture of lithium bis(fluorosulfonyl)amide (LiFSA) and tetraglyme (G4) under current reversal and re-reversal. Concentration profiles of the electrolyte at a distance of 0–600 μm from the Li electrodes were obtained using in situ laser interferometry. The Li+ transference numbers and LiFSA diffusion coefficients were calculated from these profiles. Raman spectroscopy suggested that the coordination structure surrounding Li+ ions in the electrolytes mainly contributed to the transference number. A one-dimensional unsteady diffusion equation and the finite difference method were employed to simulate the concentration profiles. The maximum error percentage between the measured and simulated values was only 3%, confirming the accuracy and validity of the interferometric measurements. Our findings on Li-ion transfer in HCEs could promote the rational design of high-energy-density Li-ion batteries with higher cation transference numbers of electrolytes and charge–discharge rates.
Scavenging of Superoxide Radical Anion by Fluorinated Organosilicon Additives
Authors: Morris Louis V. , Ortiz-Ledón César , Hamers Robert J.
Published: April 2024

We have explored a set of structurally related fluorinated and non-fluorinated organosilicon additives and quantified their rates of reaction with the superoxide radical anion O2
•−. using rapid-scan cyclic voltammetry. Absolute reaction rate measurements in acetonitrile solvent show that O2
•− reacts with the fluorinated OS compounds with bimolecular rate constants k

BM
more than 1000x larger than k

BM
for the reaction between O2
•− and ethylene carbonate. We further identified the products of reaction of a model OS compound using multiple nuclear magnetic resonance (NMR) methods and with gas chromatography/mass spectroscopy. Chemical analysis measurements show that addition of potassium superoxide KO2 to a model fluorinated OS compound produces only one product. Our results indicate that that OS compounds improve battery performance by rapidly scavenging O2
•− in a way that produces a stable product and reduces or eliminates the competing chemical pathways associated with carbonate breakdown. These results provide new insights into how chemical structure impacts critical chemical reactions and may guide the design of new additives that further improve battery safety and stability.
Factors Governing the Presodiation Degree of Hard Carbon Anode for Sodium Ion Batteries
Authors: Zhang Xiaoxiao , Xin Le , Qu Huainan , Qiu Dantong , Liu Miao , Ding Tianyao , Zheng Dong , Qu Deyang
Published: April 2024

This study explores the improvement of sodium-ion batteries by presodiating hard carbon anodes, with the goal of reducing initial capacity loss and enhancing the overall electrochemical performance of full cells. Using Na-biphenyl for presodiation and exploring its effects under various conditions—such as electrolyte composition and electrode loading—alongside two different cathode configurations (Na-stoichiometry Na3V2(PO4)3 and Na-deficient Na0.44MnO2), we seek to elevate the overall electrochemical performance of sodium-ion batteries. Our findings reveal the significance of finely tuning presodiation conditions leading to significant improvements in both initial Coulombic Efficiency and the cycling stability of full cells. Furthermore, a comparative analysis of the solid electrolyte interface formed through both chemical and electrochemical presodiation methods reveals significant similarities in impedance characteristics. This research provides valuable insights into the impact of presodiation on hard carbon anodes, offering a pathway to enhance the practical application of presodiation technology for sodium-ion batteries.
A Highly Effective Polysulfide-Trapping Approach for the Development of High Energy Density, Scalable Lithium-Sulfur Batteries
Authors: Hasan Md Wahidul , Huynh Khang , Lama Bhubnesh , Razzaq Amir Abdul , Smdani Md Gulam , Akter Farhana N. , Maddipudi Bharathkiran , Shende Rajesh , Paudel Tula R. , Xing Weibing
Published: April 2024

Lithium-sulfur (Li-S) batteries are identified as one of the most promising next-generation battery technologies owing to their high theoretical specific energy, sustainability, and affordability. However, the commercialization of Li-S batteries has been hindered by severe technical challenges, including the lithium polysulfide (PS) dissolution/shuttling effect, a major cause of fast capacity degradation over cycling. We demonstrated that, for the first time, nanolayer polymer coated high surface area porous carbons (NPCs) were coated directly on sulfur electrodes (NPC-S), which led to a high specific capacity of ∼1,600 mAh g−1 approaching the theoretical specific capacity limit in the NPC-S based Li-S batteries. The NPC-S based Li-S batteries maintained their large initial specific capacity gain compared with the Baseline-S based Li-S batteries (control) over extended cycles. A follow-on study indicated that the NPC-S approach is a necessary and critical step to boost the near-theoretical specific capacity while being stabilized over long cycles with a synergistic strategy. Our experimental and computational results suggest that NPC coated on sulfur electrodes provides not only an effective and strong PS-trapping power but also an increased redox reaction kinetics for sulfur ↔ PS’s conversions during battery charge and discharge, rendering the realization of near-theoretical discharge specific capacity in the NPC-S based Li-S batteries. The findings presented in this study may inspire a new, simple, low-cost, and commercially scalable approach, without adding any appreciable dead weight or volume to the batteries, in the effort to tackle the technical challenges facing SOA Li-S batteries.
Macrophages in necrotic liver lesion repair: opportunities for therapeutical applications
Authors: Wang Yang , Rodrigues Robim M. , Chen Cheng , Feng Dechun , Maccioni Luca , Gao Bin
Published: April 2024

Healthy livers contain 80% of body resident macrophages known as Kupffer cells. In diseased livers, the number of Kupffer cells usually drops but is compensated by infiltration of monocyte-derived macrophages, some of which can differentiate into Kupffer-like cells. Early studies suggest that Kupffer cells play important roles in both promoting liver injury and liver regeneration. Yet, the distinction between the functionalities of resident and infiltrating macrophages is not always made. By using more specific macrophage markers and targeted cell depletion and single-cell RNA sequencing, recent studies revealed several subsets of monocyte-derived macrophages that play important functions in inducing liver damage and inflammation as well as in liver repair and regeneration. In this review, we discuss the different roles that hepatic macrophages play in promoting necrotic liver lesion resolution and dead cell clearance, as well as the targeting of these cells as potential tools for the development of novel therapies for acute liver failure and acute-on-chronic liver failure.
Decoding the neurotoxic effects of propofol: insights into the RARα-Snhg1-Bdnf regulatory cascade
Authors: Xu Yuhai , Xin Xin , Tao Tianzhu
Published: April 2024

This study aimed to decode propofol’s neurotoxic effects on the regulatory cascade, provide insights into the RARα-Snhg1-Bdnf interaction, apply extensive validation techniques, provide a detailed analysis and exploration of propofol’s neurotoxicity, and offer a comprehensive approach to understanding molecular interactions.
Do Causes Influence Functional Aspects and Quality of Life in Patients with Nonfibrocystic Bronchiectasis?
Authors: Cristina da Silva Ádria , de Campos Medeiros Jessica , Pereira Monica Corso
Published: April 2024

Background. The denomination of noncystic fibrosis bronchiectasis (NCFB) includes several causes, and differences may be expected between the patient subgroups regarding age, comorbidities, and clinical and functional evolution. This study sought to identify the main causes of NCFB in a cohort of stable adult patients and to investigate whether such conditions would be different in their clinical, functional, and quality of life aspects. Methods. Between 2017 and 2019, all active patients with NCFB were prospectively evaluated searching for clinical data, past medical history, dyspnea severity grading, quality of life data, microbiological profile, and lung function (spirometry and six-minute walk test). Results. There was a female predominance; mean age was 54.7 years. Causes were identified in 82% of the patients, the most frequent being postinfections (n=39), ciliary dyskinesia (CD) (n=32), and chronic obstructive pulmonary disease (COPD) (n=29). COPD patients were older, more often smokers (or former smokers) and with more comorbidities; they also had worse lung function (spirometry and oxygenation) and showed worse performance in the six-minute walk test (6MWT) (walked distance and exercise-induced hypoxemia). Considering the degree of dyspnea, in the more symptomatic group, patients had higher scores in the three domains and total score in SGRQ, besides having more exacerbations and more patients in home oxygen therapy. Conclusions. Causes most identified were postinfections, CD, and COPD. Patients with COPD are older and have worse pulmonary function and more comorbidities. The most symptomatic patients are clinically and functionally more severe, besides having worse quality of life.
A Crude Oil Spot Price Forecasting Method Incorporating Quadratic Decomposition and Residual Forecasting
Authors: Duan Yonghui , Ming Ziru , Wang Xiang
Published: April 2024

The world economy is affected by fluctuations in the price of crude oil, making precise and effective forecasting of crude oil prices essential. In this study, we propose a combined forecasting scheme, which combines a quadratic decomposition and optimized support vector regression (SVR). In the decomposition part, the original crude oil price series are first decomposed using empirical modal decomposition (CEEMDAN), and then the residuals of the first decomposition (RES) are decomposed using variational modal decomposition (VMD). Additionally, this work proposes to optimize the support vector regression model (SVR) by the seagull optimization algorithm (SOA). Ultimately, the empirical investigation created the feature-variable system and predicted the filtered features. By computing evaluation indices like MAE, MSE, R2, and MAPE and validating using Brent and WTI crude oil spot, the prediction errors of the CEEMDAN -RES.-VMD -SOA-SVR combination prediction model presented in this paper are assessed and compared with those of the other twelve comparative models. The empirical evidence shows that the combination model being proposed in this paper outperforms the other related comparative models and improves the accuracy of the crude oil price forecasting model.
Supplementary Figure S3 from The Web-Based Portal SpatialTME Integrates Histological Images with Single-Cell and Spatial Transcriptomics to Explore the Tumor Microenvironment
Authors: Shi Jintong , Wei Xia , Xun Zhenzhen , Ding Xinyu , Liu Yao , Liu Lianxin , Ye Youqiong
Published: April 2024

Supplementary Figure S3. Reconstruction of spatial tumor microenvironment, related to Figure 3.
Supplementary Table S6 from TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma
Authors: Damayanti Nur P. , Cordova Ricardo A. , Rupert Christopher , Delle Fontane Ilaria , Shen Li , Orsi Sabrina , Klunk Angela J. , Linehan W. Marston , Staschke Kirk A. , Hollenhorst Peter C. , Heppner David E. , Pili Roberto
Published: April 2024

Supplementary Table S6
Supplementary Figure S12 from TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma
Authors: Damayanti Nur P. , Cordova Ricardo A. , Rupert Christopher , Delle Fontane Ilaria , Shen Li , Orsi Sabrina , Klunk Angela J. , Linehan W. Marston , Staschke Kirk A. , Hollenhorst Peter C. , Heppner David E. , Pili Roberto
Published: April 2024

Supplementary Figure S12
Table S3 from Th17 Cells Secrete TWEAK to Trigger Epithelial–Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis
Authors: Liu Xin , Wang Xin , Yang Qingxia , Luo Li , Liu Ziqin , Ren Xiaoxue , Lei Kai , Li Shangru , Xie Zonglin , Zheng Gaomin , Zhang Yifan , Hao Yijie , Zhou Qianying , Hou Yingdong , Fang Fei , Song Wu , Cui Ji , Ma Jinping , Xie Wenxuan , Shen Shunli , Tang Ce , Peng Sui , Yu Jun , Kuang Ming , Song Xinming , Wang Fang , Xu Lixia
Published: April 2024

Table S3. Marker genes of subcluster for each major cell type
Supplementary Data Figure S6 from KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity
Authors: Qiang Yulong , Fan Jiachen , Xie Chuanshuai , Yan Leilei , Song Xiaofei , Zhang Nan , Lin Yan , Xiong Jie , Zhang Wei , Liu Yu , Wei Lei , Li Yu , Chen Shizhen , Liang Kaiwei , Li Feng
Published: April 2024

Delineating KDM5C and BRD4 localization and illustrating the definitions of transcriptional elements.
Data from Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression
Authors: Zabransky Daniel J. , Chhabra Yash , Fane Mitchell E. , Kartalia Emma , Leatherman James M. , Hüser Laura , Zimmerman Jacquelyn W. , Delitto Daniel , Han Song , Armstrong Todd D. , Charmsaz Soren , Guinn Samantha , Pramod Sneha , Thompson Elizabeth D. , Hughes Steven J. , O'Connell Jennifer , Egan Josephine M. , Jaffee Elizabeth M. , Weeraratna Ashani T.
Published: April 2024

Abstract
Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging.
Significance:
Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression.

See related commentary by Isaacson et al., p. 1185
Data from Th17 Cells Secrete TWEAK to Trigger Epithelial–Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis
Authors: Liu Xin , Wang Xin , Yang Qingxia , Luo Li , Liu Ziqin , Ren Xiaoxue , Lei Kai , Li Shangru , Xie Zonglin , Zheng Gaomin , Zhang Yifan , Hao Yijie , Zhou Qianying , Hou Yingdong , Fang Fei , Song Wu , Cui Ji , Ma Jinping , Xie Wenxuan , Shen Shunli , Tang Ce , Peng Sui , Yu Jun , Kuang Ming , Song Xinming , Wang Fang , Xu Lixia
Published: April 2024

Abstract
Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial–mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK–Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle–encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM.
Significance:
TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK–Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis.
Supplementary Figure S2 from Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma
Authors: Griesinger Andrea M. , Calzadilla Annaliese J. , Grimaldo Enrique , Donson Andrew M. , Amani Vladimir , Pierce Angela M. , Steiner Jenna , Kargar Soudabeh , Serkova Natalie J. , Bertrand Kelsey C. , Wright Karen D. , Vibhakar Rajeev , Hankinson Todd , Handler Michael , Lindsay Holly B. , Foreman Nicholas K. , Dorris Kathleen
Published: April 2024

Combination of radiation with 5FU is synergistic in 1q+ PFA cell lines.
Supplementary Table S2 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma
Authors: Habashy Karl J. , Dmello Crismita , Chen Li , Arrieta Victor A. , Kim Kwang-Soo , Gould Andrew , Youngblood Mark W. , Bouchoux Guillaume , Burdett Kirsten B. , Zhang Hui , Canney Michael , Stupp Roger , Sonabend Adam M.
Published: April 2024

Supplementary table 2: Table illustrating the representativeness of our study participants.
Supplementary Table S1 from A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer
Authors: Dorff Tanya , Horvath Lisa G. , Autio Karen , Bernard-Tessier Alice , Rettig Matthew B. , Machiels Jean-Pascal , Bilen Mehmet A. , Lolkema Martijn P. , Adra Nabil , Rottey Sylvie , Greil Richard , Matsubara Nobuaki , Tan Daniel S.W. , Wong Alvin , Uemura Hiroji , Lemech Charlotte , Meran Johannes , Yu Youfei , Minocha Mukul , McComb Mason , Penny Hweixian Leong , Gupta Vinita , Hu Xuguang , Jurida Gabor , Kouros-Mehr Hosein , Janát-Amsbury Margit M. , Eggert Tobias , Tran Ben
Published: April 2024

Target doses evaluated in step dosing and extended intravenous dosing regimens
Supplementary Methods S1 from A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer
Authors: Dorff Tanya , Horvath Lisa G. , Autio Karen , Bernard-Tessier Alice , Rettig Matthew B. , Machiels Jean-Pascal , Bilen Mehmet A. , Lolkema Martijn P. , Adra Nabil , Rottey Sylvie , Greil Richard , Matsubara Nobuaki , Tan Daniel S.W. , Wong Alvin , Uemura Hiroji , Lemech Charlotte , Meran Johannes , Yu Youfei , Minocha Mukul , McComb Mason , Penny Hweixian Leong , Gupta Vinita , Hu Xuguang , Jurida Gabor , Kouros-Mehr Hosein , Janát-Amsbury Margit M. , Eggert Tobias , Tran Ben
Published: April 2024

Supplementary Methods
Supplementary Figure S4 from A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer
Authors: Dorff Tanya , Horvath Lisa G. , Autio Karen , Bernard-Tessier Alice , Rettig Matthew B. , Machiels Jean-Pascal , Bilen Mehmet A. , Lolkema Martijn P. , Adra Nabil , Rottey Sylvie , Greil Richard , Matsubara Nobuaki , Tan Daniel S.W. , Wong Alvin , Uemura Hiroji , Lemech Charlotte , Meran Johannes , Yu Youfei , Minocha Mukul , McComb Mason , Penny Hweixian Leong , Gupta Vinita , Hu Xuguang , Jurida Gabor , Kouros-Mehr Hosein , Janát-Amsbury Margit M. , Eggert Tobias , Tran Ben
Published: April 2024

Acapatamab-induced PSA response in patients who received prior lutetium-PSMA therapy
Supplementary Fig. S2 from Cooperative Armoring of CAR and TCR T Cells by T Cell–Restricted IL15 and IL21 Universally Enhances Solid Tumor Efficacy
Authors: Nguyen Rosa , Doubrovina Ekaterina , Mousset Charlotte M. , Jin Benjamin Y. , Okada Reona , Zhang Xiyuan , Clavel Arina , Reyes-Gonzalez Jeyshka M. , Dyomin Vadim , Diaz Louis , Zhang Ling , Abbas Shahroze , Sun Ming , Hsieh Chao-Ming , Ho Mitchell , Shern Jack F. , Gulley James L. , Hinrichs Christian S.
Published: April 2024

In vitro shedding studies.
Supplementary Fig. S1 from Cooperative Armoring of CAR and TCR T Cells by T Cell–Restricted IL15 and IL21 Universally Enhances Solid Tumor Efficacy
Authors: Nguyen Rosa , Doubrovina Ekaterina , Mousset Charlotte M. , Jin Benjamin Y. , Okada Reona , Zhang Xiyuan , Clavel Arina , Reyes-Gonzalez Jeyshka M. , Dyomin Vadim , Diaz Louis , Zhang Ling , Abbas Shahroze , Sun Ming , Hsieh Chao-Ming , Ho Mitchell , Shern Jack F. , Gulley James L. , Hinrichs Christian S.
Published: April 2024

Predicted cytokine structure and expression.
Supplementary Figure 9 from CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors
Authors: Archer Sophie , Brailey Phillip M. , Song Minjung , Bartlett Phillip D. , Figueiredo Ines , Gurel Bora , Guo Christina , Brucklacher-Waldert Verena , Thompson H. Lorraine , Akinwale Jude , Boyle Samantha E. , Rossant Christine , Birkett Neil R. , Pizzey Julia , Maginn Mark , Legg James , Williams Richard , Johnston Colette M. , Bland-Ward Philip , de Bono Johann S. , Pierce Andrew J.
Published: April 2024

Supplementary Figure 9: Neuroendocrine Differentiation Phenotypes in Prostate Cancer Liver Metastases
Supplementary Table S2 from Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial
Authors: Oh Hyung-Joo , Bae Suk-Chul , Oh In-Jae , Park Cheol-Kyu , Jung Kyoung-Mi , Kim Da-Mi , Lee Jung-Won , Kang Chang Kyun , Park Il Yeong , Kim Young-Chul
Published: April 2024

Table S2. Representativeness of Study Participants
Supplementary Table 9 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
Authors: Singh Harshabad , Sahgal Pranshu , Kapner Kevin , Corsello Steven M. , Gupta Hersh , Gujrathi Rahul , Li Yvonne Y. , Cherniack Andrew D. , El Alam Raquelle , Kerfoot Joseph , Andrews Elizabeth , Lee Annette , Nambiar Chetan , Hannigan Alison M. , Remland Joshua , Brais Lauren , Leahy Meghan E. , Rubinson Douglas A. , Schlechter Benjamin L. , Meyerson Matthew , Kuang Yanan , Paweletz Cloud P. , Lee Jessica K. , Quintanilha Julia C.F. , Aguirre Andrew J. , Perez Kimberly J. , Huffman Brandon M. , Rossi Humberto , Abrams Thomas A. , Kabraji Sheheryar , Trusolino Livio , Bertotti Andrea , Sicinska Ewa T. , Parikh Aparna R. , Wolpin Brian M. , Schrock Alexa B. , Giannakis Marios , Ng Kimmie , Meyerhardt Jeffrey A. , Hornick Jason L. , Sethi Nilay S. , Cleary James M.
Published: April 2024

Supplementary Table 9. Statistics from flow sorting for SW480-GFP and -HER2 lines.
Supplementary Table 8 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
Authors: Singh Harshabad , Sahgal Pranshu , Kapner Kevin , Corsello Steven M. , Gupta Hersh , Gujrathi Rahul , Li Yvonne Y. , Cherniack Andrew D. , El Alam Raquelle , Kerfoot Joseph , Andrews Elizabeth , Lee Annette , Nambiar Chetan , Hannigan Alison M. , Remland Joshua , Brais Lauren , Leahy Meghan E. , Rubinson Douglas A. , Schlechter Benjamin L. , Meyerson Matthew , Kuang Yanan , Paweletz Cloud P. , Lee Jessica K. , Quintanilha Julia C.F. , Aguirre Andrew J. , Perez Kimberly J. , Huffman Brandon M. , Rossi Humberto , Abrams Thomas A. , Kabraji Sheheryar , Trusolino Livio , Bertotti Andrea , Sicinska Ewa T. , Parikh Aparna R. , Wolpin Brian M. , Schrock Alexa B. , Giannakis Marios , Ng Kimmie , Meyerhardt Jeffrey A. , Hornick Jason L. , Sethi Nilay S. , Cleary James M.
Published: April 2024

Supplementary Table 8. Genomic differences between HER2 amplified, RAS/RAF wild type vs. RAS/RAF altered cases in the foundation medicine genomic cohort.
Supplementary Figure S11 from A B7-H4–Targeting Antibody–Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression
Authors: Gitto Sarah B. , Whicker Margaret , Davies Gareth , Kumar Sushil , Kinneer Krista , Xu Haineng , Lewis Arthur , Mamidi Srinivas , Medvedev Sergey , Kim Hyoung , Anderton Judith , Tang E. Jessica , Ferman Benjamin , Coats Steven , Wilkinson Robert W. , Brown Eric , Powell Daniel J. , Simpkins Fiona
Published: April 2024

Individual mouse data and statistical analysis of WO-19 PDX in vivo study.
Supplementary Table 1 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
Authors: Singh Harshabad , Sahgal Pranshu , Kapner Kevin , Corsello Steven M. , Gupta Hersh , Gujrathi Rahul , Li Yvonne Y. , Cherniack Andrew D. , El Alam Raquelle , Kerfoot Joseph , Andrews Elizabeth , Lee Annette , Nambiar Chetan , Hannigan Alison M. , Remland Joshua , Brais Lauren , Leahy Meghan E. , Rubinson Douglas A. , Schlechter Benjamin L. , Meyerson Matthew , Kuang Yanan , Paweletz Cloud P. , Lee Jessica K. , Quintanilha Julia C.F. , Aguirre Andrew J. , Perez Kimberly J. , Huffman Brandon M. , Rossi Humberto , Abrams Thomas A. , Kabraji Sheheryar , Trusolino Livio , Bertotti Andrea , Sicinska Ewa T. , Parikh Aparna R. , Wolpin Brian M. , Schrock Alexa B. , Giannakis Marios , Ng Kimmie , Meyerhardt Jeffrey A. , Hornick Jason L. , Sethi Nilay S. , Cleary James M.
Published: April 2024

Supplementary Table 1. GENIE IDs for HER2 positive CRC DFCI cohort.
Supplementary Figure 3 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
Authors: Singh Harshabad , Sahgal Pranshu , Kapner Kevin , Corsello Steven M. , Gupta Hersh , Gujrathi Rahul , Li Yvonne Y. , Cherniack Andrew D. , El Alam Raquelle , Kerfoot Joseph , Andrews Elizabeth , Lee Annette , Nambiar Chetan , Hannigan Alison M. , Remland Joshua , Brais Lauren , Leahy Meghan E. , Rubinson Douglas A. , Schlechter Benjamin L. , Meyerson Matthew , Kuang Yanan , Paweletz Cloud P. , Lee Jessica K. , Quintanilha Julia C.F. , Aguirre Andrew J. , Perez Kimberly J. , Huffman Brandon M. , Rossi Humberto , Abrams Thomas A. , Kabraji Sheheryar , Trusolino Livio , Bertotti Andrea , Sicinska Ewa T. , Parikh Aparna R. , Wolpin Brian M. , Schrock Alexa B. , Giannakis Marios , Ng Kimmie , Meyerhardt Jeffrey A. , Hornick Jason L. , Sethi Nilay S. , Cleary James M.
Published: April 2024

Supplementary Figure 3. Response and resistance to trastuzumab/lapatinib.
Figure 5 from Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging
Authors: Malviya Gaurav , Lannagan Tamsin R.M. , Johnson Emma , Mackintosh Agata , Bielik Robert , Peters Adam , Soloviev Dmitry , Brown Gavin , Jackstadt Rene , Nixon Colin , Gilroy Kathryn , Campbell Andrew , Sansom Owen J. , Lewis David Y.
Published: April 2024

PET imaging phenotypic difference between primary and metastatic tumors. A, The generation of the KrasG12D/+ Trp53fl/fl Rosa26N1icd/+ (KPN) and KPN liver metastasis organoid lines and subsequent implantation. One pair of lines, generated from a matched mouse primary tumor and liver metastasis, which were then propagated and injected subcutaneously into recipient mice (n = 5). B, Transverse and coronal PET/MRI slice images showing uptake of four PET tracers ([18F]FDG, [18F]FET, [18F]FLT, [18F]ACE) in subcutaneously implanted KPN primary and KPN liver metastasis organoids. KPN primary tumor-bearing mice are the same four PET ([18F]FDG, [18F]FET, [18F]FLT, [18F]ACE) images (primary) as displayed in Figs. 2B and 4B and D. C, Standard uptake peak values (SUVpeak) PET quantification from images in B. Sample size (n) is displayed on the bars. Error bars represent SD. Data compared using unpaired t test. Details of all mice used in these studies are presented in Supplementary Table S1. D, Representative GLUT-1 IHC and Lat-1/Slc7a5 ISH. Black scale bars represent 50 μm (*, P < 0.05; ***, P < 0.001; see also Supplementary Fig. S8). (A, Created with BioRender.com.)
Figure 2 from Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging
Authors: Malviya Gaurav , Lannagan Tamsin R.M. , Johnson Emma , Mackintosh Agata , Bielik Robert , Peters Adam , Soloviev Dmitry , Brown Gavin , Jackstadt Rene , Nixon Colin , Gilroy Kathryn , Campbell Andrew , Sansom Owen J. , Lewis David Y.
Published: April 2024

Distinct intermodel heterogeneity in PET imaging signatures. A, In the experimental imaging protocol, five colon cancer organoid models and four PET tracers were used to determine imaging signatures. Details of all mice used in these studies are presented in Supplementary Table S1. B, Representative transverse PET images from each model and tracer. The [18F]FDG PET/MR images of the KPN subcutaneous model are reproduced again in Figs. 4B and D and 5B for comparison against other tumors at different sites and stages. C, Imaging signature heatmap showing mean tracer uptake, models with highest tracer update highlighted with black outline (representation of the data matrix analyzed with two-way ANOVA). D, Correlation matrix of each tracer uptake based on Pearson correlation coefficient. E, Heatmap illustrating correlation of PET tracer uptake with gene expression in the Molecular Signatures Database (MSigDB) hallmark dataset, sorted by hierarchal clustering. (A, Created with BioRender.com.)
Supplementary Table S1 from Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors
Authors: Peters Solange , Angevin Eric , Alonso-Gordoa Teresa , Rohrberg Kristoffer , Melero Ignacio , Mellado Begoña , Perez-Gracia Jose-Luis , Tabernero Josep , Adessi Celine , Boetsch Christophe , Watson Carl , Dal Porto Joseph , Dejardin David , Del Nagro Christopher , Nicolini Valeria , Evers Stefan , Klein Christian , Leutgeb Barbara , Pisa Pavel , Rossmann Eva , Saro José , Umana Pablo , Charo Jehad , Teichgräber Volker , Steeghs Neeltje
Published: April 2024

Supplementary Table S1. Baseline demographic and clinical characteristics (safety population).
Supplementary Figure S3 from Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors
Authors: Peters Solange , Angevin Eric , Alonso-Gordoa Teresa , Rohrberg Kristoffer , Melero Ignacio , Mellado Begoña , Perez-Gracia Jose-Luis , Tabernero Josep , Adessi Celine , Boetsch Christophe , Watson Carl , Dal Porto Joseph , Dejardin David , Del Nagro Christopher , Nicolini Valeria , Evers Stefan , Klein Christian , Leutgeb Barbara , Pisa Pavel , Rossmann Eva , Saro José , Umana Pablo , Charo Jehad , Teichgräber Volker , Steeghs Neeltje
Published: April 2024

Supplementary Figure S3. Efficacy of IL-2v alone and in combination with anti-PD-L1 in A, Wild-type C57BL/6 mice and
B, B-cell deficient C57BL/6 mice. IL-2v, interleukin-2 variant; PD-L1, programmed death-ligand 1.
Supplementary Table 3 from Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial
Authors: Parra Edwin Roger , Zhang Jiexin , Duose Dzifa Yawa , Gonzalez-Kozlova Edgar , Redman Mary W. , Chen Hong , Manyam Ganiraju C. , Kumar Gayatri , Zhang Jianhua , Song Xingzhi , Lazcano Rossana , Marques-Piubelli Mario L. , Laberiano-Fernandez Caddie , Rojas Frank , Zhang Baili , Taing Len , Jhaveri Aashna , Geisberg Jacob , Altreuter Jennifer , Michor Franziska , Provencher James , Yu Joyce , Cerami Ethan , Moravec Radim , Kannan Kasthuri , Luthra Rajyalakshmi , Alatrash Gheath , Huang Hsin-Hui , Xie Hui , Patel Manishkumar , Nie Kai , Harris Jocelyn , Argueta Kimberly , Lindsay James , Biswas Roshni , Van Nostrand Stephen , Kim-Schulze Seunghee , Gray Jhanelle E. , Herbst Roy S. , Wistuba Ignacio I. , Gettinger Scott , Kelly Karen , Bazhenova Lyudmila , Gnjatic Sacha , Lee J. Jack , Zhang Jianjun , Haymaker Cara
Published: April 2024

Supplementary Table 3. Frequently observed phenotypes in the two multiplex immunofluorescence panels.
Supplementary Figure 7 from Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial
Authors: Parra Edwin Roger , Zhang Jiexin , Duose Dzifa Yawa , Gonzalez-Kozlova Edgar , Redman Mary W. , Chen Hong , Manyam Ganiraju C. , Kumar Gayatri , Zhang Jianhua , Song Xingzhi , Lazcano Rossana , Marques-Piubelli Mario L. , Laberiano-Fernandez Caddie , Rojas Frank , Zhang Baili , Taing Len , Jhaveri Aashna , Geisberg Jacob , Altreuter Jennifer , Michor Franziska , Provencher James , Yu Joyce , Cerami Ethan , Moravec Radim , Kannan Kasthuri , Luthra Rajyalakshmi , Alatrash Gheath , Huang Hsin-Hui , Xie Hui , Patel Manishkumar , Nie Kai , Harris Jocelyn , Argueta Kimberly , Lindsay James , Biswas Roshni , Van Nostrand Stephen , Kim-Schulze Seunghee , Gray Jhanelle E. , Herbst Roy S. , Wistuba Ignacio I. , Gettinger Scott , Kelly Karen , Bazhenova Lyudmila , Gnjatic Sacha , Lee J. Jack , Zhang Jianjun , Haymaker Cara
Published: April 2024

Supplementary Figure 7. LRP1B mutation associations with immune infiltration and survival.
Supplementary Table S6 from Safety Profile and Adverse Event Management for Futibatinib, An Irreversible FGFR1–4 Inhibitor: Pooled Safety Analysis of 469 Patients
Authors: Meric-Bernstam Funda , Hollebecque Antoine , Furuse Junji , Oh Do-Youn , Bridgewater John A. , Shimura Masashi , Anderson Bailey , Hangai Nanae , Wacheck Volker , Goyal Lipika
Published: April 2024

Treatment-related AEs (MedDRA preferred terms; incidence ≥10%)
Supplementary Figure S1 from Safety Profile and Adverse Event Management for Futibatinib, An Irreversible FGFR1–4 Inhibitor: Pooled Safety Analysis of 469 Patients
Authors: Meric-Bernstam Funda , Hollebecque Antoine , Furuse Junji , Oh Do-Youn , Bridgewater John A. , Shimura Masashi , Anderson Bailey , Hangai Nanae , Wacheck Volker , Goyal Lipika
Published: April 2024

Safety analysis populations
Data from Validation of the Prognostic Performance of Breast Cancer Index in Hormone Receptor–Positive Postmenopausal Breast Cancer Patients in the TEAM Trial
Authors: Bartlett John M.S. , Xu Keying , Wong Jenna , Pond Gregory , Zhang Yi , Spears Melanie , Salunga Ranelle , Mallon Elizabeth , Taylor Karen J. , Hasenburg Annette , Markopoulos Christos , Dirix Luc , van de Velde Cornelis J.H. , Rea Daniel , Schnabel Catherine A. , Treuner Kai , Bayani Jane
Published: April 2024

AbstractPurpose:
Patients with early-stage hormone receptor–positive (HR+) breast cancer face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) is significantly prognostic for overall (0–10 years) and late (5–10 years) distant recurrence (DR) risk in N0 and N1 patients. Here, BCI prognostic performance was evaluated in HR+ postmenopausal women from the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial.
Experimental Design:
3,544 patients were included in the analysis (N = 1,519 N0, N = 2,025 N+). BCI risk groups were calculated using pre-specified cutoff points. Kaplan–Meier analyses and log-rank tests were used to assess the prognostic significance of BCI risk groups based on DR. Hazard ratios (HR) and confidence intervals (CI) were calculated using Cox models with and without clinical covariates.
Results:
For overall 10-year DR, BCI was significantly prognostic in Ni0 (N = 1,196) and N1 (N = 1,234) patients who did not receive prior chemotherapy (P < 0.001). In patients who were DR-free for 5 years, 10-year late DR rates for low- and high-risk groups were 5.4% and 9.3% (N0 cohort, N = 1,285) and 4.8% and 12.2% (N1 cohort, N = 1,625) with multivariate HRs of 2.25 (95% CI, 1.30–3.88; P = 0.004) and 2.67 (95% CI, 1.53–4.63; P < 0.001), respectively. Late DR performance was substantially improved using previously optimized cutoff points, identifying BCI low-risk groups with even lower 10-year late DR rates of 3.8% and 2.7% in N0 and N1 patients, respectively.
Conclusions:
The TEAM trial represents the largest prognostic validation study for BCI to date and provides a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ patients with early-stage breast cancer.
Data from A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer
Authors: Dorff Tanya , Horvath Lisa G. , Autio Karen , Bernard-Tessier Alice , Rettig Matthew B. , Machiels Jean-Pascal , Bilen Mehmet A. , Lolkema Martijn P. , Adra Nabil , Rottey Sylvie , Greil Richard , Matsubara Nobuaki , Tan Daniel S.W. , Wong Alvin , Uemura Hiroji , Lemech Charlotte , Meran Johannes , Yu Youfei , Minocha Mukul , McComb Mason , Penny Hweixian Leong , Gupta Vinita , Hu Xuguang , Jurida Gabor , Kouros-Mehr Hosein , Janát-Amsbury Margit M. , Eggert Tobias , Tran Ben
Published: April 2024

AbstractPurpose:
Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods:
Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed.
Results:
In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0–4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0–5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion.
Conclusions:
Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.
Data from Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging
Authors: Malviya Gaurav , Lannagan Tamsin R.M. , Johnson Emma , Mackintosh Agata , Bielik Robert , Peters Adam , Soloviev Dmitry , Brown Gavin , Jackstadt Rene , Nixon Colin , Gilroy Kathryn , Campbell Andrew , Sansom Owen J. , Lewis David Y.
Published: April 2024

AbstractPurpose:
The current approach for molecular subtyping of colon cancer relies on gene expression profiling, which is invasive and has limited ability to reveal dynamics and spatial heterogeneity. Molecular imaging techniques, such as PET, present a noninvasive alternative for visualizing biological information from tumors. However, the factors influencing PET imaging phenotype, the suitable PET radiotracers for differentiating tumor subtypes, and the relationship between PET phenotypes and tumor genotype or gene expression–based subtyping remain unknown.
Experimental Design:
In this study, we conducted 126 PET scans using four different metabolic PET tracers, [18F]fluorodeoxy-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), and [11C]acetate ([11C]ACE), using a spectrum of five preclinical colon cancer models with varying genetics (BMT, AKPN, AK, AKPT, KPN), at three sites (subcutaneous, orthograft, autochthonous) and at two tumor stages (primary vs. metastatic).
Results:
The results demonstrate that imaging signatures are influenced by genotype, tumor environment, and stage. PET imaging signatures exhibited significant heterogeneity, with each cancer model displaying distinct radiotracer profiles. Oncogenic Kras and Apc loss showed the most distinctive imaging features, with [18F]FLT and [18F]FET being particularly effective, respectively. The tissue environment notably impacted [18F]FDG uptake, and in a metastatic model, [18F]FET demonstrated higher uptake.
Conclusions:
By examining factors contributing to PET-imaging phenotype, this study establishes the feasibility of noninvasive molecular stratification using multiplex radiotracer PET. It lays the foundation for further exploration of PET-based subtyping in human cancer, thereby facilitating noninvasive molecular diagnosis.
Abstract P45: REDUCED IMMUNOGENICITY DRIVES SUPERIORITY OF THE NANOLUCIFERASE (NLUC) REPORTER IN AN IMMUNOCOMPETENT GL261 MOUSE GLIOMA MODEL
Authors: Victorio Carla Bianca Luena , Novera Wisna , Ganasarajah Arun , Ong Joanne , Li Peter , Petersen Sven Hans , Msallam Rasha , Chacko Ann-Marie
Published: April 2024

Bioluminescence imaging (BLI) with luciferase-based reporters is a robust approach for monitoring tumour growth and treatment response in preclinical in vivo cancer models. Luciferases are considered foreign molecules that could elicit immune responses when introduced in immunocompetent live animal models [1, 2]. The immunogenicity of luciferases and other transgenic imaging reporters, though often overlooked, was recently discussed in relation to mouse cancer models [3-5]. Herein, we investigated the immunogenicity of two luciferase reporters: (1) red-shifted firefly luciferase (RFLuc, 61 kDa) and (2) deep-sea shrimp nanoluciferase (nLuc, 19 kDa) in an orthotopic brain tumour model using GL261 mouse glioma cells in a syngeneic C57BL/6J mouse. We evaluated their suitability for monitoring of brain tumour growth kinetics by BLI. Mice were implanted with 2 × 104 either GL261, GL261-NLuc or GL261-RFLuc cells in the right cerebrum using a stereotaxic device. GL261-RFLuc tumours could only be detected by BLI for 2 weeks, and the mice did not die of disease (median overall survival; mOS > 35 days). In contrast, GL261-nLuc cells formed lethal brain tumours that grew in volume as determined by BLI. GL261-NLuc implanted mice exhibited mOS comparable to mice implanted with GL261 cells (24.5 days vs. 23 days). These observations indicated that nLuc is not significantly immunogenic in mouse brains and did not cause rejection of the tumour cells as observed with RFluc. Cytokine expression profiles and immune cell profiles of the tumour-bearing brain hemispheres were comparable between tumours from GL261 and GL261-NLuc. In contrast, GL261-RFLuc tumours exhibited elevated CD8+ T cells, particularly effector (CD62L¯CD44+) and granzyme B-expressing (GZB+) CD8+ T cells. GL261-nLuc formed stable glioma tumors comparable to the original GL261 mouse model and is a suitable in vivo preclinical model for evaluating experimental therapeutic interventions against gliomas, when paired with Promega’s proprietary fluoro-furimazine substrate.

Funding: This research was supported by Singapore’s Health and Biomedical Sciences (HBMS) Industry Alignment Fund Pre-Positioning (IAF-PP) grant H18/01/a0/018 (to AMC) administered by A*STAR and Singapore-MIT Alliance for Research and Technology (SMART) Innovation Grant (ING-000913 BIO) (to AMC).

Citation Format: Carla Bianca Luena Victorio, Wisna Novera, Arun Ganasarajah, Joanne Ong, Peter Li, Sven Hans Petersen, Rasha Msallam, Ann-Marie Chacko. REDUCED IMMUNOGENICITY DRIVES SUPERIORITY OF THE NANOLUCIFERASE (NLUC) REPORTER IN AN IMMUNOCOMPETENT GL261 MOUSE GLIOMA MODEL [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P45.
Abstract P49: PROTAC A1874: A Potential Targeted Therapy for Breast Cancer
Authors: Marvalim Charlie , Datta Arpita , Seah Serena Bee Kee , Chow Edward Kai-Hua , Lee Soo Chin
Published: April 2024

Background

PROteolysis TArgeting Chimera (PROTAC) A1874 is a heterobifunctional structured compound consisting of a BRD4-recognizing ligand and an MDM2-recognizing ligand that functions to degrade BRD4 via the ubiquitin-proteasome system. A1874 also plays a dual role in downregulating downstream BRD4 regulator, MYC, and stabilizing p53 within nanomolar concentrations. This PROTAC thus presents itself as a potential therapy for both estrogen-receptor positive (ER+) and triple-negative breast cancer (TNBC) subtypes, which typically harbors wild-type p53 and are associated with MYC overexpression respectively. Thus, this study aims to 1) investigate the anti-oncogenic effects and mechanism of A1874 and 2) its effect in combination with existing therapies in several breast cancer (BC) cell lines.

Methods

A panel of BC cell lines harboring different p53 status were tested for their sensitivity to A1874. Several functional assays were conducted to determine the anti-oncogenic effects of A1874. Bliss scores were calculated using SynergyFinder to determine the interaction of drugs in combination with A1874.

Results

BC cell lines with p53 WT status showed significantly lower IC50 sensitivity to A1874 in the nanomolar range compared to those with p53 mutation, which exhibited sensitivity in the micromolar range regardless of subtypes. Moreover, it is effective in Tam-resistant ER+, p53 WT cells. A1874 exclusively degrades BRD4 in p53 WT cells and causes G1 arrest, inhibition of colony formation, proliferation, and migration. Knockdown of MDM2 or TP53, and lentiviral transduction of p53 mutant plasmid resulted in significant reduction in sensitivity to A1874 in p53 WT cell lines and abrogate its BRD4-degrading effect. Combination of A1874 with the mutant p53 reactivating drug, PRIMA-1, synergistically resensitize mutant p53 cells to the cytotoxic effect of A1874 across subtypes.

Conclusions

Our results highlight a promising potential of PROTAC A1874 as a therapeutic drug in breast cancer, specifically the ER+ subtype which typically retains its p53 WT status.

Citation Format: Charlie Marvalim, Arpita Datta, Serena Bee Kee Seah, Edward Kai-Hua Chow, Soo Chin Lee. PROTAC A1874: A Potential Targeted Therapy for Breast Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P49.