bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S3 from Discovery of a Novel Potent EGFR Inhibitor Against EGFR Activating Mutations and On-Target Resistance in NSCLC
Authors: Lee Eun Ji , Oh Seung Yeon , Lee You Won , Kim Ju Young , Kim Min-Je , Kim Tae Ho , Lee Jii Bum , Hong Min Hee , Lim Sun Min , Baum Anke , Woelflingseder Lydia , Engelhardt Harald , Petronczki Mark , Solca Flavio , Yun Mi Ran , Cho Byoung Chul
Published: April 2024

In vitro activity of BI-4732 in PDC cells harboring EGFR-activating mutations and T790M mutation
Supplementary Figure S2 from Discovery of a Novel Potent EGFR Inhibitor Against EGFR Activating Mutations and On-Target Resistance in NSCLC
Authors: Lee Eun Ji , Oh Seung Yeon , Lee You Won , Kim Ju Young , Kim Min-Je , Kim Tae Ho , Lee Jii Bum , Hong Min Hee , Lim Sun Min , Baum Anke , Woelflingseder Lydia , Engelhardt Harald , Petronczki Mark , Solca Flavio , Yun Mi Ran , Cho Byoung Chul
Published: April 2024

In vitro activity of BI-4732 against Ba/F3 cells expressing EGFR-activating mutations and T790M mutation
Supplementary Figure S1 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

5FU at 75mg/kg in combination with 10Gy radiation is too toxic in vivo
Supplementary Figure S2 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

Supplemental Figure 2. Continuous risk curves of BCI and BCIN+ for late 10-year DR in patients DR-free at 5 years.
A: risk of 10-year late DR as a function of continuous BCI for N0 patients (N=1285); B: risk of 10-year late DR as a function of continuous BCIN+ for N1 patients (N=1625); C: risk of 10-year late DR as a function of continuous BCI for N0 HER2- patients (N=1063); D: risk of 10-year late DR as a function of continuous BCIN+ for N1 HER2- patients (N=1394).
Supplementary Table 1 from Clinical Activity of TGF-β Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study
Authors: Ahn Jin-Hee , Lee Jeeyun , Park Changhee , Beom Seung-Hoon , Kim Seung Hyun , Lee Young Han , Yun Kum-Hee , Kim Jeung Eun , Baek Wooyeol , Han Yoon Dae , Kim Sang Kyum , Ryu Hyang Joo , Jung Inkyung , Lee JooHee , Yoon Hong In , Kim Hyo Song
Published: April 2024

Supplementary Table 1
Supplementary Table 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

Summary of treatment-related adverse events with acapatamab monotherapy occurring in ≥ 5% of patients
Supplementary Figure S5 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

Pharmacokinetics of acapatamab
Supplementary Figure S3 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 Figure 3. Paclitaxel and carboplatin exhibit synergy in vitro.
(A) Dose-response matrices illustrating the Loewe synergy score calculated for 11 glioma cell lines at clinically relevant PTX and CBDCA concentrations. (B) Bar charts showing the viability of cell lines treated with PTX, CBDCA, or a combination of both drugs at concentration that showed the highest synergy.
Supplementary Table 1 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

Characteristic marker genes for manual cluster annotations.
Supplementary Fig. S12 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

Replicate CAR T-cell studies.
Supplementary Fig. S10 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

Violin plots showing common marker expression by cluster.
Supplementary Figure 1 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 1: Validation of CD137 immunohistochemistry
Supplementary Figure S6 from Germline Mutations of Holliday Junction Resolvase Genes in Multiple Primary Malignancies Involving Lung Cancer Lead to PARP Inhibitor Sensitization
Authors: Wang Haoran , Chen Yuping , Wang Xinshu , Huang Binhao , Xie Juntao , Yin Hui , Yang Jie , Wu Jinhuan , Yuan Jian , Zhang Jie
Published: April 2024

Supplementary Figure S6: Effects of HJR-VUS on sensitivity of lung cancer cells to PARP inhibitor in H1975 cells.
Supplementary Table 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 Table 3. FH-FMI CGDB database of patients receiving HER2 directed therapy for HER2+ colorectal adenocarcinoma.
Supplementary Table 2 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 2. Clinical characteristics of patients with HER2 amplified colorectal cancer who received or did not receive anti-HER2 therapy in the DFCI Cohort. All comparisons made using Fisher’s exact test.
Table S1 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

Models Overview
Supplementary Table 4 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 4. Comparation of median densities between treatment arms according to compartments (n = 82)
Supplementary Figure 6 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 6. Immune associations with copy number variants.
Supplementary Table S2 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

Descriptions of group terms of AECIs
Data 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

AbstractPurpose:
There are no effective treatment strategies for children with highest-risk posterior fossa group A ependymoma (PFA). Chromosome 1q gains (1q+) are present in approximately 25% of newly diagnosed PFA tumors, and this number doubles at recurrence. Seventy percent of children with chromosome 1q+ PFA will die because of the tumor, highlighting the urgent need to develop new therapeutic strategies for this population.
Experimental Design:
In this study, we utilize 1q+ PFA in vitro and in vivo models to test the efficacy of combination radiation and chemotherapy in a preclinical setting.
Results:
5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental downregulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. In in vitro studies, a combination of 5FU, retinoid tretinoin (ATRA), and radiation provided the greatest reduction in cellular proliferation and greatest increase in markers of apoptosis in 1q+ PFA cell lines compared with other treatment arms. Similarly, in vivo experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA.
Conclusions:
These results are the first to identify a chromosome 1q+ specific therapy approach in 1q+ PFA. Existing phase I studies have already established single-agent pediatric safety and dosages of 5FU and ATRA, allowing for expedited clinical application as phase II trials for children with high-risk PFA.
Data 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

AbstractPurpose:
Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need.
Experimental Design:
Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non–small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink.
Results:
Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression.
Conclusions:
The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.
Abstract LT03: C/EBPα Acts as an RNA Binding Protein Essential for, and Promotes End-Stage Macrophage Differentiation
Authors: Bassal Mahmoud A. , Zhang Yanzhou , Liu Yanjing V. , Camacho Virginia , Ummarino Simone , Welner Robert S. , Tenen Daniel G
Published: April 2024

The transcription factor C/EBPα is a well characterized DNA binding protein with essential functions in controlling and regulating myeloid differentiation and lipid metabolism. Herein, we describe C/EBPα’s separate and distinct RNA binding characteristics.

Using Chromatin RNA Immunoprecipitation, we identified that C/EBPα interacts primarily with RNA introns in both HL-60 and THP-1 cells, with a preference for a palindromic GC-rich binding motif. Structural prediction in conjunction with RNA electrophoretic mobility shift assays show that C/EBPα interacts with RNA through two previously undescribed domains located towards the proteins N terminus. These domains are distinct from C/EBPα’s DNA binding b-ZIP domain which is instead located on the proteins C terminus.

Mouse bone marrow transplantation and in vitro cytokine assays reveal that C/EBPα RNA binding appears to be essential for macrophage maturation but not neutrophil differentiation. To better understand these phenotypic differences, we expanded our observations into the transcriptomic space by utilizing single-cell CITE-Seq. In line with biochemical data, notable mature cell populations were absent when the C/EBPα’s RNA binding domains are excluded from the protein. Intriguingly, differential gene expression revealed strong, selective upregulation of Lipoprotein Lipase (Lpl) in monocyte, but not neutrophil populations. It has been previously reported that dysregulation of Lpl affects bone marrow monocyte progenitor differentiation and results in dysregulated cellular mobilization from the bone marrow, a phenotype that is commonly seen in cancers such as AML. The increased abundance of monocyte and neutrophil populations in the C/EBPα RNA deletion samples is therefore suggestive that C/EBPα RNA binding is critical in regulating terminal differentiation and mobilization circuits which may become dysregulated or perturbed in diseases such as AML.

On-going analyses are investigating the RNA velocity trajectory of captured cell populations in an attempt to better understand at which stage C/EBPα RNA binding becomes essential for terminal maturation and differentiation of select cell populations. Taken together though, we demonstrate that C/EBPα is also an RNA binding protein with unique functions distinct from its DNA binding activity that is essential for monocyte maturation, differentiation and mobilization.

Citation Format: Mahmoud A. Bassal, Yanzhou Zhang, Yanjing V. Liu, Virginia Camacho, Simone Ummarino, Robert S. Welner, Daniel G Tenen. C/EBPα Acts as an RNA Binding Protein Essential for, and Promotes End-Stage Macrophage Differentiation [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT03.
Abstract LT04: Dissecting Mediator Kinase Activity in Normal Tissue Homeostasis and Cancer
Authors: Dannappel Marius , Zhu Danxi , Sun Claire , Firestein Ron
Published: April 2024

Cyclin-dependent kinase 8 (CDK8) and its paralog CDK19, collectively known as Mediator kinase, are part of the multimeric Mediator complex that fine-tune gene expression programs on multiple levels, most notably by controlling transcription factor (TF) activity at promoter- and enhancer regions as well as organising the chromatin landscape. While Mediator kinases have been predominantly studied as a therapeutic target in cancer cells, their functions in a physiologically relevant context remain poorly understood. To study in vivo functions of Mediator, we developed a comprehensive suite of genetically engineered mouse models (GEMMs), including conditional floxed alleles (Cdk8fl/fl/Cdk19fl/fl) and kinase-dead knock-ins (Cdk8D173A/fl/Cdk19D173A/fl), enabling the analysis of scaffolding and kinase-dependent functions of this critical transcriptional module. Herein, we show that Mediator kinase has distinct kinase-dependent functions in modulating homeostasis and tissue lineage specification in diverse organs. Moreover, using a proteo-genomic approach we show that the Mediator Kinase module functionally interacts with the SWI/SNF complex to mediate transcriptional output. Collectively, our work expands the understanding of how Mediator Kinase regulates tissue homeostasis and provides a framework for considering how Mediator Kinase inhibition may be effectively employed in the clinical setting.

Citation Format: Marius Dannappel, Danxi Zhu, Claire Sun, Ron Firestein. Dissecting Mediator Kinase Activity in Normal Tissue Homeostasis and 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 LT04.
Abstract LT06: Understanding the Role of Mutant TP53 in Lung Cancer Using Novel Genetically Engineered Mouse Models
Authors: Chen Tianwei , Lieschke Elizabeth , Scott Leanne , Boyd Danielle , Sutherland Kate , Strasser Andreas , Kelly Gemma
Published: April 2024

The tumour suppressor gene TP53 (Trp53 in mouse) is mutated in ~50% of human cancers and this is associated with poor therapeutic responses. Mutant TP53 protein was reported to promote tumour development in three ways: (1) loss of function (LOF) effects which abrogate normal TP53-mediated cellular processes; (2) dominant negative effects (DNE); and (3) gain of function effects (GOF) whereby mutant TP53 proteins bind to and modulate the functions of proteins that are not impacted by wildtype TP53.

Despite extensive research efforts, the relative contributions of the LOF, DNE and GOF effects of mutant TP53 in cancer are largely unknown. This project aims to understand the relative importance of these three effects of TP53 mutant proteins in the initiation and sustained expansion of lung adenocarcinoma (LUAD). We will do this by using novel LUAD mouse models with switchable Trp53 status to trigger tumorigenesis through expression of mutant Trp53 and then conversion of mutant Trp53 either back to wildtype Trp53 or into a Trp53 knock-out state when desired. In vitro and in vivo studies were performed to investigate the immediate and long-term effects of different Trp53 status on tumour growth. Our data thus far show that conversion of mutant Trp53 back to wildtype Trp53 induced cellular senescence and cell cycle arrest in LUAD cells in vitro and substantially delayed tumour progression in vivo, which improved the overall survival of mice. In contrast, conversion of mutant Trp53 into a Trp53 knock-out state did not impair the sustained growth of these tumour cells either in vitro or in vivo. This suggest that the LOF but not GOF of mutant TRP53 is critical to sustain the expansion of lung cancer. These findings have important implications for the design of novel therapeutic approaches for cancers expressing mutant TP53.

Citation Format: Tianwei Chen, Elizabeth Lieschke, Leanne Scott, Danielle Boyd, Kate Sutherland, Andreas Strasser, Gemma Kelly. Understanding the Role of Mutant TP53 in Lung Cancer Using Novel Genetically Engineered Mouse Models [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT06.
Abstract LT08: Extracellular Vesicle Surface Display Enhances the Therapeutic Efficacy and Safety Profile of Cancer Immunotherapy
Authors: Jayasinghe Migara Kavishka , Tian Dawn Liu Xiao , Lay Yock Sin , Lee Chang Yu , Yeo Brendon Zhi Jie , Van Hoang Dong , Prajogo Rebecca Carissa , Peng Boya , Pham Thach Tuan , Nguyet Le Minh Thi
Published: April 2024

As our understanding of the complex interactions between the immune system and cancer has progressed, so has the identification of novel targets and ligands that can modulate effective anti-cancer immune responses. While immunotherapy has emerged as a mainstay in cancer therapy, its efficacy has been limited by the potential for off-target toxicity against normal body cells.

In this study, we present a nanoparticle-based delivery system that enhances the signaling efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed nanoparticles released by cells, can be efficiently engineered to display multiple immunomodulatory ligands on their surface. Display of immunomodulatory ligands such as agonistic CD137 and CD40 antibodies on the EV surface significantly enhanced their therapeutic efficacy over equivalent doses of free ligands by inducing ligand multimerization, efficient receptor crosslinking and the formation of immune synapses. EVs conjugated with a complementary combination of immune stimulatory ligands and immune checkpoint inhibitors were able to shift the tumor immune milieu towards an anti-tumorigenic phenotype in a lung metastatic melanoma allograft and suppress tumor progression to a greater extent than an equivalent dose of free ligands. We also demonstrate the ability of EVs to co-deliver intraluminally loaded TLR agonists which synergize with surface displayed agonistic CD40 antibodies to induce effective anti-tumor responses and tumor regression in a metastatic autochthonous cell-derived model of PDAC. Remarkably, we also observed that EV-associated immunotherapeutics were limited in their biodistribution to the tumor microenvironment, resulting in significantly lower off-target toxicity than treatment with free ligands.

In summary, we present an EV-based delivery approach that allows the use of potent cancer immunotherapy combinations to achieve superior anti-tumor responses at significantly lower doses with less side-effects than is possible with conventional administration methods for cancer immunotherapy.

Citation Format: Migara Kavishka Jayasinghe, Dawn Liu Xiao Tian, Yock Sin Lay, Chang Yu Lee, Brendon Zhi Jie Yeo, Dong Van Hoang, Rebecca Carissa Prajogo, Boya Peng, Thach Tuan Pham, Minh Thi Nguyet Le. Extracellular Vesicle Surface Display Enhances the Therapeutic Efficacy and Safety Profile of Cancer Immunotherapy [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT08.
Abstract P15: Aberrant Non-canonical NF-κB Signalling Reprograms the Epigenome Landscape to Drive Oncogenic Transcriptomes in Multiple Myeloma
Authors: Ang Daniel A. , Carter Jean-Michel , Deka Kamalakshi , Tan Joel H.L. , Zhou Jianbiao , Chen Qingfeng , Chng Wee Joo , Harmston Nathan , Li Yinghui
Published: April 2024

Activation of the NF-κB pathway is recognized to be necessary for the survival and progression of haematological cancers including Multiple Myeloma (MM). In particular, recurrent genetic lesions resulting in the chronic induction of non-canonical NF-κB (ncNF-κB) signalling have been exclusively linked to MM. Such mutations among patients are associated with significant proliferative and metastatic advantages and have been causally linked to treatment resistance. How the constitutive activity of ncNF-κB transcription factors can support such adaptations in this common haematological malignancy has been a fundamental question in cancer. In this study, we captured the epigenomic landscape of patient-derived MM cell lines harbouring recurrent NF-κB activating mutations through perturbation of nfkb2/p52 and integrated these cis-regulatory changes with MM patient epigenome data. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.

Citation Format: Daniel A. Ang, Jean-Michel Carter, Kamalakshi Deka, Joel H.L. Tan, Jianbiao Zhou, Qingfeng Chen, Wee Joo Chng, Nathan Harmston, Yinghui Li. Aberrant Non-canonical NF-κB Signalling Reprograms the Epigenome Landscape to Drive Oncogenic Transcriptomes in Multiple Myeloma [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P15.
Abstract P20: Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma using an Advanced Human in vitro Model of the Blood-brain Barrier and Glioblastoma
Authors: Lam Maxine SY , Aw Joey JY , Tan Damien , Vijayakumar Ragavi , Lim Hui Yi Grace , Yada Swathi , Pang Qing You , Barker Nick , Tang Carol , Ang Beng Ti , Sobota Radoslaw M. , Pavesi Andrea
Published: April 2024

Glioblastoma (GBM) is the most common primary malignant brain cancer in adults, with a dismal prognosis of 15 months. This is despite decades of research and improvements in surgery and radiotherapy. Temozolomide (TMZ) is the only first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment (TME), particularly the blood-brain barrier (BBB), is unknown. Complex 3D in vitro models are able to recapitulate aspects of clinical disease such as the tumor microenvironment, such that research into the role of the TME and how it affects tumor biology and therapy resistance can be studied more easily and accurately. We have developed a complex 3D in vitro model for GBM and its surrounding BBB, that recapitulates important clinical features such as a dense tumor core with tumor cells that invade along the perivascular space; and a perfusable BBB with a physiological permeability with morphology that is altered in the presence of a tumor spheroid. We demonstrate that TMZ sensitivity decreases with increasing cancer cell spatial organization, and that the BBB can contribute to TMZ resistance. Proteomic analysis of cultured microtissues using low volume sample workflows revealed proteins linked to aggressive tumors and TMZ resistance. Notably, proteomic analysis revealed a potential role for cell cycle proteins in TMZ resistance. Preliminary data with tumor spheroids formed by patient derived GBM progenitor cells revealed a similar trend of an increase in proteins associated with tumor aggressiveness upon co-culture with a BBB. The data demonstrate the utility of combining complex physiological in vitro models and next generation mass spectrometry for interrogating the tumour microenvironment, tumor biology and accurate in vitro therapy validation.

Citation Format: Maxine SY Lam, Joey JY Aw, Damien Tan, Ragavi Vijayakumar, Hui Yi Grace Lim, Swathi Yada, Qing You Pang, Nick Barker, Carol Tang, Beng Ti Ang, Radoslaw M. Sobota, Andrea Pavesi. Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma using an Advanced Human in vitro Model of the Blood-brain Barrier and Glioblastoma [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P20.
Abstract P23: Mitochondrial Delivery of Functional Nucleic Acids for Targeting of Mitochondrial Dysfunction
Authors: Ruan Jinglin , Patzel Volker
Published: April 2024

Mitochondria is the main power supply for cellular activity and a key player for the regulation of cellular metabolism, and they contain their own DNA. Critical proteins for mitochondrial functions are not only encoded by nuclear DNA (nDNA) but also by mitochondrial DNA (mtDNA). Abnormalities in mitochondrial functions could lead to diseases including neurodegeneration, diabetes, and cancer progression.

The ability for a non-coding RNA (β2.7) of human cytomegalovirus (CMV) to localize to the host mitochondria revealed its potential to be used as a tool for mitochondria gene targeting. Using computational methods, our lab identified four thermodynamically conserved structural subdomains (D1 to D4) within the β2.7 RNA. While all four domains exhibited mitochondrial uptake potential, sub-domain D3 exhibited the highest absolute mitochondrial targeting activity and sub-domain D2 the highest activity per nucleotide. Further modifications on different sub-domain alignments found that maximum uptake efficiency was achieved by tandem repeats of 4 copies of D3 domains followed by 4 copies of D2 domains (abbreviated as D3 × 4_D2 × 4). Delivery of a GFP-coding mRNA or antisense RNA targeting mitochondrial genes mt-ATP6 and mt-ATP8 both confirmed its ability to co-deliver functional RNA into mitochondria.

To cleave and destroy mutated mitochondrial genomes for future gene therapeutic applications, we explore mitochondrial delivery of the CRISPR-Cas9 system. The mRNAs coding for the wild-type Cas9 as well as more specific Cas9 variants were fused to the mitochondrial delivery vector (D3 × 4_D2 × 4). Latest RT-qPCR on mitochondrial RNA showed delivery of Cas9 mRNA into mitochondria of HepG2 cells. Currently, we investigate co-delivery of single-guide RNA and quantify Cas9 expression in mitochondria. In an alternative approach we deliver sequences coding for functional mitochondrial protein. Examples are the mRNAs coding for mitochondrial proteins mt-ND1, -ND4 or -ND6 which are frequently mutated is patients with Leber’s hereditary optic neuropathy (LHON).

Citation Format: Jinglin Ruan, Volker Patzel. Mitochondrial Delivery of Functional Nucleic Acids for Targeting of Mitochondrial Dysfunction [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P23.
Abstract P46: Small Extracellular Vesicles from Therapy-induced Senescent TNBC Elicit Paracrine Anti-tumour Effects
Authors: Robert Matius , Jakhar Rekha , Au Bijin Veonice , Eng Gracie Wee Ling , Gao Alvin Kunyao , Chuah You Heng , Sachaphibulkij Karishma , Lim Lina Hsiu Kim , Ong Derrick Sek Tong , Lim Elaine Hsuen , Itahana Yoko , Itahana Koji , Cheong Jit Kong , Connolly John Edward , Crasta Karen Carmelina
Published: April 2024

Triple-negative breast cancers (TNBC), associated with poor prognosis and high tumour recurrence, are often treated with taxanes. However, cells may bypass treatment-induced cell death via mitotic slippage, resulting in multinucleated polyploid cells and therapy-induced senescence (TIS). TIS cancer cells represent a population of residual disease and may modulate therapy resistance and recurrence through secretion of the senescence-associated secretory phenotype (SASP). While SASP have been heavily linked with pro-tumorigenic behaviour mediated through soluble cytokines, small extracellular vesicles (sEVs) derived from TIS cancer cells represent an underappreciated aspect of the senescent tumour secretome, as its mechanistic role in mediating paracrine effects remains poorly understood.

In this study, we uncovered an unexpected role for TIS-derived sEVs within the secretome, which conferred paracrine anti-tumour activity in recipient TNBC cancer cells, in contrast to SASP that support pro-tumorigenic behaviour. SEVs profiling through mass-spectrometry revealed that DKK1, a negative regulator of WNT signalling, is enriched in TIS-derived sEVs. Further investigation into the tumour microenvironment with animal models and neoadjuvant chemo-treated patient samples revealed STING-dependent immune response. Hence, our study suggests that sEVs should be considered as distinct SASP entities within the senescent tumour secretome and provide an additional basis for combinatorial use of senomorphics with taxanes to potentially modulate senescence-associated sEVs while suppressing pro-tumorigenic SASP factors.

Citation Format: Matius Robert, Rekha Jakhar, Bijin Veonice Au, Gracie Wee Ling Eng, Alvin Kunyao Gao, You Heng Chuah, Karishma Sachaphibulkij, Lina Hsiu Kim Lim, Derrick Sek Tong Ong, Elaine Hsuen Lim, Yoko Itahana, Koji Itahana, Jit Kong Cheong, John Edward Connolly, Karen Carmelina Crasta. Small Extracellular Vesicles from Therapy-induced Senescent TNBC Elicit Paracrine Anti-tumour Effects [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P46.
Abstract P66: Off-The-Shelf Epstein Barr Virus Specific T Cells Armored with B7-H3-Targeting Chimeric Antigen Receptors Is an Effective and Safe Tumor- Agnostic Therapy For B7-H3 Positive Solid Malignancies
Authors: Yeo Siok Ping , Kua Lindsay , Tan Jin Wei , Lim Joanna Kristyn , Wong Fiona , Santos May Delos , Poh Chek Meng , XH Angeline Goh , Yu Koh Xin , Zhou Xiao Hua , R Rajarethinam , Chen Qing Feng , Her Zhisheng , Horak Ivan D , Low Lionel , Tan Kar Wai
Published: April 2024

In contrast to its limited expression in normal tissues, the B7 homolog 3 protein (B7-H3) is over-expressed in many human tumors, making it an attractive target for chimeric antigen receptor (CAR) T cell therapy.

To address the technical challenges limiting broader patient access to autologous CAR T cell therapy, we armoured Epstein-Barr Virus Specific T Cells (EBVSTs) with CARs as an off-the-shelf therapy against solid tumors. We identified and utilised a nanobody as the domain specifically targeting B7-H3 in our CAR construct to reduce the stability issues associated with scFv-based domains. Our B7H3.CAR armored EBVSTs demonstrated potent in-vitro and in-vivo activity against multiple B7-H3 positive tumor and patient-derived xenografts models. Analysis of human healthy tissues and tumors microarrays indicated that B7-H3 expression, while elevated in patient tumors, was differentially low in healthy tissues. Consistent with this, mouse T cells expressing a murine equivalent of our B7H3.CAR displayed good on-target off-tumor safety in immunocompetent mice bearing syngeneic tumors. Further in-vitro evaluation revealed that while human T, B and NK cells were unaffected by B7H3.CAR EBVSTs targeting, monocytes were readily targeted due to the upregulation of B7-H3. Consequent to this targeting and depletion of B7-H3 positive human myeloid cells which are key mediators of CRS, a low incidence of cytokine release syndrome was observed in humanized mice after B7H3.CAR EBVST treatment. Lastly, we showed that B7H3.CAR EBVSTs can target myeloid-derived suppressor cells (MDSCs) that express B7-H3 and in doing so, alleviate MDSC-driven immune suppression.

Our findings demonstrate that our nanobody-based B7H3.CAR EBVSTs present not only an effective and safe off-the-shelf approach for targeting any B7-H3-positive solid tumor while also addressing challenges that hindered the clinical development of CAR T cells in such indications.

Citation Format: Siok Ping Yeo, Lindsay Kua, Jin Wei Tan, Joanna Kristyn Lim, Fiona Wong, May Delos Santos, Chek Meng Poh, Angeline Goh XH, Xin Yu Koh, Xiao Hua Zhou, Rajarethinam R, Qing Feng Chen, Zhisheng Her, Ivan D Horak, Lionel Low, Kar Wai Tan. Off-The-Shelf Epstein Barr Virus Specific T Cells Armored with B7-H3-Targeting Chimeric Antigen Receptors Is an Effective and Safe Tumor- Agnostic Therapy For B7-H3 Positive Solid Malignancies [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P66.
Abstract P69: Immune Landscape of BRCA1/2 -mutated Breast and Ovarian Cancers in an Asian Cohort
Authors: Chong Siao Ting , Wee Felicia , Ye Jiang Feng , Joseph Craig , Lim Xinru , Neo Zhen Wei , Lee Justina Nadia , Ishak Nur Diana Binte , Toh Ming Ren , Chew Ee Ling , Yeo Claresta , Chan Sock Hoai , Lim Jeffrey , Yeong Joe , Ngeow Joanne
Published: April 2024

Background: The majority of hereditary breast and ovarian cancers (HBOC) harbor defects in the homologous recombination (HR) DNA repair pathway, such as BRCA1 and BRCA2 mutations, which may influence the response to immune checkpoint blockade (ICB) therapy. Recent clinical trials combining poly-ADP ribose inhibitors and ICB therapy in advanced breast and ovarian cancer have shown promising results. This Asian cohort study set out to determine if immune phenotype, specifically the PD-1/PD-L1 axis, was associated with germline BRCA status in advanced breast and ovarian cancer patients and to develop novel biomarkers of HR deficiency to stratify patients for clinical management.

Methods: Tissue microarrays of ovarian tumors and breast tumors were analyzed by multiplex immunohistochemistry (mIHC) to detect the expression of immune markers (CD68, CD8, PD-L1, PD-1) and HR markers (DNA polymerase theta, FANCD2, RAD51, γH2AX, phospho-ATR). The results were used to build a prediction model for BRCA using backward stepwise logistic regression analysis. In addition, we investigated immune infiltration in tumors and performed immune phenotyping on peripheral blood mononuclear cells in a subset of patients.

Results: We identified potential BRCA1/2 predictors by mIHC, namely RAD51 and PD-L1 263 for ovarian tumors and FANCD2 and phospho-ATR for breast tumors. The area under the curve was 0.770 (95% confidence interval [CI]: 0.564, 0.977) in ovarian cancer patients and 0.841 (95% CI: 0.682, 0.999) in breast cancer patients. In addition, the proportion of tumor-infiltrating CD68+PD-L1+ macrophages was significantly upregulated in BRCA1-mutated tumors, while the levels of PD-1 in circulating central memory CD8+ T cells were higher in breast cancer patients with germline BRCA2 mutations, compared with non-BRCA.

Conclusion: This study provides evidence of the association of the PD-1/PD-L1 axis with germline BRCA status in HBOC, which may aid clinical management.

Citation Format: Siao Ting Chong, Felicia Wee, Jiang Feng Ye, Craig Joseph, Xinru Lim, Zhen Wei Neo, Justina Nadia Lee, Nur Diana Binte Ishak, Ming Ren Toh, Ee Ling Chew, Claresta Yeo, Sock Hoai Chan, Jeffrey Lim, Joe Yeong, Joanne Ngeow. Immune Landscape of BRCA1/2 -mutated Breast and Ovarian Cancers in an Asian Cohort [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P69.
Figure S4 from The Cross-talk Between Intestinal Microbiota and MDSCs Fuels Colitis-associated Cancer Development
Authors: Ashkenazi-Preiser Hadas , Reuven Or , Uzan-Yulzari Atara , Komisarov Sharon , Cirkin Roy , Turjeman Sondra , Even Carmel , Twaik Nira , Ben-Meir Kerem , Mikula Ivan , Cohen-Daniel Leonor , Meirow Yaron , Pikarsky Eli , Louzoun Yoram , Koren Omry , Baniyash Michal
Published: April 2024

Supplementary Figure S4 shows the microbiota composition in the pools from CAC and control mice used for FMT and the changes in relative abundance of unique bacteria following disease progression.
Epidemiology, Characteristics of Disease, and Unmet Needs of Patients with Generalized Pustular Psoriasis: A Large Italian Delphi Consensus
Authors: Prignano Francesca , Atzori Laura , Bellinato Francesco , Damiani Giovanni , Galeone Carlotta , Mariani Paolo , Potenza Concetta , Scopinaro Annalisa , Piaserico Stefano , Fabbrocini Gabriella ,   on behalf of the Italian Delphi GPP Group
Published: April 2024

Introduction: Generalized pustular psoriasis (GPP) is a rare and chronic, debilitating skin condition characterized, in its acute flare phase, by clinically severe and potentially life-threatening systemic manifestations. Data on GPP are still scanty, particularly in Europe and at a national level. The aim of this study was to provide expert indications on several disease-related and patient-related aspects of GPP, with specific focus to the Italian context. Methods: We conducted an iterative eDelphi study following the recommended criteria for reporting methods and results. After a thorough bibliographic review aimed to identify unknown or controversial issues in GPP, the following areas were investigated through a few specific questions/statements for each area: (1) disease epidemiology; (2) disease characteristics, with specific interest toward GPP flares; (3) diagnosis and diagnostic delay; (4) GPP treatment; (5) GPP patient journey and use of healthcare resources in Italy; (6) unmet needs and quality of life. An Executive Board of 9 principal investigators revised and approved the topics to be examined and overviewed the whole project. A total of 35 experts from different Italian areas, including 34 board-certified Italian dermatologists and 1 representative of patients’ associations, took part in the study. Results: A high agreement in responses from Italian experts emerged during two eDelphi iterations on – among several other aspects – GPP prevalence and incidence in Italy, use of European Rare and Severe Psoriasis Expert Network diagnostic criteria, flare frequency and duration, best diagnostic and care pathway, and main unmet needs of Italian patients. On the other hand, a broad spectrum of treatments (of different drug classes) was reported both in the acute and chronic phases of GPP, and no consensus on the issue was thus achieved. Conclusions: Consensus findings from this Delphi study of GPP experts may be useful to fill gaps of knowledge and improve awareness of this rare disease, as well as to help clinical and public health management of GPP in Italy.