bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table S1 from Phase I Study of the Liposomal Formulation of Eribulin (E7389-LF): Results from the Advanced Gastric Cancer Expansion Cohort
Authors: Shitara Kohei , Hirao Motohiro , Iwasa Satoru , Oshima Takashi , Komatsu Yoshito , Kawazoe Akihito , Sato Yasuyoshi , Hamakawa Takuya , Yonemori Kan , Machida Nozomu , Yuki Satoshi , Suzuki Takuya , Okumura Shiori , Takase Takao , Semba Taro , Zimmermann Bob , Teng Angela , Yamaguchi Kensei
Published: April 2023

Supplementary Table S1 shows select patient baseline characteristics by time from last anti-PD-1 therapy.
Supplementary Figure S3 from Phase I Study of the Liposomal Formulation of Eribulin (E7389-LF): Results from the Advanced Gastric Cancer Expansion Cohort
Authors: Shitara Kohei , Hirao Motohiro , Iwasa Satoru , Oshima Takashi , Komatsu Yoshito , Kawazoe Akihito , Sato Yasuyoshi , Hamakawa Takuya , Yonemori Kan , Machida Nozomu , Yuki Satoshi , Suzuki Takuya , Okumura Shiori , Takase Takao , Semba Taro , Zimmermann Bob , Teng Angela , Yamaguchi Kensei
Published: April 2023

Supplementary Figure S3 shows the neutrophil count at nadir of patients who received peg-GCSF (A) and those who did not receive peg-GCSF (B).
Figure S6 from MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors
Authors: Borcherding Dana C. , Amin Neha V. , He Kevin , Zhang Xiaochun , Lyu Yang , Dehner Carina , Bhatia Himanshi , Gothra Angad , Daud Layla , Ruminski Peter , Pratilas Christine A. , Pollard Kai , Sundby Taylor , Widemann Brigitte C. , Hirbe Angela C.
Published: April 2023

Supplemental Fig.S6. TYK2 inhibition decreases expression of STAT3 target genes and increases expression of genes in the MEK/MAPK signaling cascade in MPNST cells.
Figure S3 from MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors
Authors: Borcherding Dana C. , Amin Neha V. , He Kevin , Zhang Xiaochun , Lyu Yang , Dehner Carina , Bhatia Himanshi , Gothra Angad , Daud Layla , Ruminski Peter , Pratilas Christine A. , Pollard Kai , Sundby Taylor , Widemann Brigitte C. , Hirbe Angela C.
Published: April 2023

Supplemental Fig.S3. Genetic knockout of TYK2 blocks the effects of TYK2 inhibitors on proliferation in JW23.3 cells.
Supplementary Data TS2 from Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance
Authors: Klümper Niklas , Ralser Damian J. , Ellinger Jörg , Roghmann Florian , Albrecht Julia , Below Eduard , Alajati Abdullah , Sikic Danijel , Breyer Johannes , Bolenz Christian , Zengerling Friedemann , Erben Philipp , Schwamborn Kristina , Wirtz Ralph M. , Horn Thomas , Nagy Dora , Toma Marieta , Kristiansen Glen , Büttner Thomas , Hahn Oliver , Grünwald Viktor , Darr Christopher , Erne Eva , Rausch Steffen , Bedke Jens , Schlack Katrin , Abbas Mahmoud , Zschäbitz Stefanie , Schwab Constantin , Mustea Alexander , Adam Patrick , Manseck Andreas , Wullich Bernd , Ritter Manuel , Hartmann Arndt , Gschwend Jürgen , Weichert Wilko , Erlmeier Franziska , Hölzel Michael , Eckstein Markus
Published: April 2023

Supplementary Table 2. Baseline characteristics of the multicenter EV cohort.
Supplementary Figure S1 from Impact of Genomic and Clinical Factors on Outcome of Children ≥18 Months of Age with Stage 3 Neuroblastoma with Unfavorable Histology and without MYCN Amplification: A Children's Oncology Group (COG) Report
Authors: Pinto Navin , Naranjo Arlene , Ding Xiangming , Zhang Fan F. , Hibbitts Emily , Kennedy Rebekah , Tibbetts Rachelle , Wong-Michalak Shannon , Craig David W. , Manojlovic Zarko , Hogarty Michael D. , Kreissman Susan , Bagatell Rochelle , Irwin Meredith S. , Park Julie R. , Asgharzadeh Shahab
Published: April 2023

Supplemental Figure S1 Outcome by Chromosome 5 Status. (A) EFS and (B) OS by Chromosome 5 status
Figure S1 from Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance
Authors: Klümper Niklas , Ralser Damian J. , Ellinger Jörg , Roghmann Florian , Albrecht Julia , Below Eduard , Alajati Abdullah , Sikic Danijel , Breyer Johannes , Bolenz Christian , Zengerling Friedemann , Erben Philipp , Schwamborn Kristina , Wirtz Ralph M. , Horn Thomas , Nagy Dora , Toma Marieta , Kristiansen Glen , Büttner Thomas , Hahn Oliver , Grünwald Viktor , Darr Christopher , Erne Eva , Rausch Steffen , Bedke Jens , Schlack Katrin , Abbas Mahmoud , Zschäbitz Stefanie , Schwab Constantin , Mustea Alexander , Adam Patrick , Manseck Andreas , Wullich Bernd , Ritter Manuel , Hartmann Arndt , Gschwend Jürgen , Weichert Wilko , Erlmeier Franziska , Hölzel Michael , Eckstein Markus
Published: April 2023

Supplementary Figure 1. Expression of membranous NECTIN-4 in UC histology subtypes in PRIM (A) and MET (B). (C) depicts differential NECTIN-4 expression during metastatic spread. Intergroup comparison was calculated by non-parametric Kruskal-Wallis test.
Supplemental Table S1 from [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-Inhibitor Drug-Target Engagement as a Biomarker of Response in Ovarian Cancer, a Pilot Study
Authors: Pantel Austin R. , Gitto Sarah B. , Makvandi Mehran , Kim Hyoung , Medvedv Sergey , Weeks Joanna K. , Torigian Drew A. , Hsieh Chia-Ju , Ferman Benjamin , Latif Nawar A. , Tanyi Janos L. , Martin Lainie P. , Lanzo Shannon M. , Liu Fang , Cao Quy , Mills Gordon B. , Doot Robert K. , Mankoff David A. , Mach Robert H. , Lin Lilie L. , Simpkins Fiona
Published: April 2023

Subject and Tumor Genomic Summary.
Figure S2 from Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive Iodine Therapy
Authors: Boucai Laura , Saqcena Mahesh , Kuo Fengshen , Grewal Ravinder K. , Socci Nicholas , Knauf Jeffrey A. , Krishnamoorthy Gnana P. , Ryder Mabel , Ho Alan L. , Ghossein Ronald A. , Morris Luc G.T. , Seshan Venkatraman , Fagin James A.
Published: April 2023

Supplementary Figure S2.
Figure S1 from Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive Iodine Therapy
Authors: Boucai Laura , Saqcena Mahesh , Kuo Fengshen , Grewal Ravinder K. , Socci Nicholas , Knauf Jeffrey A. , Krishnamoorthy Gnana P. , Ryder Mabel , Ho Alan L. , Ghossein Ronald A. , Morris Luc G.T. , Seshan Venkatraman , Fagin James A.
Published: April 2023

Supplementary Figure S1.
Supplemental Figure S4 from [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-Inhibitor Drug-Target Engagement as a Biomarker of Response in Ovarian Cancer, a Pilot Study
Authors: Pantel Austin R. , Gitto Sarah B. , Makvandi Mehran , Kim Hyoung , Medvedv Sergey , Weeks Joanna K. , Torigian Drew A. , Hsieh Chia-Ju , Ferman Benjamin , Latif Nawar A. , Tanyi Janos L. , Martin Lainie P. , Lanzo Shannon M. , Liu Fang , Cao Quy , Mills Gordon B. , Doot Robert K. , Mankoff David A. , Mach Robert H. , Lin Lilie L. , Simpkins Fiona
Published: April 2023

Baseline [18F]FTT imaging correlates.
Supplemental Figure S3 from [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-Inhibitor Drug-Target Engagement as a Biomarker of Response in Ovarian Cancer, a Pilot Study
Authors: Pantel Austin R. , Gitto Sarah B. , Makvandi Mehran , Kim Hyoung , Medvedv Sergey , Weeks Joanna K. , Torigian Drew A. , Hsieh Chia-Ju , Ferman Benjamin , Latif Nawar A. , Tanyi Janos L. , Martin Lainie P. , Lanzo Shannon M. , Liu Fang , Cao Quy , Mills Gordon B. , Doot Robert K. , Mankoff David A. , Mach Robert H. , Lin Lilie L. , Simpkins Fiona
Published: April 2023

Anatomic imaging corelates.
Figure S1 from Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases
Authors: Jenkins Sarah , Zhang Wei , Steinberg Seth M. , Nousome Darryl , Houston Nicole , Wu Xiaolin , Armstrong Terri S. , Burton Eric , Smart Dee Dee , Shah Ritu , Peer Cody J. , Mozarsky Brett , Arisa Oluwatobi , Figg William D. , Mendoza Tito R. , Vera Elizabeth , Brastianos Priscilla , Carter Scott , Gilbert Mark R. , Anders Carey K. , Connolly Roisín M. , Tweed Carol , Smith Karen L. , Khan Imran , Lipkowitz Stanley , Steeg Patricia S. , Zimmer Alexandra S.
Published: April 2023

Supplemental Fig. 1. Neurocognitive assessments comparing patients presenting progression versus no progression.
Supplementary Table S1 from Cell-Free Urine and Plasma DNA Mutational Analysis Predicts Neoadjuvant Chemotherapy Response and Outcome in Patients with Muscle-Invasive Bladder Cancer
Authors: Christensen Emil , Nordentoft Iver , Birkenkamp-Demtröder Karin , Elbæk Sara K. , Lindskrog Sia V. , Taber Ann , Andreasen Tine G. , Strandgaard Trine , Knudsen Michael , Lamy Philippe , Agerbæk Mads , Jensen Jørgen B. , Dyrskjøt Lars
Published: April 2023

Summarized metrics for WES data
Supplementary Table S5 from Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Kumar Ashwin S. , Rosario Spencer R. , Gu Liqun , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Fernandez-Del Castillo Carlos , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: April 2023

Longitudinal analysis of circulating biomarkers in the plasma of treated patients.
Supplementary Table S3 from Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Kumar Ashwin S. , Rosario Spencer R. , Gu Liqun , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Fernandez-Del Castillo Carlos , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: April 2023

Losartan+FFX+CRT and FFX+CRT gene correlation with overall survival (OS).
Supplementary materials and methods 1 from Single-Cell Transcriptomics Reveals Immune Reconstitution in Patients with R/R T-ALL/LBL Treated with Donor-Derived CD7 CAR-T Therapy
Authors: Chen Wei , Shi Hui , Liu Zhuojun , Yang Fan , Liu Jia , Zhang Leqiang , Wu Yajin , Xia Yuanshi , Ou Yuxuan , Li Ruiting , Zhang Ting , Zhang Jiecheng , Ke Xiaoyan , Hu Kai , Yu Jian
Published: April 2023

Supplementary materials and methods
Supplementary Figure S5 from Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Kumar Ashwin S. , Rosario Spencer R. , Gu Liqun , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Fernandez-Del Castillo Carlos , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: April 2023

Immunofluorescence staining of residual PDAC in pathological responders and non-responders in FFX+CRT and losartan+FFX+CRT.
Supplementary Figure S3 from Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Kumar Ashwin S. , Rosario Spencer R. , Gu Liqun , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Fernandez-Del Castillo Carlos , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: April 2023

Effect of losartan+FFX+CRT and FFX+CRT on genes involved in angiogenesis and the migration and maturation of DCs.
Supplementary Table S6 from The Oral PI3Kδ Inhibitor Linperlisib for the Treatment of Relapsed and/or Refractory Follicular Lymphoma: A Phase II, Single-Arm, Open-Label Clinical Trial
Authors: Wang Tingyu , Sun Xiuhua , Qiu Lihua , Su Hang , Cao Junning , Li Zhiming , Song Yuqin , Zhang Li , Li Dengju , Wu Huijing , Zhang Wei , Li Junmin , Zhou Keshu , Zhou Hui , Yang Yu , Li Zhifeng , Cen Hong , Cai Zhen , Zhang Zhihui , Fu Weijun , Jin Jie , Li Fei , Wu Weixin , Gu Xuekui , Zhu Weiliang , Liu Lihong , Li Zengjun , Yi Shuhua , Bao Hanying , Xu Zusheng , Qiu Lugui
Published: April 2023

Comparison of PI3K inhibitor toxicities and their efficacies for relapsed and/or refractory indolent lymphoma treatments
Supplementary Figure S4 from Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer
Authors: Denkert Carsten , Lambertini Chiara , Fasching Peter A. , Pogue-Geile Katherine L. , Mano Max S. , Untch Michael , Wolmark Norman , Huang Chiun-Sheng , Loibl Sibylle , Mamounas Eleftherios P. , Geyer Charles E. , Lucas Peter C. , Boulet Thomas , Song Chunyan , Lewis Gail D. , Nowicka Malgorzata , de Haas Sanne , Basik Mark
Published: April 2023

Comparison of IDFS outcomes in the ITT population compared to the (A) RNA-evaluable population (REP) (including pre- and post-NAT surgical samples) and in patients with (B) pre-NAT REP samples (left) or post-NAT surgical REP samples (right). HER2, human epidermal growth factor receptor 2; IDFS, invasive disease-free survival; IHC, immunohistochemistry; ITT, intent-to-treat; NAT, neoadjuvant therapy; T-DM1, trastuzumab emtansine.
Supplementary Table S4 from The Oral PI3Kδ Inhibitor Linperlisib for the Treatment of Relapsed and/or Refractory Follicular Lymphoma: A Phase II, Single-Arm, Open-Label Clinical Trial
Authors: Wang Tingyu , Sun Xiuhua , Qiu Lihua , Su Hang , Cao Junning , Li Zhiming , Song Yuqin , Zhang Li , Li Dengju , Wu Huijing , Zhang Wei , Li Junmin , Zhou Keshu , Zhou Hui , Yang Yu , Li Zhifeng , Cen Hong , Cai Zhen , Zhang Zhihui , Fu Weijun , Jin Jie , Li Fei , Wu Weixin , Gu Xuekui , Zhu Weiliang , Liu Lihong , Li Zengjun , Yi Shuhua , Bao Hanying , Xu Zusheng , Qiu Lugui
Published: April 2023

Investigator-assessed response outcomes (FAS)
Supplementary Figure S3 from The Oral PI3Kδ Inhibitor Linperlisib for the Treatment of Relapsed and/or Refractory Follicular Lymphoma: A Phase II, Single-Arm, Open-Label Clinical Trial
Authors: Wang Tingyu , Sun Xiuhua , Qiu Lihua , Su Hang , Cao Junning , Li Zhiming , Song Yuqin , Zhang Li , Li Dengju , Wu Huijing , Zhang Wei , Li Junmin , Zhou Keshu , Zhou Hui , Yang Yu , Li Zhifeng , Cen Hong , Cai Zhen , Zhang Zhihui , Fu Weijun , Jin Jie , Li Fei , Wu Weixin , Gu Xuekui , Zhu Weiliang , Liu Lihong , Li Zengjun , Yi Shuhua , Bao Hanying , Xu Zusheng , Qiu Lugui
Published: April 2023

Comparison of the concentrations of serum markers measured in patients with and without a response to linperlisib
Supplementary Figure S8 from Better than RECIST and Faster than iRECIST: Defining the Immunotherapy Progression Decision Score to Better Manage Progressive Tumors on Immunotherapy
Authors: Belkouchi Younes , Talbot Hugues , Lassau Nathalie , Lawrance Littisha , Farhane Siham , Feki-Mkaouar Rahma , Hadchiti Joya , Dawi Lama , Vibert Julien , Cournède Paul-Henry , Cousteix Clara , Mazza Camille , Kind Michele , Italiano Antoine , Marabelle Aurelien , Ammari Samy , Champiat Stephane
Published: April 2023

Effect of the removal of each criterion on the accuracy of a multinomial logistic regression fit to predict the category of each patient. The minimal losses are underlined, and the maximum are written in bold.
Supplementary Figure S7 from Better than RECIST and Faster than iRECIST: Defining the Immunotherapy Progression Decision Score to Better Manage Progressive Tumors on Immunotherapy
Authors: Belkouchi Younes , Talbot Hugues , Lassau Nathalie , Lawrance Littisha , Farhane Siham , Feki-Mkaouar Rahma , Hadchiti Joya , Dawi Lama , Vibert Julien , Cournède Paul-Henry , Cousteix Clara , Mazza Camille , Kind Michele , Italiano Antoine , Marabelle Aurelien , Ammari Samy , Champiat Stephane
Published: April 2023

InterpretML Overall Importance using Explainable Boosting Machines (EBM). The mean absolute score reflects the overall importance assigned by the model to predict each patient's category. All features appear important, with the number of organs affected by metastasis and the emergence of new lesions as the most important ones
Supplementary Figure S2 from Better than RECIST and Faster than iRECIST: Defining the Immunotherapy Progression Decision Score to Better Manage Progressive Tumors on Immunotherapy
Authors: Belkouchi Younes , Talbot Hugues , Lassau Nathalie , Lawrance Littisha , Farhane Siham , Feki-Mkaouar Rahma , Hadchiti Joya , Dawi Lama , Vibert Julien , Cournède Paul-Henry , Cousteix Clara , Mazza Camille , Kind Michele , Italiano Antoine , Marabelle Aurelien , Ammari Samy , Champiat Stephane
Published: April 2023

Correlation tables of our criteria. Bottom left are spearman coefficients, top right are Phi_K coefficients.
Supplementary Figure S10 from Better than RECIST and Faster than iRECIST: Defining the Immunotherapy Progression Decision Score to Better Manage Progressive Tumors on Immunotherapy
Authors: Belkouchi Younes , Talbot Hugues , Lassau Nathalie , Lawrance Littisha , Farhane Siham , Feki-Mkaouar Rahma , Hadchiti Joya , Dawi Lama , Vibert Julien , Cournède Paul-Henry , Cousteix Clara , Mazza Camille , Kind Michele , Italiano Antoine , Marabelle Aurelien , Ammari Samy , Champiat Stephane
Published: April 2023

Log hazard ratios (HR) computed by cox model. The variables studied were: GRIm, RMH, NLR BL & the iPD score. The only significant variable was the iPD score (HR = 2, p < 0.005).
Supplementary Figure S5 from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh B. , Piscitello Desiree , Rajendra Eeson , Stockley Martin L. , Boulton Simon J. , Hammond Ester M. , Heald Robert A. , Smith Graeme C.M. , Robinson Helen M.R. , Higgins Geoff S.
Published: April 2023

Accompanies Figure 4 (Characterization of ART899 as a specific and potent Polθ inhibitor with improved stability)
Supplementary Data DS1 from A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer
Authors: Halford Sarah , Veal Gareth J. , Wedge Stephen R. , Payne Geoffrey S. , Bacon Chris M. , Sloan Philip , Dragoni Ilaria , Heinzmann Kathrin , Potter Sarah , Salisbury Becky M. , Chénard-Poirier Maxime , Greystoke Alastair , Howell Elizabeth C. , Innes William A. , Morris Karen , Plummer Chris , Rata Mihaela , Petrides George , Keun Hector C. , Banerji Udai , Plummer Ruth
Published: April 2023

supplementary data: Methods, tables, figure.
Supplementary Figure S3 from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh B. , Piscitello Desiree , Rajendra Eeson , Stockley Martin L. , Boulton Simon J. , Hammond Ester M. , Heald Robert A. , Smith Graeme C.M. , Robinson Helen M.R. , Higgins Geoff S.
Published: April 2023

Accompanies Figure 2 (ART558 treatment leads to increased residual IR-induced DNA damage foci)
Supplementary Table S2 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

Descriptive analysis of the clinical characteristics of the two main clusters resulted from the unsupervised hierarchical clustering of fifty-one differentially expressed genes in extreme responders to palbociclib plus ET
Supplementary Table S9 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

Demographic, radiological and surgical characteristics of IPMN patients.
Supplementary Figure S9 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

Drug combination studies in MCF7, T47D and T47D-FPR cells
Supplementary Table S7 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

List of extra miRNA classifiers.
Supplementary Figure S7 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

Generation and characterization of ER+ breast cancer cell lines resistant to palbociclib alone or in combination with fulvestrant
Supplementary Figure S5 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

Analysis of gene expression associated with treatment benefit
Supplementary Table S2 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

List of antibody target proteins.
Supplementary Figure S3 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

Diagnostic performance obtained by four independent repetitions of creating a SVM classifier on the basis of the clinical parameters recorded for the 302 IPMN patients.
Supplementary Figure S2 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

Diagnostic performance of serum miRNA panels.
Supplementary Figure S1 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

CONSORT diagram of the study
Supplementary figure 3: Cytokines and Chemokines from Concurrent Definitive Immunoradiotherapy for Patients with Stage III–IV Head and Neck Cancer and Cisplatin Contraindication
Authors: Weiss Jared , Sheth Siddharth , Deal Allison M. , Grilley Olson Juneko E. , Patel Samip , Hackman Trevor G. , Blumberg Jeffrey M. , Galloway Thomas J. , Patel Shetal , Zanation Adam M. , Shen Colette J. , Hayes D. Neil , Hilliard Christopher , Mehra Ranee , McKinnon Karen P. , Wang Hsing-Hui , Weissler Mark Christian , Bauman Jessica R. , Chera Bhishamjit S. , Vincent Benjamin G.
Published: April 2023

Cytokines and Chemokines
Data from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

AbstractPurpose:
Intraductal papillary mucinous neoplasm (IPMN) is a precursor of pancreatic ductal adenocarcinoma. Low-grade dysplasia has a relatively good prognosis, whereas high-grade dysplasia and IPMN invasive carcinoma require surgical intervention. However, diagnostic distinction is difficult. We aimed to identify biomarkers in peripheral blood for accurate discrimination.
Experimental Design:
Sera were obtained from 302 patients with IPMNs and 88 healthy donors. For protein biomarkers, serum samples were analyzed on microarrays made of 2,977 antibodies. A support vector machine (SVM) algorithm was applied to define classifiers, which were validated on a separate sample set. For microRNA biomarkers, a PCR-based screen was performed for discovery. Biomarker candidates confirmed by quantitative PCR were used to train SVM classifiers, followed by validation in a different sample set. Finally, a combined SVM classifier was established entirely independent of the earlier analyses, again using different samples for training and validation.
Results:
Panels of 26 proteins or seven microRNAs could distinguish high- and low-risk IPMN with an AUC value of 95% and 94%, respectively. Upon combination, a panel of five proteins and three miRNAs yielded an AUC of 97%. These values were much better than those obtained in the same patient cohort by using the guideline criteria for discrimination. In addition, accurate discrimination was achieved between other patient subgroups.
Conclusions:
Protein and microRNA biomarkers in blood allow precise diagnosis and risk stratification of IPMN cases, which should improve patient management and thus the prognosis of IPMN patients.

See related commentary by Löhr and Pantel, p. 1387
Data from Phase II Study of Palbociclib (PD-0332991) in CCND1, 2, or 3 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1B
Authors: Clark Amy S. , Hong Fangxin , Finn Richard S. , DeMichele Angela M. , Mitchell Edith P. , Zwiebel James , Arnaldez Fernanda I. , Gray Robert J. , Wang Victoria , McShane Lisa M. , Rubinstein Larry V. , Patton David , Williams P. Mickey , Hamilton Stanley R. , Copur Mehmet S. , Kasbari Samer S. , Thind Ravneet , Conley Barbara A. , Arteaga Carlos L. , O'Dwyer Peter J. , Harris Lyndsay N. , Chen Alice P. , Flaherty Keith T.
Published: April 2023

AbstractPurpose:
Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3.
Patients and Methods:
Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles.
Results:
Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%).
Conclusions:
Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification.
Data from Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance in EGFR-Mutant Lung Adenocarcinomas
Authors: Elkrief Arielle , Makhnin Alex , Moses Khadeja A. , Ahn Linda S. , Preeshagul Isabel R. , Iqbal Afsheen N. , Hayes Sara A. , Plodkowski Andrew J. , Paik Paul K. , Ladanyi Marc , Kris Mark G. , Riely Gregory J. , Michor Franziska , Yu Helena A.
Published: April 2023

AbstractPurpose:
Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance.
Patients and Methods:
We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation.
Results:
Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%–88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%–58%).
Conclusions:
We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.
Data from Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases
Authors: Jenkins Sarah , Zhang Wei , Steinberg Seth M. , Nousome Darryl , Houston Nicole , Wu Xiaolin , Armstrong Terri S. , Burton Eric , Smart Dee Dee , Shah Ritu , Peer Cody J. , Mozarsky Brett , Arisa Oluwatobi , Figg William D. , Mendoza Tito R. , Vera Elizabeth , Brastianos Priscilla , Carter Scott , Gilbert Mark R. , Anders Carey K. , Connolly Roisín M. , Tweed Carol , Smith Karen L. , Khan Imran , Lipkowitz Stanley , Steeg Patricia S. , Zimmer Alexandra S.
Published: April 2023

AbstractPurpose:
Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in patients with HER2+ breast cancer.
Patients and Methods:
Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of whole brain radiation therapy (WBRT), stereotactic radiosurgery, and/or surgery. Standard doses of T-DM1 were administered intravenously every 21 days (3.6 mg/kg) and TMZ was given orally daily in a 3+3 phase I dose escalation design at 30, 40, or 50 mg/m2, continuously. DLT period was one 21-day cycle. Primary endpoint was safety and recommended phase II dose. Symptom questionnaires, brain MRI, and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing was performed on patients’ plasma and CSF.
Results:
Twelve women enrolled, nine (75%) with prior SRS therapy and three (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12), and decreased CD4 (6/12), requiring pentamidine for Pneumocystis jirovecii pneumonia prophylaxis. No DLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 6 of 12 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6 m (2.8–33.9); only 2 patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome.
Conclusions:
Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2+ brain metastases.
Data from The Oral PI3Kδ Inhibitor Linperlisib for the Treatment of Relapsed and/or Refractory Follicular Lymphoma: A Phase II, Single-Arm, Open-Label Clinical Trial
Authors: Wang Tingyu , Sun Xiuhua , Qiu Lihua , Su Hang , Cao Junning , Li Zhiming , Song Yuqin , Zhang Li , Li Dengju , Wu Huijing , Zhang Wei , Li Junmin , Zhou Keshu , Zhou Hui , Yang Yu , Li Zhifeng , Cen Hong , Cai Zhen , Zhang Zhihui , Fu Weijun , Jin Jie , Li Fei , Wu Weixin , Gu Xuekui , Zhu Weiliang , Liu Lihong , Li Zengjun , Yi Shuhua , Bao Hanying , Xu Zusheng , Qiu Lugui
Published: April 2023

AbstractPurpose:
To investigate the efficacy and safety of the novel orally active PI3Kδ inhibitor in relapsed and/or refractory patients with follicular lymphoma (FL) who had received at least two prior systemic treatments.
Patients and Methods:
Histologically confirmed relapsed and/or refractory patients with FL with disease progression after receiving second-line or greater systemic therapy were enrolled. Linperlisib was administered at 80 mg every day, orally in a 28-day cycle until disease progression or intolerable toxicity occurred. The primary outcome for the study was the objective response rate (ORR), with secondary outcomes including the duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate, and drug safety profile.
Results:
Of 114 screened relapsed and/or refractory patients with FL, 84 were enrolled in the full analysis set (FAS). The ORR of the 84 FAS patients was 79.8% [95% confidence interval (CI), 69.6–87.8, 67 patients], with 13 patients (15.5%) achieving a complete response and 54 patients (64.3%) with a partial response. The median DOR was 12.3 months (95% CI, 9.3–15.9). The median PFS was 13.4 months (95% CI, 11.1–16.7). The 12-month OS rate was 91.4% (95% CI, 82.7–95.8) and a median OS not reached by 42 months. The most frequent (>3%) treatment-related adverse events Grade ≥3 were infectious pneumonia (19.0%), neutropenia (15.5%), decreased lymphocyte count (4.8%), decreased leukocyte count (4.8%), increased lipase (3.6%), decreased platelet count (3.6%), hypertriglyceridemia (3.6%), and interstitial lung disease (3.6%).
Conclusions:
Linperlisib demonstrated compelling clinical activity and manageable tolerability for relapsed and/or refractory patients with FL who had received at least two prior systemic therapies.
Data from Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101)
Authors: Carmagnani Pestana Roberto , Moyers Justin T. , Roszik Jason , Sen Shiraj , Hong David S. , Naing Aung , Herzog Cynthia E. , Fu Siqing , Piha-Paul Sarina A. , Rodon Jordi , Yap Timothy A. , Karp Daniel D. , Tsimberidou Apostolia M. , Pant Shubham , Zarzour Maria A. , Ratan Ravin , Ravi Vinod , Benjamin Robert S. , Lazar Alexander J. , Wang Wei-Lien , Daw Najat , Gill Jonathan B. , Harrison Douglas J. , Lewis Valerae O. , Roland Christina L. , Patel Shreyaskumar R. , Livingston J. Andrew , Somaiah Neeta , Ludwig Joseph A. , Conley Anthony P. , Hamerschlak Nelson , Gorlick Richard , Meric-Bernstam Funda , Subbiah Vivek
Published: April 2023

AbstractPurpose:
Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma.
Experimental Design:
In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021.
Results:
Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, 60 gastrointestinal stromal tumor (GIST); median of three prior lines of therapy]. Most common subtypes were leiomyosarcoma (17.2%), liposarcoma (14.0%), and GIST (10.2%). Molecular testing was available for 511 patients (87.1%); 221 patients (37.6%) were treated in matched trials. Overall response rate was 13.1% matched compared with 4.9% in unmatched (P < 0.001); the clinical benefit rate at 6 months was 43.9% vs. 19.9% (P < 0.001). Progression-free survival was longer for patients in matched trials (median, 5.5 vs. 2.4 months; P < 0.001), and overall survival was also superior for patients in matched trials (median, 21.5 vs. 12.3 months; P < 0.001). The benefit of enrollment in matched trials was maintained when patients with GIST were excluded from the analysis.
Conclusions:
Enrollment in biomarker-matched early-phase trials is associated with improved outcomes in heavily pretreated patients with metastatic sarcoma. Molecular testing of tumors from patients with advanced sarcoma and enrollment in matched trials is a reasonable therapeutic strategy.
Abstract CT238: Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor
Authors: Yoo Stephen Sunghan , Lee Soohyeon , Shin Sangjoon , Jung Hyunjin , Hong David S.
Published: April 2023

A Phase I clinical trial is currently underway to test Nelmastobart (hSTC810), an antibody targeting butyrophilin 1A1 (BTN1A1), a novel immune checkpoint protein. This Phase I clinical trial is using a standard 3 + 3 escalation design to (i) explore safety, tolerability, dose-limiting toxicities, and pharmacokinetics, (ii) define a recommended Phase II dose, and (iii) evaluate preliminary efficacy in patients with advanced solid tumors. The current dose range for the clinical trial is 0.3 mg/kg to 15 mg/kg. Currently, all the dose levels have been completed without any dose-limiting toxicity having been observed. Here, we provide an update on the clinical trial data shown previously. First, we provide the results of the pharmacokinetics study of these patients for the selected doses and dosing intervals, including the peak plasma concentration (Cmax), the time to reach Cmax (tmax), and the average plasma concentration of hSTC810 over the dosing interval in steady state (Cavg). The change in cytokine expression and immune cell concentrations in patient blood samples were also analyzed. Specifically, a panel of cytokines was measured including IFN- γ, IL-2, IL-4, IL-6, IL-10, TNF-α, MCP-1, and TGF- β, while flow cytometry was used to detect a panel of immunological marker proteins including CD3, CD4, CD8, CD19, CD14, CD16, CD56, CD25, CD45. For pharmacokinetic studies, the concentrations of hSTC810 and anti-hSTC810 antibodies were quantified. Immunohistochemistry was performed on patient tumor biopsies that were stained for PD-L1, CD3, CD4, CD8, and BTN1A1 expression. The resultant slides were analyzed for PD-L1 tumor proportional score (TPS), PD-L1 combined positive score (CPS), BTN1A1 scoring, the percentage of CD3+ lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, tumor-infiltrating lymphocytes, and necrosis.

Citation Format: Stephen Sunghan Yoo, Soohyeon Lee, Sangjoon Shin, Hyunjin Jung, David S. Hong. Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT238.
Abstract LB032: Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2
Authors: Naderinezhad Samira , Zhang Guoliang , Wang Zheng , Zheng Dayong , Lian Junwei , Li Wenliang
Published: April 2023

Treatment-related neuroendocrine prostate cancer (t-NEPC, here as NEPC) is an aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% of lethal CRPC. The mechanisms underlying the progression of prostate cancer to NEPC are largely unclear, and new drug targets are desperately needed. NEPC is known to be highly vascularized. Elevated expression of NE markers and increased angiogenesis are two prominent phenotypes of NEPC, and thus are expected to be linked. However, direct molecular links between these two phenotypes are still elusive, whose elucidation will substantially expand our knowledge in NEPC and enable the development of effective treatments for NEPC. Through RNAi & cDNA screening and functional validations, we previously discovered that GPCR-kinase 3 (GRK3) is essential preferentially for highly metastatic cancer cells as compared to lowly metastatic cancer cells. The mechanisms of GRK3 in prostate cancer progression were mostly unknown.

Our new data indicate that GRK3 is significantly overexpressed in metastatic prostate tumors from patients, especially in NEPC. GRK3 promotes both angiogenesis and neuroendocrine differentiation in prostate cancer cells, indicating that it is a key missing link for these two phenotypes. Mechanistically, GRK3 enhances the epigenetic repressor activity of histone deacetylase 2 (HDAC2) to suppress key repressors of angiogenesis or NE phenotype. Through compound library screening, we have identified several compounds that block kinase activity of GRK3 much more potently than that of GRK2, the closest-related kinase to GRK3. Of note, our GRK3 inhibitors could substantially reduce angiogenesis and NE marker expression, as well as significantly inhibit NEPC cell growth in culture and in mouse xenografts.

In summary, kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression. Its mechanism of actions is at least in part through enhancing HDAC2’s epigenetic activity. Results based on our novel GRK3 inhibitors suggest that GRK3 is a valuable new drug target for aggressive prostate cancer.

Citation Format: Samira Naderinezhad, Guoliang Zhang, Zheng Wang, Dayong Zheng, Junwei Lian, Wenliang Li. Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB032.
Abstract LB085: Antitumor activity of AZD0754, a dnTGFbRII armored STEAP2 targeted CAR-T therapy, in preclinical models of prostate cancer
Authors: van Dyk Dewald , Zanvit Peter , Fazenbaker Christine , McGlinchey Kelly , Luo Weichuan , Pezold Jessica , Meekin John , Chang Chien-ying , Clark Benjamin , Martin Philip L. , Hoover Clare , Tu Eric , Gilbreth Ryan , Cobbold Mark , Moody Gordon , Bosco Emily E.
Published: April 2023

Prostate cancer is traditionally considered an immunologically “cold” tumor type rendering patients insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent anti tumor immune response to “heat up” the tumor microenvironment. However, many antigens expressed on prostate tumors are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a sub-optimal therapeutic index. Our target discovery and validation efforts identified STEAP2 as a superior prostate antigen for therapeutic targeting. Importantly, STEAP2 is a highly prevalent prostate cancer antigen displaying high, homogeneous cell surface expression across all stages of disease. A novel lead generation approach facilitated the development of a potent and specific armored STEAP2 CAR-T therapeutic candidate, AZD0754. This second generation CAR-T product is armored with a dominant-negative TGFβRII, thereby bolstering activity in the TGFβ-rich immunosuppressive environment of prostate cancer. Armored STEAP2 CAR-T cells demonstrate favorable in vitro properties, robust dose dependent in vivo efficacy in STEAP2 expressing cell line- and patient derived- mouse xenograft models and encouraging preclinical safety. Taken together, this data builds confidence in the specificity and potency of this potential first in class STEAP2 targeted CAR-T therapy and supports future clinical development.

Citation Format: Dewald van Dyk, Peter Zanvit, Christine Fazenbaker, Kelly McGlinchey, Weichuan Luo, Jessica Pezold, John Meekin, Chien-ying Chang, Benjamin Clark, Philip L. Martin, Clare Hoover, Eric Tu, Ryan Gilbreth, Mark Cobbold, Gordon Moody, Emily E. Bosco. Antitumor activity of AZD0754, a dnTGFbRII armored STEAP2 targeted CAR-T therapy, in preclinical models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB085.