bluuebunny/crossref_metadata_2025 huggingface dataset:
Not All Populations of Hispanic Children Have an Increased Frequency of Acute Lymphoblastic Leukemia
Authors: Mejía-Aranguré Juan Manuel , Núñez-Enríquez Juan Carlos
Published: August 2023

The frequency of acute lymphoblastic leukemia (ALL) has been reported with a higher incidence among the populations of Hispanic children. However, in the article by Montes-Rodríguez and colleagues, they found that in the Puerto Rican population, the frequency was below the incidence reported for the U.S. Hispanic pediatric population, but they found that the incidence of ALL had an annual increase of 5%. In other Hispanic pediatric populations during the 1980s, the incidence of ALL was found to be even lower than the general rate in the United States. However, in less than 20 years that incidence had already been exceeded. It is evident that the Hispanic pediatric population is more susceptible to develop ALL than other populations, so it is important to consider that what is happening to the pediatric population of Puerto Rico gives us a great opportunity to identify risk factors that could potentially explain this increase. It is more likely that the risk factors that are capable of causing ALL could be identified in their role in the origin of the disease in populations with high susceptibility, given the greater number of cases of ALL that said factor is causing in that population.

See related article by Montes-Rodríguez et al., p. 1030
Supplementary Table 1 from Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor–Resistant Homologous Recombination–Deficient Ovarian Cancer
Authors: Wethington Stephanie L. , Shah Payal D. , Martin Lainie , Tanyi Janos L. , Latif Nawar , Morgan Mark , Torigian Drew A. , Rodriguez Diego , Smith Simon A. , Dean Emma , Domchek Susan M. , Drapkin Ronny , Shih Ie-Ming , Brown Eric J. , Hwang Wei-Ting , Armstrong Deborah K. , Gaillard Stephanie , Giuntoli Robert , Simpkins Fiona
Published: August 2023

Representativeness of Study Participants
Supplementary Figure 1 from Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor–Resistant Homologous Recombination–Deficient Ovarian Cancer
Authors: Wethington Stephanie L. , Shah Payal D. , Martin Lainie , Tanyi Janos L. , Latif Nawar , Morgan Mark , Torigian Drew A. , Rodriguez Diego , Smith Simon A. , Dean Emma , Domchek Susan M. , Drapkin Ronny , Shih Ie-Ming , Brown Eric J. , Hwang Wei-Ting , Armstrong Deborah K. , Gaillard Stephanie , Giuntoli Robert , Simpkins Fiona
Published: August 2023

Trial schema
Supplementary Table S4 from Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade
Authors: Hong Dong-Chun , Yang Jing , Sun Cong , Liu Yuan-Tao , Shen Lu-Jun , Xu Bu-Shu , Que Yi , Xia Xiaojun , Zhang Xing
Published: August 2023

Treatment-related adverse events of 30 RIS patients treated with chemotherapy plus anti-PD-1 antibody.
Supplementary Table S1 from Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade
Authors: Hong Dong-Chun , Yang Jing , Sun Cong , Liu Yuan-Tao , Shen Lu-Jun , Xu Bu-Shu , Que Yi , Xia Xiaojun , Zhang Xing
Published: August 2023

Clinical characteristics of patients in RIS group and SARC group as a whole, or for WES, or for mRNA- seq.
Supplementary Figure S2 from Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade
Authors: Hong Dong-Chun , Yang Jing , Sun Cong , Liu Yuan-Tao , Shen Lu-Jun , Xu Bu-Shu , Que Yi , Xia Xiaojun , Zhang Xing
Published: August 2023

RNA-seq analysis between RIS and RIS groups and some subtypes.(A) Venn plot showing differentially expressed genes (DEG) of FS and OS subtype comparison between RIS and SARC groups.(B) Volcano plot showing up-regulated and down-regulated genes in the RIFS group versus the RIOS group.(C) GO pathway enrichment of mRNA-seq between the RIS group and SARC group, and between the RIFS and RIOS subtypes.(D) Relative abundances of activated immune cells and immunosuppression-related cells in subtypes of RIS and primary sarcomas.
Supplementary Figure S1 from Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade
Authors: Hong Dong-Chun , Yang Jing , Sun Cong , Liu Yuan-Tao , Shen Lu-Jun , Xu Bu-Shu , Que Yi , Xia Xiaojun , Zhang Xing
Published: August 2023

The flowchart showing patient screening and identification, and analysis steps for mRNA-seq and WES data. FS: fibrosarcoma; OS: osteosarcoma.
Supplementary Table S3 from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: August 2023

Multivariable Cox proportional hazards models for time to progression and time to death
Supplementary Methods from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: August 2023

Additional methodological details
Supplementary Figure S4 from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: August 2023

Frequency of recurrent somatic alterations compared to published cohorts
Supplementary Figure S2 from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: August 2023

On-treatment ctDNA fraction, PSA and LDH changes and durability of treatment response
Supplementary Fig. 3 from A Phase 1/2 Multicenter Randomized Trial of Local Ablation plus Toripalimab versus Toripalimab Alone for Previously Treated Unresectable Hepatocellular Carcinoma
Authors: Zhou Chunhui , Li Yan , Li Jiaping , Song Botian , Li Hanfeng , Liang Bin , Gu Shanzhi , Li Haiping , Chen Changyong , Li Sai , Peng Changli , Liu Fei , Xiao Juxiong , Long Xueying , Li Ping , Xiong Zhengping , Yi Xiaoping , Liao Weihua , Shi Liangrong
Published: August 2023

Supplementary Fig. 3 A. Progression-free survival by CD8+ TIL density. B. Overall survival by CD8+ TIL density. Dot marks indicate censored data.
Supplementary Table1 from Somatic Exonic Deletions in RUNX1 Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia
Authors: Eriksson Anna , Engvall Marie , Mathot Lucy , Österroos Albin , Rippin Martin , Cavelier Lucia , Ladenvall Claes , Baliakas Panagiotis
Published: August 2023

Supplementary Table1
Supplementary Fig. 6 from An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer
Authors: Chandarlapaty Sarat , Dickler Maura N. , Perez Fidalgo Jose Alejandro , Villanueva-Vázquez Rafael , Giltnane Jennifer , Gates Mary , Chang Ching-Wei , Cheeti Sravanthi , Fredrickson Jill , Wang Xiaojing , Collier Ann , Moore Heather M. , Metcalfe Ciara , Lauchle Jennifer , Humke Eric W. , Bardia Aditya
Published: August 2023

Supplementary Fig. S6. Detection of short variant gene alterations using the FACT next generation sequencing assay on ctDNA samples from patients dosed at 1400 mg dose (n=23).
Supplementary Table 2 from Somatic Exonic Deletions in RUNX1 Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia
Authors: Eriksson Anna , Engvall Marie , Mathot Lucy , Österroos Albin , Rippin Martin , Cavelier Lucia , Ladenvall Claes , Baliakas Panagiotis
Published: August 2023

Supplementary Table 2
Supplementary Data 1 from Somatic Exonic Deletions in RUNX1 Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia
Authors: Eriksson Anna , Engvall Marie , Mathot Lucy , Österroos Albin , Rippin Martin , Cavelier Lucia , Ladenvall Claes , Baliakas Panagiotis
Published: August 2023

Supplementary Data
Supplementary Fig. 4 from An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer
Authors: Chandarlapaty Sarat , Dickler Maura N. , Perez Fidalgo Jose Alejandro , Villanueva-Vázquez Rafael , Giltnane Jennifer , Gates Mary , Chang Ching-Wei , Cheeti Sravanthi , Fredrickson Jill , Wang Xiaojing , Collier Ann , Moore Heather M. , Metcalfe Ciara , Lauchle Jennifer , Humke Eric W. , Bardia Aditya
Published: August 2023

Supplementary Fig. S4. ESR1 mutation analysis in ctDNA.
Supplementary Figure S7 from HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance
Authors: Stupia Simone , Heeke Christina , Brüggemann Alicia , Zaremba Anne , Thier Beatrice , Kretz Julia , Sucker Antje , Philip Manuel , Zelinskyy Gennadiy , Ferrone Soldano , Roesch Alexander , Horn Susanne , Hadaschik Eva , Schadendorf Dirk , Trilling Mirko , Dittmer Ulf , Griewank Klaus , Zhao Fang , Paschen Annette
Published: August 2023

HLA-II APM transcript levels in melanoma biopsies from ICB-treated patients
Supplementary Figure S6 from HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance
Authors: Stupia Simone , Heeke Christina , Brüggemann Alicia , Zaremba Anne , Thier Beatrice , Kretz Julia , Sucker Antje , Philip Manuel , Zelinskyy Gennadiy , Ferrone Soldano , Roesch Alexander , Horn Susanne , Hadaschik Eva , Schadendorf Dirk , Trilling Mirko , Dittmer Ulf , Griewank Klaus , Zhao Fang , Paschen Annette
Published: August 2023

JAK inhibition downregulates HLA-II but not HLA-I or PD-L1 expression in melanoma cells
Supplementary Figure S4 from HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance
Authors: Stupia Simone , Heeke Christina , Brüggemann Alicia , Zaremba Anne , Thier Beatrice , Kretz Julia , Sucker Antje , Philip Manuel , Zelinskyy Gennadiy , Ferrone Soldano , Roesch Alexander , Horn Susanne , Hadaschik Eva , Schadendorf Dirk , Trilling Mirko , Dittmer Ulf , Griewank Klaus , Zhao Fang , Paschen Annette
Published: August 2023

CD4 T-cell sensitivity of constHLA-II melanoma cells
Supplementary Tables 1 from Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line–Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST)
Authors: De Sutter Luna , Wozniak Agnieszka , Verreet Jasper , Vanleeuw Ulla , De Cock Lore , Linde Nina , Drechsler Christine , Esdar Christina , Sciot Raf , Schöffski Patrick
Published: August 2023

Supplementary Tables 1-3
Figure S1 from Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer
Authors: Lin Yansong , Qin Shukui , Yang Hui , Shi Feng , Yang Aimin , Han Xingmin , Liu Bin , Li Zhiyong , Ji Qinghai , Tang Lijun , Deng Zhiyong , Ding Yong , Fu Wei , Xie Xianhe , Li Linfa , He Xiaohui , Lv Zhongwei , Ma Qingjie , Shen Zan , Guo Zhuming , Chen Zhendong , Cui Yali , Tan Jian , Gao Zairong , Jing Shanghua , Lu Keyi , Luo Xianyang , Zhang Yuan , Fang Yong , Li Zhendong , Cheng Yizhuang , Lei Shangtong , Luan Sha , Chen Guang , Wang Guihua , Wu Liqing , Liu Lingling
Published: August 2023

Figure S1: Thyroglobulin concentrations changes for individual patients with negative thyroglobulin antibody from baseline to the end of cycle 2.
Table S1 from A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML
Authors: Levitz David , Saunthararajah Yogen , Fedorov Kateryna , Shapiro Lauren C. , Mantzaris Ioannis , Shastri Aditi , Kornblum Noah , Sica R. Alejandro , Shah Nishi , Konopleva Marina , Gritsman Kira , Braunschweig Ira , Cooper Dennis L. , Pradhan Kith , Verma Amit , Feldman Eric J. , Goldfinger Mendel
Published: August 2023

Supplementary table on representativeness
Supplementary Fig. 4 from Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line–Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST)
Authors: De Sutter Luna , Wozniak Agnieszka , Verreet Jasper , Vanleeuw Ulla , De Cock Lore , Linde Nina , Drechsler Christine , Esdar Christina , Sciot Raf , Schöffski Patrick
Published: August 2023

Supplementary Fig. 4.(A) Average number of mitotic cells per treatment group in 10 high power fields assessed on phospho-histone H3 (pHH3) immunostaining and (B) percentage of proliferative cells per treatment group per 5 high-power fields assessed on Ki-67 immunostaining.
Supplementary Fig. 3 from Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line–Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST)
Authors: De Sutter Luna , Wozniak Agnieszka , Verreet Jasper , Vanleeuw Ulla , De Cock Lore , Linde Nina , Drechsler Christine , Esdar Christina , Sciot Raf , Schöffski Patrick
Published: August 2023

Supplementary Fig. 3. One histologically representative picture of H&E staining per treatment group in the experiment with GIST882KIT13.
Figure S2 from Immunogenomic Landscape of Neuroendocrine Prostate Cancer
Authors: Bhinder Bhavneet , Ferguson Alison , Sigouros Michael , Uppal Manik , Elsaeed Ahmed G. , Bareja Rohan , Alnajar Hussein , Eng Kenneth Wha , Conteduca Vincenza , Sboner Andrea , Mosquera Juan Miguel , Elemento Olivier , Beltran Himisha
Published: August 2023

Suppl Figure 2. T-cell signature-based classification of prostate cancer types and other independent cancer cohorts.
Supplementary Table S2 from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

References used for filtering hits from drug screen
Supplementary Figure S1 from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

AZD1208 Synergy Plots and BETi Resensitization Data
Supplementary Data S2 from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

Raw RNAseq data corresponding to Figures 2C, 4D and Supplemental Figure 2B
Supplementary Table S8 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Multivariable Cox Proportional Hazard for PFS in HER2-targeted retrospective cohort (n=217).
Supplementary Figure 1 from Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors
Authors: Vieito Maria , Moreno Victor , Spreafico Anna , Brana Irene , Wang Judy S. , Preis Meir , Hernández Tatiana , Genta Sofia , Hansen Aaron R. , Doger Bernard , Galvao Vladimir , Lenox Laurie , Brown Regina J. , Kalota Anna , Mehta Jaydeep , Pastore Friederike , Patel Bharvin , Mistry Pankaj , Gu Junchen , Lauring Josh , Patel Manish R.
Published: August 2023

Supplementary Figure 1: Overall Response Over Time on JNJ-64619178 Treatment A. Dose Cohorts 0.5 mg - 1.5 mg (schedule A&B). B. Dose Cohorts 2.0 mg - 4.0 mg (schedule A&B)
Supplementary Table S5 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Genes with Oncogenic Alterations Identified by MSK-IMPACT with Frequency > 5%.
Supplementary Table S1 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Pembrolizumab/Trastuzumab/Chemotherapy Protocol Patient Demographics
Supplementary Figure S9 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Serial plasma ctDNA in an individual patient demonstrating pre-treatment genomic heterogeneity and selection for resistant clones. Plasma ctDNA at diagnosis revealed ERBB2 amplification in a patient with HER2+ EG cancer, as well as numerous pre-existing resistance mechanisms including EGFR amplification, PIK3CA amplification, and an FGFR3-TACC3 fusion that was not identified on tumor sequencing (Figure 2b).
Supplementary Figure S8 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

PIK3CD S367L demonstrate increased phosphorylation of AKT. Upon progression, 1 patient developed a PIK3CD S367L mutation (location indicated in gene map), a variant of undetermined significance in the carboxy terminal C2 domain. Above, western blot demonstrating pAKT expression in 3T3 cells stably expressing p110δ WT or mutations at p110d E1021K, L806M, S367L, R894Q, G971E, or R338W relative to non-transformed parental 3T3 cells, which do not express p110δ. Below, lollipop plot of PIK3CD.
Supplementary Figure S5 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Lesions without pre-treatment ERBB2 amplification appear less likely to respond to pembrolizumab and trastuzumab induction. Lesion-level CT response after 1 dose of pembrolizumab and trastuzumab among patients with baseline tumor-matched ctDNA color-coded according to pre-treatment a, ctDNA ERBB2 amplification status and b, tissue WES ERBB2 amplification status.
Supplementary Figure S2 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Survival and response in patients receiving trastuzumab/chemotherapy + PD-1 inhibition on- or off-protocol (n=66). a, Progression-free survival and objective response rate by cohort. b, Overall survival by cohort.
Data from Somatic Exonic Deletions in RUNX1 Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia
Authors: Eriksson Anna , Engvall Marie , Mathot Lucy , Österroos Albin , Rippin Martin , Cavelier Lucia , Ladenvall Claes , Baliakas Panagiotis
Published: August 2023

AbstractPurpose:
In acute myeloid leukemia (AML), somatic mutations (commonly missense, nonsense, and frameshift indels) in RUNX1 are associated with a dismal clinical outcome. Inherited RUNX1 mutations cause familial platelet disorder. As approximately 5%–10% of germline RUNX1 mutations are large exonic deletions, we hypothesized that such exonic RUNX1 aberrations may also be acquired during the development of AML.
Experimental Design:
Sixty patients with well-characterized AML were analyzed with multiplex ligation-dependent probe amplification (n = 60), microarray (n = 11), and/or whole-genome sequencing (n = 8).
Results:
In total, 25 (42% of the cohort) RUNX1-aberrant patients (defined by the presence of classical mutations and/or exonic deletions) were identified. Sixteen patients (27%) carried only exonic deletions, 5 (8%) carried classical mutations, and 4 (7%) carried both exonic deletions and mutations. No significant difference was observed between patients with classical RUNX1 mutations and RUNX1 exonic deletions in median overall survival (OS, 53.1 vs. 38.8 months, respectively, P = 0.63). When applying the European Leukemia Net (ELN) classification including the RUNX1-aberrant group, 20% of the patients initially stratified as intermediate-risk (5% of the whole cohort) were reassigned to the high-risk group, which improved the performance of ELN classification regarding OS between intermediate- and high-risk groups (18.9 vs. 9.6 months, P = 0.09).
Conclusions:
Somatic RUNX1 exonic deletions constitute a novel recurrent aberration in AML. Our findings have important clinical implications regarding AML classification, risk stratification, and treatment decision. Moreover, they argue in favor of further investigating such genomic aberrations not only in RUNX1 but also in other genes implicated in cancer biology and management.

See related commentary by Chakraborty and Stengel, p. 2742
Data from Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer
Authors: Lin Yansong , Qin Shukui , Yang Hui , Shi Feng , Yang Aimin , Han Xingmin , Liu Bin , Li Zhiyong , Ji Qinghai , Tang Lijun , Deng Zhiyong , Ding Yong , Fu Wei , Xie Xianhe , Li Linfa , He Xiaohui , Lv Zhongwei , Ma Qingjie , Shen Zan , Guo Zhuming , Chen Zhendong , Cui Yali , Tan Jian , Gao Zairong , Jing Shanghua , Lu Keyi , Luo Xianyang , Zhang Yuan , Fang Yong , Li Zhendong , Cheng Yizhuang , Lei Shangtong , Luan Sha , Chen Guang , Wang Guihua , Wu Liqing , Liu Lingling
Published: August 2023

AbstractPurpose:
The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC.
Patients and Methods:
This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR–DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc.
Results:
Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25–0.61; P < 0.0001] in Chinese patients with RAIR–DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand–foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation.
Conclusions:
Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.
Data from Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors
Authors: Vieito Maria , Moreno Victor , Spreafico Anna , Brana Irene , Wang Judy S. , Preis Meir , Hernández Tatiana , Genta Sofia , Hansen Aaron R. , Doger Bernard , Galvao Vladimir , Lenox Laurie , Brown Regina J. , Kalota Anna , Mehta Jaydeep , Pastore Friederike , Patel Bharvin , Mistry Pankaj , Gu Junchen , Lauring Josh , Patel Manish R.
Published: August 2023

AbstractPurpose:
In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178.
Patients and Methods:
Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated.
Results:
Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months.
Conclusions:
JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.
Specific Targeting of Multiple Myeloma by Dual Split-signaling Chimeric Antigen Receptor T cells Directed against CD38 and CD138
Authors: van der Schans Jort J. , Wang Ziyu , van Arkel Jennemiek , van Schaik Thijs , Katsarou Afroditi , Ruiter Ruud , Baardemans Thomas , Yuan Huipin , de Bruijn Joost , Zweegman Sonja , van de Donk Niels W.C.J. , Groen Richard W.J. , Themeli Maria , Mutis Tuna
Published: August 2023

Purpose:

The success of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells illustrates the potential of this novel therapy for multiple myeloma. Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few multiple myeloma– or plasma cell–specific target antigens. We investigated the feasibility of achieving multiple myeloma specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR).

Experimental Design:

Using various combinations of CD38 and CD138 sCARs and cCARs with different affinities, we generated several dual-split CAR T cells and analyzed them for multiple myeloma–specific effector functions in vitro. The best-functioning CAR T cells were tested in vivo in a murine xenograft model.

Results:

We found optimal designs of both CD38sCAR/CD138cCAR and CD138sCAR/CD38cCAR combinations, that effectively lysed multiple myeloma cells but spared single CD38- or CD138-positive healthy hematopoietic cells. While the CD38sCAR/CD138cCAR T cells achieved multiple myeloma–specific activity solely due to the low affinity of the CD38sCARs, the multiple myeloma–specific cytotoxicity, cytokine release, and proliferation of CD138sCAR/CD38cCAR T cells were established through a true combinatorial stimulatory and costimulatory effect. The most optimal combination comprised a low-affinity CD138sCAR combined with a high-affinity CD38cCAR. These CD138sCAR/CD38cCAR T cells also showed dual-antigen specific anti–multiple myeloma effects in vivo. Importantly, they were also effective against multiple myeloma cells from daratumumab pretreated patients with decreased CD38 expression levels.

Conclusions:

We demonstrate the possibility to specifically target multiple myeloma cells, even after CD38 targeted therapy, with carefully-designed dual-split CARs directed against CD38 and CD138.
Supplementary Figure Legends from Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma
Authors: Rana Manjul , Kansal Rita G. , Bisunke Bijay , Fang Jie , Shibata David , Bajwa Amandeep , Yang Jun , Glazer Evan S.
Published: August 2023

Supplementary Figure Legends
Supplementary Figure S3 from Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication
Authors: Murai Junko , Ceribelli Michele , Fu Haiqing , Redon Christophe E. , Jo Ukhyun , Murai Yasuhisa , Aladjem Mirit I. , Thomas Craig J. , Pommier Yves
Published: August 2023

Figure S3
Supplementary Figure S2 from Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication
Authors: Murai Junko , Ceribelli Michele , Fu Haiqing , Redon Christophe E. , Jo Ukhyun , Murai Yasuhisa , Aladjem Mirit I. , Thomas Craig J. , Pommier Yves
Published: August 2023

Figure S2
Table S2 from Discordance of HER2 Expression and/or Amplification on Repeat Testing
Authors: DiPeri Timothy P. , Kong Kathleen , Varadarajan Kaushik , Karp Daniel D. , Ajani Jaffer A. , Pant Shubham , Press Michael F. , Piha-Paul Sarina A. , Dumbrava Ecaterina E. , Meric-Bernstam Funda
Published: August 2023

Characteristics of individual discordant HER2 cases
Table S1 from Discordance of HER2 Expression and/or Amplification on Repeat Testing
Authors: DiPeri Timothy P. , Kong Kathleen , Varadarajan Kaushik , Karp Daniel D. , Ajani Jaffer A. , Pant Shubham , Press Michael F. , Piha-Paul Sarina A. , Dumbrava Ecaterina E. , Meric-Bernstam Funda
Published: August 2023

Distribution of HER2 IHC and FISH results between local and central testing.
Supplementary Figure 1 from Vincristine Enhances the Efficacy of MEK Inhibitors in Preclinical Models of KRAS-mutant Colorectal Cancer
Authors: Ghosh Susmita , Fan Fan , Powell Reid T. , Roszik Jason , Park Yong Sung , Stephan Clifford , Sebastian Manu , Tan Lin , Sorokin Alexey V. , Lorenzi Philip L. , Kopetz Scott , Ellis Lee M. , Bhattacharya Rajat
Published: August 2023

Supplementary Figure 1 shows that the combination of trametinib and vincristine is synergistic in multiple KRAS-mutant CRC cell lines and enhances apoptotic cell death.
Supplementary Table S5 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Analytical results of MW282 mAb and 9MW2821
Supplementary Table S2 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Patient information for prostate cancer formalin-fixed paraffin-embedded samples
Supplementary Table S10 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Binding capacity of MW282 mAb and 9MW2821 to human Fcγ and FcRn receptors based on surface plasmon resonance
Supplementary Fig.S9 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Affinity of 9MW2821 and enfortumab vedotin (EV) to recombinant human Fcγ and FcRn receptors based on surface plasmon resonance measurements.
Supplementary Fig.S4 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Characterization of 9MW2821.
Supplementary Fig.S13 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Cynomolgus monkey body weight in safety evaluation study
Supplementary Fig.S12 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Mouse body weight from BL3578, CV13641, LU3073, BR9457, BR9479, BR1282 and BR1458 patient-derived xenograft studies.
Supplementary Data from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

p53Null_log2FC of genes
Figure S1 from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary figure 1
Data from The Role of Protein Arginine Methyltransferases in Pathogenesis and Treatment of Digestive System Carcinoma
Authors: Wang Bin , Ding Dong , Zhang Xiaoan , Zhang Junxi , Zhang Huanhuan , Liu Xinxin , Chang Hui , Gao Zhan , Yu Zengli
Published: August 2023

Abstract
Posttranslational modification of proteins increases their diversity and maintains the stability of the intracellular environment. Protein arginine methyltransferases (PRMT) are an important family of epigenetic modification enzymes, which play a critical role in posttranslational modification. In recent years, with the in-depth study of the role of epigenetics, the structure and function of PRMTs have been gradually understood. PRMT enzymatic activity is related to a variety of cellular processes in digestive system malignancies, such as inflammation and immune response, activation of cell cycle and proliferation, inhibition of apoptosis, DNA damage repair, and epithelial–mesenchymal transition. A variety of chemical tools are developed to inhibit PRMT activity, which have been verified by tumor models and clinical trials. This review summarizes the structure and functions of PRMTs as a prelude to our further studies on their role in tumors. The involvement of different PRMTs in the pathogenesis of gastrointestinal tumors is then reviewed. In addition, the application of PRMT inhibitors as therapeutic agents for digestive system cancers is highlighted. In conclusion, PRMTs play an important role in the pathogenesis of gastrointestinal tumors, and their prognostic and therapeutic potential warrants further investigation.
Data from Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma
Authors: Rana Manjul , Kansal Rita G. , Bisunke Bijay , Fang Jie , Shibata David , Bajwa Amandeep , Yang Jun , Glazer Evan S.
Published: August 2023

Abstract
Identifying novel, unique, and personalized molecular targets for patients with pancreatic ductal adenocarcinoma (PDAC) remains the greatest challenge in altering the biology of fatal tumors. Bromo- and extra-terminal domain (BET) proteins are activated in a noncanonical fashion by TGFβ, a ubiquitous cytokine in the PDAC tumor microenvironment (TME). We hypothesized that BET inhibitors (BETi) represent a new class of drugs that attack PDAC tumors via a novel mechanism. Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX]). BMS-986158 reduced cell viability and proliferation across multiple PDAC cell lines in a dose-dependent manner, even more so in combination with cytotoxic chemotherapy (P < 0.0001). We found that BMS-986158 reduced both human and murine PDAC organoid growth (P < 0.001), with associated perturbations in the cell cycle leading to cell-cycle arrest. BMS-986158 disrupts normal cancer-dependent mitochondrial function, leading to aberrant mitochondrial metabolism and stress via dysfunctional cellular respiration, proton leakage, and ATP production. We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.
Data from Discordance of HER2 Expression and/or Amplification on Repeat Testing
Authors: DiPeri Timothy P. , Kong Kathleen , Varadarajan Kaushik , Karp Daniel D. , Ajani Jaffer A. , Pant Shubham , Press Michael F. , Piha-Paul Sarina A. , Dumbrava Ecaterina E. , Meric-Bernstam Funda
Published: August 2023

Abstract
We sought to assess discordance of HER2 status in patients with HER2-amplified/expressing solid tumors who underwent reevaluation of HER2 status. Patients with metastatic solid tumors and HER2 expression by IHC or amplification by FISH/next-generation sequencing on local testing underwent central HER2 IHC/FISH testing with either archival or fresh biopsies and were evaluated for discordance in HER2 status. 70 patients (12 cancer types) underwent central HER2 reevaluation, including 57 (81.4%) with a new biopsy. In 30 patients with HER2 3+ on local IHC, 21 (70.0%) were 3+, 5 (16.7%) were 2+, 2 (6.7%) were 1+, and 2 (6.7%) had 0 HER2 expression on central IHC. In 15 patients whose cancers were 2+ on local IHC, 2 (13.3%) were 3+, 5 (33.3%) were 2+, 7 (46.7%) were 1+, and 1 (6.7%) had 0 HER2 expression on central IHC. HER2 discordance was seen in 16 of 52 (30.8%) of patients with HER2 overexpression/amplification who underwent a new image-guided biopsy. Discordance was observed in 10 (33.3%) of 30 patients who received intervening HER2-targeted therapy and in 6 (23.8%) of 22 patients who did not. In the 8 patients who had central HER2 assessment from the same archival block used for local testing, none were discordant. Discordance of HER2 status is common in patients with tumors previously identified as HER2-expressing, especially in patients with HER2 2+ tumors. Repeat biomarker evaluation may have value when considering HER2-targeted therapies.
Data from ABBV-184: A novel survivin-specific TCR/CD3 bispecific T cell engager is active against both solid tumor and hematological malignancies
Authors: Chervin Adam S. , Stone Jennifer D. , Konieczna Iwona , Calabrese Kelly M. , Wang Ningyan , Haribhai Dipica , Dong Feng , White Michael K. , Rodriguez Luis E. , Bukofzer Gail T. , Ellis Paul A. , Cosgrove Cormack , Hecquet Claudie , Clarin Jerry D. , Palma Joann P. , Reilly Edward B.
Published: August 2023

Abstract
CD3 bispecific T cell engagers (TCE), comprised of a tumor targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected T cell-mediated killing of tumor cells. Although the majority of CD3 bispecific molecules in clinical development incorporate tumor-targeting antibody-based binding domains, many tumor-associated antigens derive from intracellular proteins and are not accessible to targeting via antibody. Intracellular proteins processed into short peptide fragments and presented on the cell surface by major histocompatibility complex proteins (MHC) are recognized by T cell receptors (TCR) on the surface of T cells. Here we describe the generation and preclinical evaluation of ABBV-184, a novel TCR/anti-CD3 bispecific composed of a highly selective soluble TCR that binds a peptide derived from the oncogene survivin (BIRC5) bound to the Class I MHC allele human leukocyte antigen (HLA)-A*02:01 expressed on tumor cells, linked to a specific binder to the CD3 receptor on T cells. ABBV-184 drives an optimal distance between T cell and target cell thereby enabling sensitive recognition of low-density peptide/MHC targets. Consistent with the expression profile of survivin across a broad range of both hematological and solid tumors, treatment of AML and NSCLC cell lines with ABBV-184 results in T cell activation, proliferation, and potent redirected cytotoxicity of HLA-A2 positive target cell lines, both in vitro and in vivo, including patient-derived AML samples. These results indicate that ABBV-184 is an attractive clinical candidate for the treatment of patients with AML and NSCLC.