bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table 1 from Integrated Molecular and Immune Phenotype of HER2-Positive Breast Cancer and Response to Neoadjuvant Therapy: A NeoALTTO Exploratory Analysis
Authors: Pizzamiglio Sara , Ciniselli Chiara Maura , Triulzi Tiziana , Gargiuli Chiara , De Cecco Loris , de Azambuja Evandro , Fumagalli Debora , Sotiriou Christos , Harbeck Nadia , Izquierdo Miguel , Nuciforo Paolo , Huober Jens , Cappelletti Vera , Cinieri Saverio , Piccart Martine , Daidone Maria Grazia , Pruneri Giancarlo , Colombo Mario Paolo , Tagliabue Elda , Verderio Paolo , Di Cosimo Serena
Published: April 2023

Table S1. Association of clinico-pathological variables and the molecular classifiers TRAR and PAM50 with pathological complete response (pCR) and Event Free survival (EFS) in the study cohort (n=226; 80 pCR and 64 events).
Supplementary Figure 1 from Integrated Molecular and Immune Phenotype of HER2-Positive Breast Cancer and Response to Neoadjuvant Therapy: A NeoALTTO Exploratory Analysis
Authors: Pizzamiglio Sara , Ciniselli Chiara Maura , Triulzi Tiziana , Gargiuli Chiara , De Cecco Loris , de Azambuja Evandro , Fumagalli Debora , Sotiriou Christos , Harbeck Nadia , Izquierdo Miguel , Nuciforo Paolo , Huober Jens , Cappelletti Vera , Cinieri Saverio , Piccart Martine , Daidone Maria Grazia , Pruneri Giancarlo , Colombo Mario Paolo , Tagliabue Elda , Verderio Paolo , Di Cosimo Serena
Published: April 2023

Supplementary Figure S1. Correlation of immune-related metagenes, tumor-infiltrating immune cells, and expression of ERBB2, ESR1 and TRAR. The color indicates the direction of the correlation (yellow: negative-correlation; light blue: positive correlation) according to Spearman's correlation coefficient values.
Table S2 from Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer
Authors: Jin Ying , Chen Yamei , Tang Huarong , Hu Xiao , Hubert Shawna M. , Li Qian , Su Dan , Xu Haimiao , Fan Yun , Yu Xinmin , Chen Qixun , Liu Jinshi , Hong Wei , Xu Yujin , Deng Huan , Zhu Dapeng , Li Pansong , Gong Yuhua , Xia Xuefeng , Gay Carl M. , Zhang Jianjun , Chen Ming
Published: April 2023

Table S2
Clinical characteristics for the 51 extensive-stage SCLCs receiving first-linechemotherapy (chemo-resistant, n=28 ; chemo-sensitive, n=23).
Supplementary Figure S4 from Development and Validation of Machine Learning–based Model for the Prediction of Malignancy in Multiple Pulmonary Nodules: Analysis from Multicentric Cohorts
Authors: Chen Kezhong , Nie Yuntao , Park Samina , Zhang Kai , Zhang Yangming , Liu Yuan , Hui Bengang , Zhou Lixin , Wang Xun , Qi Qingyi , Li Hao , Kang Guannan , Huang Yuqing , Chen Yingtai , Liu Jiabao , Cui Jian , Li Mingru , Park In Kyu , Kang Chang Hyun , Shen Haifeng , Yang Yingshun , Guan Tian , Zhang Yaxiao , Yang Fan , Kim Young Tae , Wang Jun
Published: April 2023

Risk category judged by clinicians
Supplementary Figure 2 from Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer
Authors: Fountzilas Christos , Bajor David L. , Mukherjee Sarbajit , Saltzman Joel , Witkiewicz Agnieszka K. , Maguire Orla , Minderman Hans , Nambiar Ram , Rosenheck Hanna R. , Knudsen Erik S. , Muhitch Jason B. , Abrams Scott I. , Wang Chong , Hutson Alan D. , Attwood Kristopher , Hicks Karen A. , Jurcevic Jennifer A. , Kalinski Pawel , Iyer Renuka , Boland Patrick M.
Published: April 2023

Change in CEA over time.
Supplementary fig 6 from A Modified Nucleoside 6-Thio-2′-Deoxyguanosine Exhibits Antitumor Activity in Gliomas
Authors: Yu Shengnan , Wei Shiyou , Savani Milan , Lin Xiang , Du Kuang , Mender Ilgen , Siteni Silvia , Vasilopoulos Themistoklis , Reitman Zachary J. , Ku Yin , Wu Di , Liu Hao , Tian Meng , Chen Yaohui , Labrie Marilyne , Charbonneau Casey M. , Sugarman Eric , Bowie Michelle , Hariharan Seethalakshmi , Waitkus Matthew , Jiang Wen , McLendon Roger E. , Pan Edward , Khasraw Mustafa , Walsh Kyle M. , Lu Yiling , Herlyn Meenhard , Mills Gordon , Herbig Utz , Wei Zhi , Keir Stephen T. , Flaherty Keith , Liu Lunxu , Wu Kongming , Shay Jerry W. , Abdullah Kalil , Zhang Gao , Ashley David M.
Published: April 2023

Supplementary Figure 6. (A) Creation of primary patient-derived glioblastoma organoids. (B) Quantification of tumor weight of U87MG xenograft model. (C) The curve of body weight of mice of U87MG xenograft model during THIO treatment. (D) Quantification of tumor weight of GBM PDX model. (E) The curve of body weight of mice of GBM PDX model during THIO treatment. (F) The curve of body weight of mice of U251MG xenograft model during THIO treatment.
Supplementary fig 5 from A Modified Nucleoside 6-Thio-2′-Deoxyguanosine Exhibits Antitumor Activity in Gliomas
Authors: Yu Shengnan , Wei Shiyou , Savani Milan , Lin Xiang , Du Kuang , Mender Ilgen , Siteni Silvia , Vasilopoulos Themistoklis , Reitman Zachary J. , Ku Yin , Wu Di , Liu Hao , Tian Meng , Chen Yaohui , Labrie Marilyne , Charbonneau Casey M. , Sugarman Eric , Bowie Michelle , Hariharan Seethalakshmi , Waitkus Matthew , Jiang Wen , McLendon Roger E. , Pan Edward , Khasraw Mustafa , Walsh Kyle M. , Lu Yiling , Herlyn Meenhard , Mills Gordon , Herbig Utz , Wei Zhi , Keir Stephen T. , Flaherty Keith , Liu Lunxu , Wu Kongming , Shay Jerry W. , Abdullah Kalil , Zhang Gao , Ashley David M.
Published: April 2023

Supplementary Figure 5. (A-C) The heatmap of proteins changed by THIO in M059K, LN229 and U87MG cells from RPPA data. (D-F) Western blot was performed to confirm the change of these proteins in H4 (more sensitive to THIO) (D), U87MG (less sensitive to THIO) (E), and U251MG (more resistant to THIO) (F) after treatment with THIO at 5 µM. Actin serves as a loading control. (G) Heatmap of pathways regulated by THIO in M059K, LN229 and U87MG cells.
Supplementary fig 3 from A Modified Nucleoside 6-Thio-2′-Deoxyguanosine Exhibits Antitumor Activity in Gliomas
Authors: Yu Shengnan , Wei Shiyou , Savani Milan , Lin Xiang , Du Kuang , Mender Ilgen , Siteni Silvia , Vasilopoulos Themistoklis , Reitman Zachary J. , Ku Yin , Wu Di , Liu Hao , Tian Meng , Chen Yaohui , Labrie Marilyne , Charbonneau Casey M. , Sugarman Eric , Bowie Michelle , Hariharan Seethalakshmi , Waitkus Matthew , Jiang Wen , McLendon Roger E. , Pan Edward , Khasraw Mustafa , Walsh Kyle M. , Lu Yiling , Herlyn Meenhard , Mills Gordon , Herbig Utz , Wei Zhi , Keir Stephen T. , Flaherty Keith , Liu Lunxu , Wu Kongming , Shay Jerry W. , Abdullah Kalil , Zhang Gao , Ashley David M.
Published: April 2023

Supplementary Figure 3. (A) Relative initial telomere length of 17 glioma cell lines and NHA. (B) Correlation of IC50s of THIO and initial telomere length in 17 glioma cell lines. (C) Baseline relative expression of hTERT in 17 glioma cell lines and NHA. (D) RNAseq data of hTERT expression in 11 glioma cell lines obtained from CCLE. (E) Correlation of IC50s of THIO and baseline expression of hTERT in 17 glioma cell lines. (F) Correlation of IC50s of THIO and baseline expression of hTERT in 11 glioma cell lines from CCLE. (G) The heatmap of the enrichment scores of 5 telomere/telomerase-related gene signatures for 65 glioma cell lines from CCLE. (H-I) Relative telomere length of M059K and DBTRG-05MG cells following THIO treatment at 2.5 µM for 5 days. (J-K) Telomerase activity of M059K and DBTRG-05MG cells following THIO treatment at 5 µM for 72 hours. (L) Baseline telomerase activity of 10 glioma cell lines, including 5 cell lines that more sensitive to THIO and 5 cell lines that more resistant to THIO. (M) Correlation of baseline telomerase activity and cell viability (%) following THIO treatment. (N) Quantification of western blot of γH2AX expression in 8 glioma cell lines treated with THIO for 72 hours.
Supplementary Tables from A Modified Nucleoside 6-Thio-2′-Deoxyguanosine Exhibits Antitumor Activity in Gliomas
Authors: Yu Shengnan , Wei Shiyou , Savani Milan , Lin Xiang , Du Kuang , Mender Ilgen , Siteni Silvia , Vasilopoulos Themistoklis , Reitman Zachary J. , Ku Yin , Wu Di , Liu Hao , Tian Meng , Chen Yaohui , Labrie Marilyne , Charbonneau Casey M. , Sugarman Eric , Bowie Michelle , Hariharan Seethalakshmi , Waitkus Matthew , Jiang Wen , McLendon Roger E. , Pan Edward , Khasraw Mustafa , Walsh Kyle M. , Lu Yiling , Herlyn Meenhard , Mills Gordon , Herbig Utz , Wei Zhi , Keir Stephen T. , Flaherty Keith , Liu Lunxu , Wu Kongming , Shay Jerry W. , Abdullah Kalil , Zhang Gao , Ashley David M.
Published: April 2023

Supplementary Tables
Supplementary Table from Predictable Clinical Benefits without Evidence of Synergy in Trials of Combination Therapies with Immune-Checkpoint Inhibitors
Authors: Palmer Adam C. , Izar Benjamin , Hwangbo Haeun , Sorger Peter K.
Published: April 2023

Supplementary Table from Predictable Clinical Benefits without Evidence of Synergy in Trials of Combination Therapies with Immune-Checkpoint Inhibitors
Supplementary Figure from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data
Authors: Williamson Casey W. , Nelson Tyler J. , Thompson Caroline A. , Vitzthum Lucas K. , Zakeri Kaveh , Riviere Paul J. , Bryant Alex K. , Sharabi Andrew B. , Zou Jingjing , Mell Loren K.
Published: April 2023

Supplementary Figure from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data
Supplementary Data from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data
Authors: Williamson Casey W. , Nelson Tyler J. , Thompson Caroline A. , Vitzthum Lucas K. , Zakeri Kaveh , Riviere Paul J. , Bryant Alex K. , Sharabi Andrew B. , Zou Jingjing , Mell Loren K.
Published: April 2023

Supplementary Data from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data
Supplementary Data from Improved T-cell Immunity Following Neoadjuvant Chemotherapy in Ovarian Cancer
Authors: Liu Min , Tayob Nabihah , Penter Livius , Sellars MacLean , Tarren Anna , Chea Vipheaviny , Carulli Isabel , Huang Teddy , Li Shuqiang , Cheng Su-Chun , Le Phuong , Frackiewicz Laura , Fasse Julia , Qi Courtney , Liu Joyce F. , Stover Elizabeth H. , Curtis Jennifer , Livak Kenneth J. , Neuberg Donna , Zhang Guanglan , Matulonis Ursula A. , Wu Catherine J. , Keskin Derin B. , Konstantinopoulos Panagiotis A.
Published: April 2023

Supplementary Data from Improved T-cell Immunity Following Neoadjuvant Chemotherapy in Ovarian Cancer
Supplementary Data from Gene Expression–Based Prediction of Neoadjuvant Chemotherapy Response in Early Breast Cancer: Results of the Prospective Multicenter EXPRESSION Trial
Authors: Edlund Karolina , Madjar Katrin , Lebrecht Antje , Aktas Bahriye , Pilch Henryk , Hoffmann Gerald , Hofmann Manfred , Kolberg Hans-Christian , Boehm Daniel , Battista Marco , Seehase Martina , Stewen Kathrin , Gebhard Susanne , Cadenas Cristina , Marchan Rosemarie , Brenner Walburgis , Hasenburg Annette , Koelbl Heinz , Solbach Christine , Gehrmann Mathias , Tanner Berno , Weber Karsten E. , Loibl Sibylle , Sachinidis Agapios , Rahnenführer Jörg , Schmidt Marcus , Hengstler Jan G.
Published: April 2023

Pipeline for classifier construction (a), PCA of the EXPRESSION cohort (b), performance of classifier variants (c), cross-tables of complete responders and non-complete responders (d), classifier performance (e) and calibration (f), comparison with published classifiers (g), and the AUC for of classifiers from ranked probesets (h)
Supplementary Data from Gene Expression–Based Prediction of Neoadjuvant Chemotherapy Response in Early Breast Cancer: Results of the Prospective Multicenter EXPRESSION Trial
Authors: Edlund Karolina , Madjar Katrin , Lebrecht Antje , Aktas Bahriye , Pilch Henryk , Hoffmann Gerald , Hofmann Manfred , Kolberg Hans-Christian , Boehm Daniel , Battista Marco , Seehase Martina , Stewen Kathrin , Gebhard Susanne , Cadenas Cristina , Marchan Rosemarie , Brenner Walburgis , Hasenburg Annette , Koelbl Heinz , Solbach Christine , Gehrmann Mathias , Tanner Berno , Weber Karsten E. , Loibl Sibylle , Sachinidis Agapios , Rahnenführer Jörg , Schmidt Marcus , Hengstler Jan G.
Published: April 2023

Published classifiers for prediction of pCR (a), study centers that contributed to the EXPRESSION trial (b), baseline characteristics of patients in the EXPRESSION trial (c), publicly available breast cancer datasets (d), comparison of patients who achieved versus not achieved a pCR (e), association of clinicopathologic parameters with pCR (f)
Table S3 from Comprehensive Molecular Analysis of Inflammatory Myofibroblastic Tumors Reveals Diverse Genomic Landscape and Potential Predictive Markers for Response to Crizotinib
Authors: Lee Che-Jui , Schöffski Patrick , Modave Elodie , van Wezel Tom , Boeckx Bram , Sufliarsky Jozef , Gelderblom Hans , Blay Jean-Yves , Debiec-Rychter Maria , Sciot Raf , Bovée Judith V.M.G. , Lambrechts Diether , Wozniak Agnieszka
Published: April 2023

Detailed information for recurrent mutations and mutated CGCs
Table S1 from Comprehensive Molecular Analysis of Inflammatory Myofibroblastic Tumors Reveals Diverse Genomic Landscape and Potential Predictive Markers for Response to Crizotinib
Authors: Lee Che-Jui , Schöffski Patrick , Modave Elodie , van Wezel Tom , Boeckx Bram , Sufliarsky Jozef , Gelderblom Hans , Blay Jean-Yves , Debiec-Rychter Maria , Sciot Raf , Bovée Judith V.M.G. , Lambrechts Diether , Wozniak Agnieszka
Published: April 2023

Significant focal CNAs detected in IMFT. Significance was determined by q value < 0.25.
Supplementary Data from Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy
Authors: Mills Bradley N. , Qiu Haoming , Drage Michael G. , Chen Chunmo , Mathew Jocelyn S. , Garrett-Larsen Jesse , Ye Jian , Uccello Taylor P. , Murphy Joseph D. , Belt Brian A. , Lord Edith M. , Katz Alan W. , Linehan David C. , Gerber Scott A.
Published: April 2023

Supplementary Data from Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy
Supplementary Figure from Pamiparib Monotherapy for Patients with Germline BRCA1/2-Mutated Ovarian Cancer Previously Treated with at Least Two Lines of Chemotherapy: A Multicenter, Open-Label, Phase II Study
Authors: Wu Xiaohua , Zhu Jianqing , Wang Jing , Lin Zhongqiu , Yin Rutie , Sun Wei , Zhou Qi , Zhang Songling , Wang Danbo , Shi Hong , Gao Yunong , Huang Yi , Li Guiling , Wang Xiuli , Cheng Ying , Lou Ge , Gao Qinglei , Wang Li , Du Xiuping , Pan Mei , Mu Xiyan , Li Li , Li Miao , Mu Song , Kong Beihua
Published: April 2023

Supplementary Figure from Pamiparib Monotherapy for Patients with Germline BRCA1/2-Mutated Ovarian Cancer Previously Treated with at Least Two Lines of Chemotherapy: A Multicenter, Open-Label, Phase II Study
Supplementary Data from Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2− Breast Cancer
Authors: Dowsett Mitch , Kilburn Lucy , Rimawi Mothaffar F. , Osborne C. Kent , Pogue-Geile Katherine , Liu Yuan , Jacobs Samuel A. , Finnigan Melanie , Puhalla Shannon , Dodson Andrew , Martins Vera , Cheang Maggie , Perry Sophie , Holcombe Chris , Turner Nick , Swift Claire , Bliss Judith M. , Johnston Stephen
Published: April 2023

Supplementary Data from Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2− Breast Cancer
Supplementary Figure from Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Luginbuhl Adam J. , Johnson Jennifer M. , Harshyne Larry A. , Linnenbach Alban J. , Shukla Sanket K. , Alnemri Angela , Kumar Gaurav , Cognetti David M. , Curry Joseph M. , Kotlov Nikita , Antysheva Zoya , Degryse Sandrine , Mannion Kyle , Gibson Michael K. , Netterville James , Brown Brandee , Axelrod Rita , Zinner Ralph , Tuluc Madalina , Gargano Stacey , Leiby Benjamin E. , Shimada Ayako , Mahoney My G. , Martinez-Outschoorn Ubaldo , Rodeck Ulrich , Kim Young J. , South Andrew P. , Argiris Athanassios
Published: April 2023

Supplementary Figure from Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma
Table S2 from Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription
Authors: Pang John , Nguyen Nam , Luebeck Jens , Ball Laurel , Finegersh Andrey , Ren Shuling , Nakagawa Takuya , Flagg Mitchell , Sadat Sayed , Mischel Paul S. , Xu Guorong , Fisch Kathleen , Guo Theresa , Cahill Gabrielle , Panuganti Bharat , Bafna Vineet , Califano Joseph
Published: April 2023

List of Genes Upregulated With ecDNA.
Figure S5 from Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription
Authors: Pang John , Nguyen Nam , Luebeck Jens , Ball Laurel , Finegersh Andrey , Ren Shuling , Nakagawa Takuya , Flagg Mitchell , Sadat Sayed , Mischel Paul S. , Xu Guorong , Fisch Kathleen , Guo Theresa , Cahill Gabrielle , Panuganti Bharat , Bafna Vineet , Califano Joseph
Published: April 2023

Verification of full-length transcript identified by Amplicon Architect.
Figure S3 from Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription
Authors: Pang John , Nguyen Nam , Luebeck Jens , Ball Laurel , Finegersh Andrey , Ren Shuling , Nakagawa Takuya , Flagg Mitchell , Sadat Sayed , Mischel Paul S. , Xu Guorong , Fisch Kathleen , Guo Theresa , Cahill Gabrielle , Panuganti Bharat , Bafna Vineet , Califano Joseph
Published: April 2023

Downstream expression at site of integration of human/viral hybrid RNA sequence.
Figure S1 from Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription
Authors: Pang John , Nguyen Nam , Luebeck Jens , Ball Laurel , Finegersh Andrey , Ren Shuling , Nakagawa Takuya , Flagg Mitchell , Sadat Sayed , Mischel Paul S. , Xu Guorong , Fisch Kathleen , Guo Theresa , Cahill Gabrielle , Panuganti Bharat , Bafna Vineet , Califano Joseph
Published: April 2023

Output from Amplicon Architect of the institutional and TCGA cohorts. URL: dx.doi.org/10.6084/m9.figshare.13520087
Supplementary Table S3 from Cell Type–specific Adaptive Signaling Responses to KRASG12C Inhibition
Authors: Solanki Hitendra S. , Welsh Eric A. , Fang Bin , Izumi Victoria , Darville Lancia , Stone Brandon , Franzese Ryan , Chavan Sandip , Kinose Fumi , Imbody Denis , Koomen John M. , Rix Uwe , Haura Eric B.
Published: April 2023

Supplementary Table S3. The complete list of identified phosphopeptides after global (pS/T/Y) phosphopeptides enrichment in ARS-1620 treated cells with fold change quantisation and p-value calculation.
Supplementary Table S2 from Cell Type–specific Adaptive Signaling Responses to KRASG12C Inhibition
Authors: Solanki Hitendra S. , Welsh Eric A. , Fang Bin , Izumi Victoria , Darville Lancia , Stone Brandon , Franzese Ryan , Chavan Sandip , Kinose Fumi , Imbody Denis , Koomen John M. , Rix Uwe , Haura Eric B.
Published: April 2023

Supplementary Table S2. The complete list of identified phosphopeptides after (pY) enrichment in ARS-1620 treated cells with fold change quantisation and p-value calculation.
Legends to Supplementary Data from Cell Type–specific Adaptive Signaling Responses to KRASG12C Inhibition
Authors: Solanki Hitendra S. , Welsh Eric A. , Fang Bin , Izumi Victoria , Darville Lancia , Stone Brandon , Franzese Ryan , Chavan Sandip , Kinose Fumi , Imbody Denis , Koomen John M. , Rix Uwe , Haura Eric B.
Published: April 2023

Legends to Supplementary Figures and Tables
Supplementary Table from ImmunoPET of Ovarian and Pancreatic Cancer with AR9.6, a Novel MUC16-Targeted Therapeutic Antibody
Authors: Sharma Sai Kiran , Mack Kyeara N. , Piersigilli Alessandra , Pourat Jacob , Edwards Kimberly J. , Keinänen Outi , Jiao Maria S. , Zhao Huiyong , White Brandy , Brooks Cory L. , de Stanchina Elisa , Madiyalakan Madi R. , Hollingsworth Michael A. , Radhakrishnan Prakash , Lewis Jason S. , Zeglis Brian M.
Published: April 2023

Supplementary Table from ImmunoPET of Ovarian and Pancreatic Cancer with AR9.6, a Novel MUC16-Targeted Therapeutic Antibody
Supplementary Data from Deuterium Metabolic Imaging Reports on TERT Expression and Early Response to Therapy in Cancer
Authors: Batsios Georgios , Taglang Céline , Tran Meryssa , Stevers Nicholas , Barger Carter , Gillespie Anne Marie , Ronen Sabrina M. , Costello Joseph F. , Viswanath Pavithra
Published: April 2023

Supplementary Data from Deuterium Metabolic Imaging Reports on TERT Expression and Early Response to Therapy in Cancer
Supplementary Data from Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma
Authors: Noh Joseph J. , Cho Young-Jae , Ryu Ji-Yoon , Choi Jung-Joo , Hwang Jae Ryoung , Choi Ju-Yeon , Lee Jeong-Won
Published: April 2023

Supplementary Data from Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma
Supplementary Figure from Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-Grade Dysplasia
Authors: Yu Ming , Moinova Helen R. , Willbanks Amber , Cannon Victoria K. , Wang Ting , Carter Kelly , Kaz Andrew , Reddi Deepti , Inadomi John , Luebeck Georg , Iyer Prasad G. , Canto Marcia I. , Wang Jean S. , Shaheen Nicholas J. , Thota Prashanti N. , Willis Joseph E. , LaFramboise Thomas , Chak Amitabh , Markowitz Sanford D. , Grady William M.
Published: April 2023

Supplementary Figure from Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-Grade Dysplasia
Supplementary Data from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
Authors: Chi Ping , Qin Li-Xuan , Camacho Niedzica , Kelly Ciara M. , D'Angelo Sandra P. , Dickson Mark A. , Gounder Mrinal M. , Keohan Mary L. , Movva Sujana , Nacev Benjamin A. , Rosenbaum Evan , Thornton Katherine A. , Crago Aimee M. , Francis Jasmine H. , Martindale Moriah , Phelan Haley T. , Biniakewitz Matthew D. , Lee Cindy J. , Singer Samuel , Hwang Sinchun , Berger Michael F. , Chen Yu , Antonescu Cristina R. , Tap William D.
Published: April 2023

Supplementary Data from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
Supplementary Table from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer
Authors: Lim Joline S.J. , Wong Andrea L.A. , Ow Samuel G.W. , Ngoi Natalie Y.L. , Chan Gloria H.J. , Ang Yvonne L.E. , Chong Wan Qin , Lim Siew Eng , Lim Yi Wan , Lee Matilda , Choo Joan R.E. , Tan Hon Lyn , Yong Wei Peng , Soo Ross A. , Tan David S.P. , Chee Cheng Ean , Sundar Raghav , Yadav Kritika , Jain Supriya , Wang Lingzhi , Tai Bee Choo , Goh Boon Cher , Lee Soo-Chin
Published: April 2023

Supplementary Table from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer
Supplementary Figure from RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition
Authors: Hunihan Lisa , Zhao Dejian , Lazowski Heather , Li Man , Qian Yuping , Abriola Laura , Surovtseva Yulia V. , Muthusamy Viswanathan , Tanoue Lynn T. , Rothberg Bonnie E. Gould , Schalper Kurt A. , Herbst Roy S. , Wilson Frederick H.
Published: April 2023

Supplementary Figure from RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition
Supplementary Data from RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition
Authors: Hunihan Lisa , Zhao Dejian , Lazowski Heather , Li Man , Qian Yuping , Abriola Laura , Surovtseva Yulia V. , Muthusamy Viswanathan , Tanoue Lynn T. , Rothberg Bonnie E. Gould , Schalper Kurt A. , Herbst Roy S. , Wilson Frederick H.
Published: April 2023

Supplementary Data from RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition
Supplementary Table 4 from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
Authors: Hahn Andrew W. , Menk Ashley V. , Rivadeneira Dayana B. , Augustin Ryan C. , Xu Mingchu , Li Jun , Wu Xiaogang , Mishra Aditya K. , Gide Tuba N. , Quek Camelia , Zang Yan , Spencer Christine N. , Menzies Alexander M. , Daniel Carrie R. , Hudgens Courtney W. , Nowicki Theodore , Haydu Lauren E. , Khan M.A. Wadud , Gopalakrishnan Vancheswaran , Burton Elizabeth M. , Malke Jared , Simon Julie M. , Bernatchez Chantale , Putluri Nagireddy , Woodman Scott E. , Vashisht Gopal Y.N. , Guerrieri Renato , Fischer Grant M. , Wang Jian , Wani Khalida M. , Thompson John F. , Lee Jeffrey E. , Hwu Patrick , Ajami Nadim , Gershenwald Jeffrey E. , Long Georgina V. , Scolyer Richard A. , Tetzlaff Michael T. , Lazar Alexander J. , Schadendorf Dirk , Wargo Jennifer A. , Kirkwood John M. , DeBerardinis Ralph J. , Liang Han , Futreal Andrew , Zhang Jianhua , Wilmott James S. , Peng Weiyi , Davies Michael A. , Delgoffe Greg M. , Najjar Yana G. , McQuade Jennifer L.
Published: April 2023

Body mass index values by patient ID for all RNASeq cohorts.
Supplementary Table 3 from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
Authors: Hahn Andrew W. , Menk Ashley V. , Rivadeneira Dayana B. , Augustin Ryan C. , Xu Mingchu , Li Jun , Wu Xiaogang , Mishra Aditya K. , Gide Tuba N. , Quek Camelia , Zang Yan , Spencer Christine N. , Menzies Alexander M. , Daniel Carrie R. , Hudgens Courtney W. , Nowicki Theodore , Haydu Lauren E. , Khan M.A. Wadud , Gopalakrishnan Vancheswaran , Burton Elizabeth M. , Malke Jared , Simon Julie M. , Bernatchez Chantale , Putluri Nagireddy , Woodman Scott E. , Vashisht Gopal Y.N. , Guerrieri Renato , Fischer Grant M. , Wang Jian , Wani Khalida M. , Thompson John F. , Lee Jeffrey E. , Hwu Patrick , Ajami Nadim , Gershenwald Jeffrey E. , Long Georgina V. , Scolyer Richard A. , Tetzlaff Michael T. , Lazar Alexander J. , Schadendorf Dirk , Wargo Jennifer A. , Kirkwood John M. , DeBerardinis Ralph J. , Liang Han , Futreal Andrew , Zhang Jianhua , Wilmott James S. , Peng Weiyi , Davies Michael A. , Delgoffe Greg M. , Najjar Yana G. , McQuade Jennifer L.
Published: April 2023

Differential gene expression analysis for each subgroup.
Data from Association of Intratumoral Vascular Endothelial Growth Factor Expression and Clinical Outcome for Patients with Gastrointestinal Stromal Tumors Treated with Imatinib Mesylate
Authors: McAuliffe John C. , Lazar Alexander J.F. , Yang Dan , Steinert Dejka M. , Qiao Wei , Thall Peter F. , Raymond A. Kevin , Benjamin Robert S. , Trent Jonathan C.
Published: April 2023

Abstract
Purpose: Imatinib mesylate (imatinib) has revolutionized clinical outcomes of patients with advanced gastrointestinal stromal tumor (GIST). However, the degree of individual benefit varies, and little is known about prognostic factors for these patients. Importantly, selected patients may be treated with an approach to target both Kit and vascular endothelial growth factor receptor (VEGFR) expression.

Experimental Design: Using tissue microarray technology, we analyzed 53 imatinib-naive GISTs for vascular endothelial growth factor (VEGF) expression from patients who then received imatinib. In multivariate analyses, we evaluated overall survival (OS) and progression-free survival (PFS) of these patients based on putative prognostic factors, including VEGF expression. In a separate study, 12 matched pre-imatinib and post-imatinib GIST patient specimens and two human GIST cell lines were assessed for VEGF production in response to imatinib.

Results: Independent of kit genotype, patients with GIST expressing high VEGF had inferior median PFS (7.1 months versus 29 months, P = 0.42) and median OS (20 months versus not reached at >50 months; P = 0.02) compared with weak or nonexpressers of VEGF. Non–exon 11 kit mutation predicted inferior PFS but not OS. High mitotic rate was marginally predictive of improved OS. Imatinib resulted in decreased production of VEGF in only a subset of GIST patients (2 of 12) and both cell lines.

Conclusions: We present a study to address the prognostic factors for patients with GIST in the imatinib era. We present a rationale to consider exploration of a front-line therapy of GIST with a regimen targeting both Kit and VEGFR based on the presence of tumor VEGF levels.
Data from Bortezomib-Mediated Inhibition of Steroid Receptor Coactivator-3 Degradation Leads to Activated Akt
Authors: Ayala Gustavo , Yan Jun , Li Rile , Ding Yi , Thompson Timothy C. , Mims Martha P. , Hayes Teresa G. , MacDonnell Vivian , Lynch R. Garret , Frolov Anna , Miles Brian J. , Wheeler Thomas M. , Harper J. Wade , Tsai Ming-Jer , Ittmann Michael M. , Kadmon Dov
Published: April 2023

Abstract
Purpose: To assess the safety of administering bortezomib to patients undergoing a radical prostatectomy, to assess pathologic changes induced by bortezomib in prostate cancer specimen, and to verify alterations by the drug in proteasome protein targets.

Experimental Design: Bortezomib is a proteasome inhibitor that has shown activity in vitro and in vivo in prostate cancer. We performed a neoadjuvant clinical trial of bortezomib in men with prostate cancer at high risk of recurrence. The primary endpoints were to evaluate safety and biological activity.

Results: Bortezomib is generally safe in the preoperative setting. Antitumor activity was manifested by tumor cytopathic effect, drops in serum prostate-specific antigen in some patients, and increases in tumor apoptosis. This was associated with cytoplasmic entrapment of nuclear factor-κB. We found an unexpected increase in proliferation in treated tissues and in vitro. Bortezomib also increased SRC-3 levels and phosphorylated Akt, both in vitro and in treated prostate cancer tissues. Knockdown of SRC-3 blocked the increase in activated Akt in vitro. Combined treatment with bortezomib and the Akt inhibitor perifosine was more effective than either agent alone in vitro.

Conclusion: These data suggest that combined therapies targeting the proteasome and the Akt pathway may have increased efficacy.
Data from Derlin-1 Is Overexpressed on the Tumor Cell Surface and Enables Antibody-Mediated Tumor Targeting Therapy
Authors: Ran Yuliang , Hu Hai , Hu Dong , Zhou Zhuan , Sun Yuemin , Yu Long , Sun Lixin , Pan Jian , Liu Jun , Liu Tong , Yang Zhihua
Published: April 2023

Abstract
Purpose: Tumor targeting therapy is one of the most promising strategies for anticancer treatment. Derlin-1 has been reported to participate in misfolded protein dislocation and integrates into the endoplasmic reticulum (ER) membrane to survey for such protein aggregates. We elucidate herein that Derlin-1 can leak to the plasmalemma from the ER in tumor cells and may have clinical application as a novel cancer target in the hope of developing a new tumor targeting therapy.

Experimental Design: The cell surface expression of Derlin-1 was shown by immunofluorescence analysis of nonpermeabilized cells and Western blotting of fractional proteins of tumor cells. Derlin-1 expression in cancerous tissues was also shown by immunohistochemistry. Biodistribution analysis and γ-scintigraphic imaging were done using 125I-labeled Derlin-1 targeting antibody in isogenic mice models. Finally, tumor-bearing mice were treated by the anti-Derlin-1 polyclonal antibody and monoclonal antibodies.

Results: Derlin-1 was expressed on various tumor cell surfaces and adopted a homodimer conformation. Robust cytoplasmic and membrane expression of Derlin-1 was detected in various types of human cancers tissues but was not correlated with any clinicopathologic features of pancreatic cancer. Derlin-1 directed antibodies specifically targeted to colon tumors and significantly suppress tumor growth in isogenic mice.

Conclusions: These preclinical data show that Derlin-1 protein is a functional molecular target expressed on the tumor cell surface and is a candidate therapeutic target that may be translated into clinical applications.
Data from A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia
Authors: Friedman Daphne R. , Weinberg J. Brice , Barry William T. , Goodman Barbara K. , Volkheimer Alicia D. , Bond Karen M. , Chen Youwei , Jiang Ning , Moore Joseph O. , Gockerman Jon P. , Diehl Louis F. , Decastro Carlos M. , Potti Anil , Nevins Joseph R.
Published: April 2023

Abstract
Purpose: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients.

Experimental Design: We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients.

Results: A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and nonresponding CLL patients.

Conclusions: Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients. (Clin Cancer Res 2009;15(22):694755)
Data from Circulating Levels of Soluble KIT Serve as a Biomarker for Clinical Outcome in Gastrointestinal Stromal Tumor Patients Receiving Sunitinib following Imatinib Failure
Authors: DePrimo Samuel E. , Huang Xin , Blackstein Martin E. , Garrett Christopher R. , Harmon Charles S. , Schöffski Patrick , Shah Manisha H. , Verweij Jaap , Baum Charles M. , Demetri George D.
Published: April 2023

Abstract
Purpose: To evaluate changes in circulating levels of soluble KIT (sKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study.

Experimental Design: Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma sKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis.

Results: From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in sKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in sKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in sKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% CI, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% CI, 0.39-3.40).

Conclusions: The results suggest that circulating plasma sKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings. (Clin Cancer Res 2009;15(18):5869–77)
Data from Use of Oral N-Acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress: Towards a Novel Paradigm for Melanoma Chemoprevention
Authors: Goodson Agnessa Gadeliya , Cotter Murray A. , Cassidy Pamela , Wade Mark , Florell Scott R. , Liu Tong , Boucher Kenneth M. , Grossman Douglas
Published: April 2023

Abstract
Purpose: Induction of oxidative stress has been implicated in UV-induced melanoma. We sought to determine whether the antioxidant N-acetylcysteine (NAC) could be safely administered to protect melanocytic nevi from the oxidative stress resulting from acute UV exposure.

Experimental Design: Patients at increased risk for melanoma were recruited from a screening clinic. Induction and detection of oxidative stress (reactive oxygen species and glutathione depletion) was optimized in nevi following ex vivo UV irradiation. Nevi were removed from patients before, and following, oral ingestion of a single (1,200 mg) dose of NAC, and then these nevi were UV irradiated (4,000 J/m2).

Results: Oxidative stress was induced in nevi 24 to 48 hours following ex vivo UV irradiation. A single oral dose of NAC was well tolerated in all patients (n = 72). Basal levels of reduced glutathione and the NAC metabolite cysteine were well correlated between similar-appearing nevi from the same patient and were significantly increased in nevi removed 3 hours after NAC ingestion compared with nevi removed before drug ingestion. In approximately half (9 of 19) of patients tested, UV-induced glutathione depletion was attenuated in the postdrug (compared with predrug) nevus.

Conclusions: NAC can be safely administered to patients for the purpose of modulating UV-induced oxidative stress in nevi. This study suggests the feasibility of patients taking NAC prophylactically before acute UV exposure, to prevent pro-oncogenic oxidative stress in nevi and ultimately reduce long-term melanoma risk. (Clin Cancer Res 2009;15(23):7434–40)
Data from Methylation of p16 CpG Island Associated with Malignant Progression of Oral Epithelial Dysplasia: A Prospective Cohort Study
Authors: Cao Jie , Zhou Jing , Gao Yan , Gu Liankun , Meng Huanxin , Liu Hongwei , Deng Dajun
Published: April 2023

Abstract
Purpose: Inactivation of p16 gene by CpG methylation is a frequent event in oral epithelial dysplasia. To investigate the predictive value of p16 methylation on malignant potential in oral epithelial dysplasia, we carried out the prospective cohort study.

Experimental Design: One hundred one patients with histologically confirmed mild or moderate oral epithelial dysplasia were included in the present cohort study. p16 Methylation status of the oral epithelial dysplasia lesions from 93 cases was obtained by methylation-specific PCR. Progression of the oral epithelial dysplasia lesions was examined in 78 cases histologically during a 45.8 months follow-up period. The association between p16 methylation and progression of oral epithelial dysplasia was analyzed.

Results: Of the 93 enrolled cases, 15 cases were lost during the follow-up because of changes of contact information, with a compliance of 83.9%. p16 Methylation was detectable in oral epithelial dysplasia lesions from 32 (41.0%) of 78 enrolled patients. Oral epithelial dysplasia–related squamous cell carcinomas were observed in 22 patients (28.2%) during the follow-up. Rate of progression to oral cancer in patients with the p16-methylated oral epithelial dysplasia was significantly higher than that with the p16-unmethylated oral epithelial dysplasia (43.8% versus 17.4%; adjusted odds ratio, 3.7; P = 0.013), especially for patients at the baseline age of ≥60 years (adjusted odds ratio, 12.0; P = 0.003) and patients with moderate oral epithelial dysplasia (adjusted odds ratio, 15.6; P = 0.022). The overall sensitivity and specificity of prediction of malignant transformation of oral epithelial dysplasia by p16 methylation were 63.6% and 67.9%, respectively.

Conclusion: p16 Methylation was correlated with malignant transformation of oral epithelial dysplasia and is a potential biomarker for prediction of prognosis of mild or moderate oral epithelial dysplasia. (Clin Cancer Res 2009;15(16):5178–83)
Data from Mechanisms of Ascorbate-Induced Cytotoxicity in Pancreatic Cancer
Authors: Du Juan , Martin Sean M. , Levine Mark , Wagner Brett A. , Buettner Garry R. , Wang Sih-han , Taghiyev Agshin F. , Du Changbin , Knudson Charles M. , Cullen Joseph J.
Published: April 2023

Abstract
Purpose: Pharmacologic concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with i.v. dosing would be cytotoxic in pancreatic cancer for which the 5-year survival is <3%.

Experimental Design: Pancreatic cancer cell lines were treated with ascorbate (0, 5, or 10 mmol/L) for 1 hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered s.c. into the flank region of nude mice and allowed to grow at which time they were randomized to receive either ascorbate (4 g/kg) or osmotically equivalent saline (1 mol/L) i.p. for 2 weeks.

Results: There was a time- and dose-dependent increase in measured H2O2 production with increased concentrations of ascorbate. Ascorbate decreased viability in all pancreatic cancer cell lines but had no effect on an immortalized pancreatic ductal epithelial cell line. Ascorbate decreased clonogenic survival of the pancreatic cancer cell lines, which was reversed by treatment of cells with scavengers of H2O2. Treatment with ascorbate induced a caspase-independent cell death that was associated with autophagy. In vivo, treatment with ascorbate inhibited tumor growth and prolonged survival.

Conclusions: These results show that pharmacologic doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer. Clin Cancer Res; 16(2); 509–20
Data from MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer
Authors: Landi Maria Teresa , Zhao Yingdong , Rotunno Melissa , Koshiol Jill , Liu Hui , Bergen Andrew W. , Rubagotti Maurizia , Goldstein Alisa M. , Linnoila Ilona , Marincola Francesco M. , Tucker Margaret A. , Bertazzi Pier Alberto , Pesatori Angela C. , Caporaso Neil E. , McShane Lisa M. , Wang Ena
Published: April 2023

Abstract
Purpose: The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histologic subtypes and predict survival for non–small cell lung cancer.

Experimental Design: We analyzed miR expression in 165 adenocarcinoma and 125 squamous cell carcinoma (SQ) tissue samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t tests and F tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards, and survival risk prediction models, accounting for demographic and tumor characteristics.

Results: MiR expression profiles strongly differed between adenocarcinoma and SQ (Pglobal < 0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were downregulated in SQ. Major findings were confirmed by quantitative real time-polymerase chain reaction (qRT-PCR) in EAGLE samples and in an independent set of lung cancer cases. In SQ, the low expression of miRs that are downregulated in the histology comparison was associated with 1.2- to 3.6-fold increased mortality risk. A five-miR signature significantly predicted survival for SQ.

Conclusions: We identified a miR expression profile that strongly differentiated adenocarcinoma from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches. Clin Cancer Res; 16(2); 430–41
Data from Molecular Target Modulation, Imaging, and Clinical Evaluation of Gastrointestinal Stromal Tumor Patients Treated with Sunitinib Malate after Imatinib Failure
Authors: Demetri George D. , Heinrich Michael C. , Fletcher Jonathan A. , Fletcher Christopher D.M. , Van den Abbeele Annick D. , Corless Christopher L. , Antonescu Cristina R. , George Suzanne , Morgan Jeffrey A. , Chen Ming Hui , Bello Carlo L. , Huang Xin , Cohen Darrel P. , Baum Charles M. , Maki Robert G.
Published: April 2023

Abstract
Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules.

Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed.

Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity.

Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. (Clin Cancer Res 2009;15(18):5902–9)