bluuebunny/crossref_metadata_2025 huggingface dataset:
Table TS3 from Combination of a New Oral Demethylating Agent, OR2100, and Venetoclax for Treatment of Acute Myeloid Leukemia
Authors: Kamachi Kazuharu , Ureshino Hiroshi , Watanabe Tatsuro , Yoshida-Sakai Nao , Fukuda-Kurahashi Yuki , Kawasoe Kazunori , Hoshiko Toshimi , Yamamoto Yuta , Kurahashi Yuki , Kimura Shinya
Published: April 2023

The Bliss score in combination of S63845
Supplementary Figures S1-S9 from Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia
Authors: Dupouy Sandra , Marchiq Ibtissam , Derippe Thibaud , Almena-Carrasco Maria , Jozwik Agnieszka , Fouliard Sylvain , Adimy Yasmina , Geronimi Julia , Graham Charlotte , Jain Nitin , Maus Marcela V. , Mohty Mohamad , Boissel Nicolas , Teshima Takanori , Kato Koji , Benjamin Reuben , Balandraud Svetlana
Published: April 2023

Fig.S1: Schematic diagram of CALM study design; Fig.S2: Correlation of UCART19 transgene levels evaluated by qPCR in paired peripheral blood and bone marrow aspirate samples; Fig.S3 & S4: Impact of demographic characteristics, prior therapies and tumor burden on UCART19 in vivo expansion (Cmax) or persistence (AUCTlast), respectively; Fig.S5: Impact of tumor burden at the time of UCART19 infusion on UCART19 kinetics based on response status; Fig.S6: UCART19 product characteristics; Fig.S7: Scatter plots of UCART19 cellular kinetic parameters by qPCR vs transduction efficiency and cell viability; Fig.S8: Impact of lymphodepletion on homeostatic cytokines (IL-7 and IL-15) and UCART19 cellular kinetics; Fig.S9: Impact of number of prior treatment lines on IL-7 exposure (AUC28).
Supplementary Table ST2 from Mouse IgG2a Isotype Therapeutic Antibodies Elicit Superior Tumor Growth Control Compared with mIgG1 or mIgE
Authors: Vukovic Natasa , Segués Aina , Huang Shuyu , Waterfall Martin , Sijts Alice J.A.M. , Zaiss Dietmar M.
Published: April 2023

Amino acid sequence of designed Thy1.1-MHC-1 construct
Supplementary Table ST1 from Mouse IgG2a Isotype Therapeutic Antibodies Elicit Superior Tumor Growth Control Compared with mIgG1 or mIgE
Authors: Vukovic Natasa , Segués Aina , Huang Shuyu , Waterfall Martin , Sijts Alice J.A.M. , Zaiss Dietmar M.
Published: April 2023

Amino acid sequences of anti-Thy1.1 antibodies.
Supplementary Figure SF4 from Mouse IgG2a Isotype Therapeutic Antibodies Elicit Superior Tumor Growth Control Compared with mIgG1 or mIgE
Authors: Vukovic Natasa , Segués Aina , Huang Shuyu , Waterfall Martin , Sijts Alice J.A.M. , Zaiss Dietmar M.
Published: April 2023

No synergistic effected is achieved combining anti-thy1.1 antibodies with adoptive cell transfer of activated OT-1s.
Supplementary Tables 1-6 from Evaluating Pneumonitis Incidence in Patients with Non–small Cell Lung Cancer Treated with Immunotherapy and/or Chemotherapy Using Real-world and Clinical Trial Data
Authors: Liu Qi , Zhang Chenan , Huang Yue , Huang Ruihao , Huang Shiew-Mei , Larkins Erin , Stapleford Liza , Rivera Donna R. , Kluetz Paul G. , Wang Shenggang , Zhu Hao , Weese James , Cromartie Elizabeth , Teka Mahder , Walters Sheetal , Wolf Frank , Brown Thomas D.
Published: April 2023

Supplementary Table 1. Pneumonitis defined using A) ICD-9 and B) ICD-10 codes that included ‘pneumonitis’ or associated concepts in the Unified Medical Language System, with Bidirectional General Equivalence Mappings used to identify equivalent terms between ICD-9 and ICD-10 in the Real World Data (RWD) cohort

Supplementary Table 2: ICD codes used to identify history of chronic lung condition in the Real World Data (RWD) cohort

Supplementary Table 3. Selection of clinical trial (RCT) population

Supplementary Table 4. Incidence of Treatment-Associated Pneumonitis in the Randomized Clinical Trial (RCT) Cohort and the Real World Data (RWD) Cohort based on sensitivity analyses

Supplementary Table 5. Treatment-associated pneumonitis counts by grade in the Randomized Clinical Trial (RCT) cohort

Supplementary Table 6. Demographic and Clinical Characteristics of Patients With and Without Radiation Therapy (RT) status available in the Real World Data (RWD) Cohort
Supplementary Table ST1 from IL9 Polarizes Macrophages to M1 and Induces the Infiltration of Antitumor Immune Cells via MIP-1 and CXCR3 Chemokines
Authors: Do-Thi Van Anh , Park Sang Min , Park Song Mi , Jeong Hye Jin , Cho Geunyoung , An Hyun-Jung , Kim Young Sang , Lee Hayyoung , Lee Jie-Oh
Published: April 2023

Primers used in this study
Supplementary Data SD1 from Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation
Authors: Maneix Laure , Iakova Polina , Moree Shannon E. , Hsu Joanne I. , Mistry Ragini M. , Stossi Fabio , Lulla Premal , Sun Zheng , Sahin Ergun , Yellapragada Sarvari V. , Catic André
Published: April 2023

RNA-seq data for Volcano plot Fig. 1A
Figure S7 from Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation
Authors: Maneix Laure , Iakova Polina , Moree Shannon E. , Hsu Joanne I. , Mistry Ragini M. , Stossi Fabio , Lulla Premal , Sun Zheng , Sahin Ergun , Yellapragada Sarvari V. , Catic André
Published: April 2023

The SIAH2 ubiquitin ligase antagonizes HDAC3-mediated repression in MM cells.
Figure S6 from Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation
Authors: Maneix Laure , Iakova Polina , Moree Shannon E. , Hsu Joanne I. , Mistry Ragini M. , Stossi Fabio , Lulla Premal , Sun Zheng , Sahin Ergun , Yellapragada Sarvari V. , Catic André
Published: April 2023

Association of c-MYC and HDAC3 DNA occupancy with protein turnover at the promoters of c-MYC target genes and at the c-MYC super-enhancer.
Figure S5 from Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation
Authors: Maneix Laure , Iakova Polina , Moree Shannon E. , Hsu Joanne I. , Mistry Ragini M. , Stossi Fabio , Lulla Premal , Sun Zheng , Sahin Ergun , Yellapragada Sarvari V. , Catic André
Published: April 2023

HDAC3 mediates repression of the H3K27ac mark at super-enhancers of genes relevant for MM biology following proteasome inhibition.
Figure S4 from Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation
Authors: Maneix Laure , Iakova Polina , Moree Shannon E. , Hsu Joanne I. , Mistry Ragini M. , Stossi Fabio , Lulla Premal , Sun Zheng , Sahin Ergun , Yellapragada Sarvari V. , Catic André
Published: April 2023

DNA site-specific stabilization of HDAC3 by proteasome inhibition in MM cells.
Supplementary Figure S5 from IL9 Polarizes Macrophages to M1 and Induces the Infiltration of Antitumor Immune Cells via MIP-1 and CXCR3 Chemokines
Authors: Do-Thi Van Anh , Park Sang Min , Park Song Mi , Jeong Hye Jin , Cho Geunyoung , An Hyun-Jung , Kim Young Sang , Lee Hayyoung , Lee Jie-Oh
Published: April 2023

Bodyweight change in the tumor-implanted mice in Figure 3
Figure S3 from Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation
Authors: Maneix Laure , Iakova Polina , Moree Shannon E. , Hsu Joanne I. , Mistry Ragini M. , Stossi Fabio , Lulla Premal , Sun Zheng , Sahin Ergun , Yellapragada Sarvari V. , Catic André
Published: April 2023

Proteasome inhibition represses cell proliferation and mitochondrial activity in MM.
Supplementary Figure S4 from IL9 Polarizes Macrophages to M1 and Induces the Infiltration of Antitumor Immune Cells via MIP-1 and CXCR3 Chemokines
Authors: Do-Thi Van Anh , Park Sang Min , Park Song Mi , Jeong Hye Jin , Cho Geunyoung , An Hyun-Jung , Kim Young Sang , Lee Hayyoung , Lee Jie-Oh
Published: April 2023

Expression of IL-9R on the surface of B16F10 and 4T1 cells
Figure S2 from Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation
Authors: Maneix Laure , Iakova Polina , Moree Shannon E. , Hsu Joanne I. , Mistry Ragini M. , Stossi Fabio , Lulla Premal , Sun Zheng , Sahin Ergun , Yellapragada Sarvari V. , Catic André
Published: April 2023

Proteasome inhibition down-regulates cell cycle and mitochondrial gene expression in three different MM cell lines.
Supplementary Table ST2 from Trends of Ovarian Cancer Incidence by Histotype and Race/Ethnicity in the United States 1992–2019
Authors: Phung Minh Tung , Pearce Celeste Leigh , Meza Rafael , Jeon Jihyoun
Published: April 2023

Supplementary Table 2 shows Akaike Information Criteria (AIC) for Age-Cohort models and Age-Period-Cohort models and their differences, SEER-12, 1992-2019
Supplementary Figure S3 from Trends of Ovarian Cancer Incidence by Histotype and Race/Ethnicity in the United States 1992–2019
Authors: Phung Minh Tung , Pearce Celeste Leigh , Meza Rafael , Jeon Jihyoun
Published: April 2023

Supplementary Figure 3 shows period effects in the age-period models, SEER-12, 1992-2019
Supplementary Figure S1 from Trends of Ovarian Cancer Incidence by Histotype and Race/Ethnicity in the United States 1992–2019
Authors: Phung Minh Tung , Pearce Celeste Leigh , Meza Rafael , Jeon Jihyoun
Published: April 2023

Supplementary Figure 1 shows the flow chart of case exclusion for analysis, SEER-12, 1992-2019
Supplemental Table 9 from Association Between Recreational Physical Activity and mTOR Signaling Pathway Protein Expression in Breast Tumor Tissue
Authors: Cheng Ting-Yuan David , Zhang Runzhi , Gong Zhihong , Qin Bo , Cannioto Rikki A. , Datta Susmita , Zhang Weizhou , Omilian Angela R. , Yao Song , Khoury Thaer , Hong Chi-Chen , Bandera Elisa V. , Ambrosone Christine B.
Published: April 2023

Supplemental Table 9 reported stratified analysis for postmenopausal and premenopausal women.
Supplementary Figure FS3 from Quantitative, Spatially Defined Expression of Leukocyte-associated Immunoglobulin-like Receptor in Non–small Cell Lung Cancer
Authors: Aung Thazin N. , Gavrielatou Niki , Vathiotis Ioannis A. , Fernandez Aileen I. , Shafi Saba , Yaghoobi Vesal , Burela Sneha , MacNeil Tyler , Ahmed Fahad Shabbir , Myint Han , Flies Dallas B. , Langermann Solomon , Rimm David L.
Published: April 2023

LAIR-1 expression in different molecular subtypes of within Storma and Tumor. (A) Umap (Uniform Manifold Approximation and Projection) plot showing the expression of LAIR-1 RNA in patient lung tumor biopsies (n=7) derived single cell RNA-seq data. (B) Quantification of LAIR-1 expression in LM22 immune cells showing highest expression of LAIR-1 in macrophages.
Supplemental Figure 6 from Digital spatial profiling links beta-2-microglobulin expression with immune checkpoint blockade outcomes in head and neck squamous cell carcinoma
Authors: Gavrielatou Niki , Vathiotis Ioannis A. , Aung Thazin Nwe , Shafi Saba , Burela Sneha , Fernandez Aileen I. , Moutafi Myrto , Burtness Barbara A. , Economopoulou Panagiota , Anastasiou Maria , Foukas Periklis , Psyrri Amanda , Rimm David L.
Published: April 2023

expression of immune-related and immune-checkpoint markers in B2M high vs low groups
Supplementary Table S2 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

Summary of WGS, methylation and expression data.
Supplementary Figure 1 from Induction of PARP7 Creates a Vulnerability for Growth
Inhibition by RBN2397 in Prostate Cancer Cells
Authors: Yang Chunsong , Wierbilowicz Krzysztof , Dworak Natalia M , Bae Song Yi , Tengse Sachi B , Abianeh Nicki , Drake Justin M , Abbas Tarek , Ratan Aakrosh , Wotton David , Paschal Bryce M
Published: April 2023

Cell cycle distributions of cell lines treated with RBN2397 plus androgen or plus AHR agonist
Supplementary Data S5 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

Expression data of probes used for the volcano plot comparing between malignant GISTs carrying KIT Δ557–558 and other GISTs.
Supplementary Data S2 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

SNVs/Indels identified in the 30 GIST cases in our study cohort.
Table S1 from Systemic LRG1 expression in melanoma is associated with disease progression and recurrence
Authors: Hoefsmit Esmee P. , Völlmy Franziska , Rozeman Elisa A. , Reijers Irene L. M. , Versluis Judith M. , Hoekman Liesbeth , van Akkooi Alexander C. J. , Long Georgina V. , Schadendorf Dirk , Dummer Reinhard , Altelaar Maarten , Blank Christian U.
Published: April 2023

Table S1 shows an overview evaluated immuno-oncology markers by Olink proteomic assay
Supplemental Table 1 from Treatment Patterns and Outcomes of Pre-operative Neoadjuvant Radiotherapy in Patients with Early-onset Rectal Cancer
Authors: Badesha Jasleen K , Zhou Marilyn , Arif Arif A , Gill Sharlene , Speers Caroline , Peacock Michael , De Vera Mary A , Stuart Heather C , Brown Carl J , Donellan Fergal , Loree Jonathan M
Published: April 2023

Supplemental Table 1 – Characteristics and treatment response in rectal cancers treated with neoadjuvant therapy.
Supplemental Figure 4 from Treatment Patterns and Outcomes of Pre-operative Neoadjuvant Radiotherapy in Patients with Early-onset Rectal Cancer
Authors: Badesha Jasleen K , Zhou Marilyn , Arif Arif A , Gill Sharlene , Speers Caroline , Peacock Michael , De Vera Mary A , Stuart Heather C , Brown Carl J , Donellan Fergal , Loree Jonathan M
Published: April 2023

Supplemental Figure 4. Disease-free survival (DFS) by age in early-stage rectal cancers. The Kaplan-Meier survival curves are shown for a period of 10 years. The survival curves begin to separate towards the end of the routine follow-up period of 5 years.
Figure S1 from Systemic LRG1 expression in melanoma is associated with disease progression and recurrence
Authors: Hoefsmit Esmee P. , Völlmy Franziska , Rozeman Elisa A. , Reijers Irene L. M. , Versluis Judith M. , Hoekman Liesbeth , van Akkooi Alexander C. J. , Long Georgina V. , Schadendorf Dirk , Dummer Reinhard , Altelaar Maarten , Blank Christian U.
Published: April 2023

Figure S1 shows a flowchart of patients OpACIN-neo study
Supplemental Figure 2 from Treatment Patterns and Outcomes of Pre-operative Neoadjuvant Radiotherapy in Patients with Early-onset Rectal Cancer
Authors: Badesha Jasleen K , Zhou Marilyn , Arif Arif A , Gill Sharlene , Speers Caroline , Peacock Michael , De Vera Mary A , Stuart Heather C , Brown Carl J , Donellan Fergal , Loree Jonathan M
Published: April 2023

Supplemental Figure 2. (A) Overall clinical stage and (B) overall pathological stage distribution stratified by age.
Table ST3 from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models
Authors: Shorning Boris , Trent Neil , Griffiths David F. , Worzfeld Thomas , Offermanns Stefan , Smalley Matthew J. , Williamson Magali
Published: April 2023

Expression of Plexin-B1 in human prostate cancer
Table ST2 from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models
Authors: Shorning Boris , Trent Neil , Griffiths David F. , Worzfeld Thomas , Offermanns Stefan , Smalley Matthew J. , Williamson Magali
Published: April 2023

List of antibodies used
Supplementary Video SV2 from Toll-like Receptor Signaling–deficient Cells Enhance Antitumor Activity of Cell-based Immunotherapy by Increasing Tumor Homing
Authors: Morales-Molina Alvaro , Rodriguez-Milla Miguel Ángel , Gambera Stefano , Cejalvo Teresa , de Andrés Belén , Gaspar María-Luisa , García-Castro Javier
Published: April 2023

OAd-MSC TLR4−/−
Supplementary Figure S9 from Toll-like Receptor Signaling–deficient Cells Enhance Antitumor Activity of Cell-based Immunotherapy by Increasing Tumor Homing
Authors: Morales-Molina Alvaro , Rodriguez-Milla Miguel Ángel , Gambera Stefano , Cejalvo Teresa , de Andrés Belén , Gaspar María-Luisa , García-Castro Javier
Published: April 2023

Silent OAd-MSC using TLR4−/−, TLR9−/− or MyD88−/− cells presents similar antitumor efficacy in vivo
Supplementary Figure S8 from Toll-like Receptor Signaling–deficient Cells Enhance Antitumor Activity of Cell-based Immunotherapy by Increasing Tumor Homing
Authors: Morales-Molina Alvaro , Rodriguez-Milla Miguel Ángel , Gambera Stefano , Cejalvo Teresa , de Andrés Belén , Gaspar María-Luisa , García-Castro Javier
Published: April 2023

In vitro signaling of OAd-MSC MyD88−/−
Supplementary Figure S7 from Toll-like Receptor Signaling–deficient Cells Enhance Antitumor Activity of Cell-based Immunotherapy by Increasing Tumor Homing
Authors: Morales-Molina Alvaro , Rodriguez-Milla Miguel Ángel , Gambera Stefano , Cejalvo Teresa , de Andrés Belén , Gaspar María-Luisa , García-Castro Javier
Published: April 2023

OAd-MSC TLR4−/− induces lower systemic pro-inflammatory response than OAd-MSC WT in vivo
Supplementary Figure S5 from Toll-like Receptor Signaling–deficient Cells Enhance Antitumor Activity of Cell-based Immunotherapy by Increasing Tumor Homing
Authors: Morales-Molina Alvaro , Rodriguez-Milla Miguel Ángel , Gambera Stefano , Cejalvo Teresa , de Andrés Belén , Gaspar María-Luisa , García-Castro Javier
Published: April 2023

OAd-MSC WT and OAd-MSC TLR4−/− induce similar changes in immune populations of the spleen
Figure SF11 from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models
Authors: Shorning Boris , Trent Neil , Griffiths David F. , Worzfeld Thomas , Offermanns Stefan , Smalley Matthew J. , Williamson Magali
Published: April 2023

Model of possible effects of P1597L mutation
Figure SF10 from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models
Authors: Shorning Boris , Trent Neil , Griffiths David F. , Worzfeld Thomas , Offermanns Stefan , Smalley Matthew J. , Williamson Magali
Published: April 2023

Summary of results
Supplementary Table S2 from Structurally complex osteosarcoma genomes exhibit limited heterogeneity within individual tumors and across evolutionary time
Authors: Rajan Sanjana , Zaccaria Simone , Cannon Matthew , Cam Maren , Gross Amy C , Raphael Benjamin J , Roberts Ryan D.
Published: April 2023

Characteristics of patient samples obtained from Childhood Solid Tumor Network
Figure S3 from Detection of MET Polysomy by Next-generation Sequencing and Its Clinical Relevance for MET Inhibitors
Authors: Sun Boyang , Qiu Tian , Zeng Xiaoling , Duan Jianchun , Bai Hua , Xu Jiachen , Li Jin , Li Junling , Hao Xuezhi , Liu Yutao , Lin Lin , Wang Hongyu , Zhang Xin , Zhong Jia , Wang Jie , Ying Jianming , Wang Zhijie
Published: April 2023

One MET-FISH-positive tumor was identified as negative by NGS
Figure S1 from Detection of MET Polysomy by Next-generation Sequencing and Its Clinical Relevance for MET Inhibitors
Authors: Sun Boyang , Qiu Tian , Zeng Xiaoling , Duan Jianchun , Bai Hua , Xu Jiachen , Li Jin , Li Junling , Hao Xuezhi , Liu Yutao , Lin Lin , Wang Hongyu , Zhang Xin , Zhong Jia , Wang Jie , Ying Jianming , Wang Zhijie
Published: April 2023

Flowchart of the study design
Data from The Vaginal Microbiome is Associated with Endometrial Cancer Grade and Histology
Authors: Hakimjavadi Hesamedin , George Sophia H. , Taub Michael , Dodds Leah V. , Sanchez-Covarrubias Alex P. , Huang Marilyn , Pearson J. Matt , Slomovitz Brian M. , Kobetz Erin N. , Gharaibeh Raad , Sowamber Ramlogan , Pinto Andre , Chamala Srikar , Schlumbrecht Matthew P.
Published: April 2023

The human microbiome has been strongly correlated with disease pathology and outcomes, yet remains relatively underexplored in patients with malignant endometrial disease. In this study, vaginal microbiome samples were prospectively collected at the time of hysterectomy from 61 racially and ethnically diverse patients from three disease conditions: (i) benign gynecologic disease (controls, n = 11), (ii) low-grade endometrial carcinoma (n = 30), and (iii) high-grade endometrial carcinoma (n = 20). Extracted DNA underwent shotgun metagenomics sequencing, and microbial α and β diversities were calculated. Hierarchical clustering was used to describe community state types (CST), which were then compared by microbial diversity and grade. Differential abundance was calculated, and machine learning utilized to assess the predictive value of bacterial abundance to distinguish grade and histology. Both α- and β-diversity were associated with patient tumor grade. Four vaginal CST were identified that associated with grade of disease. Different histologies also demonstrated variation in CST within tumor grades. Using supervised clustering algorithms, critical microbiome markers at the species level were used to build models that predicted benign versus carcinoma, high-grade carcinoma versus benign, and high-grade versus low-grade carcinoma with high accuracy. These results confirm that the vaginal microbiome segregates not just benign disease from endometrial cancer, but is predictive of histology and grade. Further characterization of these findings in large, prospective studies is needed to elucidate their potential clinical applications.
Significance:
The vaginal microbiome reliably segregates not just benign gynecologic condition from endometrial cancer, but also predicts cancer grade and histology. Patterns of microbial abundance and gene expression should be increasingly considered as a factor in the evolution of precision medicine approaches, especially as they relate to cancer screening, disease pathogenesis, and patient-centered outcomes.
Data from Combined Treatment with a WNT Inhibitor and the NSAID Sulindac Reduces Colon Adenoma Burden in Mice with Truncated APC
Authors: Faux Maree C. , Weinstock Janet , Gogos Sophia , Prato Emma , Azimpour Alexander I. , O'Keefe Ryan , Cathcart-King Yasmin , Garnham Alexandra L. , Ernst Matthias , Preaudet Adele , Christie Michael , Putoczki Tracy L. , Buchert Michael , Burgess Antony W.
Published: April 2023

Adenomatous polyposis coli (APC) truncations occur in many colorectal cancers and are often associated with immune infiltration. The aim of this study was to determine whether a combination of Wnt inhibition with anti-inflammatory (sulindac) and/or proapototic (ABT263) drugs can reduce colon adenomas. Apcmin/+ and doublecortin-like kinase 1 (Dclk1)Cre/+;Apcfl/fl mice were exposed to dextran sulphate sodium (DSS) in their drinking water to promote the formation of colon adenomas. Mice were then treated with either a Wnt-signaling antagonist pyrvinium pamoate (PP), an anti-inflammatory agent sulindac or proapoptotic compound ABT263 or a combination of PP+ABT263, or PP+sulindac. Colon adenoma frequency, size, and T-cell abundance were measured. DSS treatment resulted in significant increases in colon adenoma number (P < 0.001, n > 5) and burden in Apcmin/+ (P < 0.01, n > 5) and Dclk1Cre/+;Apcfl/fl (P < 0.02, n > 5) mice. There was no effect on adenomas following treatment with PP in combination with ABT263. Adenoma number and burden were reduced with PP+sulindac treatment in Dclk1Cre/+;Apcfl/fl mice (P < 0.01, n > 17) and in Apcmin/+ mice (P < 0.001, n > 7) treated with sulindac or PP+sulindac with no detectable toxicity. PP treatment of Apcmin/+ mice increased the frequency of CD3+ cells in the adenomas. The combination of Wnt pathway inhibition with sulindac was more effective in Dclk1Cre/+;Apcfl/fl mice and provides an opportunity for killing Apc-mutant colon adenoma cells, indicating a strategy for both colorectal cancer prevention and potential new treatments for patients with advanced colorectal cancer. Outcomes from the results of this study may be translatable to the clinic for management of FAP and other patients with a high risk of developing colorectal cancer.
Significance:
Colorectal cancer is one of the most common cancers worldwide with limited therapeutic options. APC and other Wnt signaling mutations occur in the majority of colorectal cancers but there are currently no Wnt inhibitors in the clinic. The combination of Wnt pathway inhibition with sulindac provides an opportunity for killing Apc-mutant colon adenoma cells and suggests a strategy for colorectal cancer prevention and new treatments for patients with advanced colorectal cancer.
Data from Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma
Authors: Hamlin Paul A. , Musteata Vasile , Park Steven I. , Burnett Christine , Dabovic Kristina , Strack Thomas , Williams Eric T. , Anand Banmeet S. , Higgins Jack P. , Persky Daniel O.
Published: April 2023

MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the MTD and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. Twenty-seven patients enrolled. MTD was 50 μg/kg/dose with 6,000 μg/dose cap. Thirteen patients experienced at least one grade ≥3 treatment-related adverse events; the most common grade ≥3 event was myalgia (11.1%). Two patients (75 μg/kg/dose) experienced grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL (n = 12), overall response rate was 41.7% (complete response, n = 2; partial response, n = 3). In patients with detectable baseline peripheral B cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADA) increased during treatment and the majority appeared to be neutralizing based on an in vitro assay; nevertheless, tumor regression and responses were observed. MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events.
Significance:
This work describes the safety and efficacy of a new pharmaceutical pathway that could provide a treatment option for a subset of patients with a critical unmet therapeutic need. The study drug, MT-3724, is capable of targeting B-cell lymphomas via a unique, potent cell-killing mechanism that appears to be promising.
Data from Drug–gene Interaction Screens Coupled to Tumor Data Analyses Identify the Most Clinically Relevant Cancer Vulnerabilities Driving Sensitivity to PARP Inhibition
Authors: Jamal Kunzah , Galbiati Alessandro , Armenia Joshua , Illuzzi Giuditta , Hall James , Bentouati Sabrina , Barrell Daniel , Ahdesmäki Miika , O'Connor Mark J. , Leo Elisabetta , Forment Josep V.
Published: April 2023

PARP inhibitors (PARPi) are currently indicated for the treatment of ovarian, breast, pancreatic, and prostate cancers harboring mutations in the tumor suppressor genes BRCA1 or BRCA2. In the case of ovarian and prostate cancers, their classification as homologous recombination repair (HRR) deficient (HRD) or mutated also makes PARPi an available treatment option beyond BRCA1 or BRCA2 mutational status. However, identification of the most relevant genetic alterations driving the HRD phenotype has proven difficult and recent data have shown that other genetic alterations not affecting HRR are also capable of driving PARPi responses. To gain insight into the genetics driving PARPi sensitivity, we performed CRISPR-Cas9 loss-of-function screens in six PARPi-insensitive cell lines and combined the output with published PARPi datasets from eight additional cell lines. Ensuing exploration of the data identified 110 genes whose inactivation is strongly linked to sensitivity to PARPi. Parallel cell line generation of isogenic gene knockouts in ovarian and prostate cancer cell lines identified that inactivation of core HRR factors is required for driving in vitro PARPi responses comparable with the ones observed for BRCA1 or BRCA2 mutations. Moreover, pan-cancer genetic, transcriptomic, and epigenetic data analyses of these 110 genes highlight the ones most frequently inactivated in tumors, making this study a valuable resource for prospective identification of potential PARPi-responsive patient populations. Importantly, our investigations uncover XRCC3 gene silencing as a potential new prognostic biomarker of PARPi sensitivity in prostate cancer.
Significance:
This study identifies tumor genetic backgrounds where to expand the use of PARPis beyond mutations in BRCA1 or BRCA2. This is achieved by combining the output of unbiased genome-wide loss-of-function CRISPR-Cas9 genetic screens with bioinformatics analysis of biallelic losses of the identified genes in public tumor datasets, unveiling loss of the DNA repair gene XRCC3 as a potential biomarker of PARPi sensitivity in prostate cancer.
Data from NetrinG1+ Cancer-Associated Fibroblasts Generate Unique Extracellular Vesicles that Support the Survival of Pancreatic Cancer Cells Under Nutritional Stress
Authors: Raghavan Kristopher S. , Francescone Ralph , Franco-Barraza Janusz , Gardiner Jaye C. , Vendramini-Costa Débora B. , Luong Tiffany , Pourmandi Narges , Andren Anthony , Kurimchak Alison , Ogier Charline , Campbell Paul M. , Duncan James S. , Lyssiotis Costas A. , Languino Lucia R. , Cukierman Edna
Published: April 2023

It is projected that in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). These pathogenic stroma CAF/ECM units cause the collapse of local blood vessels rendering the tumor microenvironment nutrient-poor. PDAC cells are able to survive this state of nutrient stress via support from CAF-secreted material, which includes small extracellular vesicles (sEV). The tumor-supportive CAFs possess a distinct phenotypic profile, compared with normal-like fibroblasts, expressing NetrinG1 (NetG1) at the plasma membrane, and active Integrin α5β1 localized to the multivesicular bodies; traits indicative of poor patient survival. We herein report that NetG1+ CAFs secrete sEVs that stimulate Akt-mediated survival in nutrient-deprived PDAC cells, protecting them from undergoing apoptosis. Furthermore, we show that NetG1 expression in CAFs is required for the prosurvival properties of sEVs. In addition, we report that the above-mentioned CAF markers are secreted in distinct subpopulations of EVs; with NetG1 being enriched in exomeres, and Integrin α5β1 being enriched in exosomes. Finally, we found that NetG1 and Integrin α5β1 were detected in sEVs collected from plasma of patients with PDAC, while their levels were significantly lower in plasma-derived sEVs of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF-EVs elucidates novel avenues in tumor–stroma interactions and pathogenic stroma detection.
Significance:
Results from this study identified two unique types of tumor-supporting CAF EVs, with evidence of these being detected in patients. Thus, this study facilitates a novel avenue to further dissect the subtleties of the tumor–stroma interactions responsible for PDAC homeostasis and progression, as well as the possibility of establishing future means to detect and monitor dynamic stroma staging.
Data from Boosting of Waned Humoral and Cellular Responses to SARS-CoV-2 Variants of Concern Among Patients with Cancer
Authors: McKenzie Duncan R. , Graham Rosalind , Lechmere Thomas , Domingo-Vila Clara , Alaguthurai Thanussuyah , Arman Celeste , Pollock Emily , Gousis Charalampos , Kakkassery Helen , Carpenter Esme , Kurshan Ashwini , Vidler Jennifer , Kulasekararaj Austin , Patten Piers , North Bernard V. , Tree Timothy , Doores Katie J. , Hayday Adrian C. , Irshad Sheeba
Published: April 2023

This study offers longitudinal insight into the impact of three SARS-CoV-2 vaccinations on humoral and cellular immunity in patients with solid cancers, patients with hematologic malignancies, and persons without cancer. For all cohorts, virus-neutralizing immunity was significantly depleted over a period of up to 9 months following the second vaccine dose, the one striking exception being IL2 production by SARS-CoV-2 antigen-specific T cells. Immunity was restored by the third vaccine dose, except in a substantial number of patients with hematologic malignancy, for whom both cancer type and treatment schedule were associated with nonresponse. Thus, whereas most patients with myelodysplastic syndrome were conspicuously good responders, some patients with other hematologic malignancies receiving cancer therapies within 2 weeks of vaccination showed no seroconversion despite three vaccine doses. Moreover, SARS-CoV-2 exposure during the course of the study neither prevented immunity waning, even in healthy controls, nor guaranteed vaccine responsiveness. These data offer real-world human immunologic insights that can inform health policy for patients with cancer.
Significance:
Global health policy reliant on SARS-CoV-2 vaccine effectiveness is underpinned by our understanding of the durability of protection offered by sequential vaccinations and the efficacy of boosting, especially in immunocompromised patient populations who might constitute virus reservoirs. Here, we have: (i) clarified in patients with cancer the degree of waning of antibodies, serum neutralization titres against parental virus and variants of concern, and T-cell responses; (ii) evaluated the immune response among patients with cancer to a third dose of COVID-19 vaccine; and (iii) provided safety data following the third dose of the BNT162b2 COVID-19 vaccine in patients with cancer.
Data from Mixed Response to Cancer Immunotherapy is Driven by Intratumor Heterogeneity and Differential Interlesion Immune Infiltration
Authors: Morinaga Takao , Inozume Takashi , Kawazu Masahito , Ueda Youki , Sax Nicolas , Yamashita Kazuo , Kawashima Shusuke , Nagasaki Joji , Ueno Toshihide , Lin Jason , Ohara Yuuki , Kuwata Takeshi , Yukami Hiroki , Kawazoe Akihito , Shitara Kohei , Honobe-Tabuchi Akiko , Ohnuma Takehiro , Kawamura Tatsuyoshi , Umeda Yoshiyasu , Kawahara Yu , Nakamura Yasuhiro , Kiniwa Yukiko , Morita Ayako , Ichihara Eiki , Kiura Katsuyuki , Enokida Tomohiro , Tahara Makoto , Hasegawa Yoshinori , Mano Hiroyuki , Suzuki Yutaka , Nishikawa Hiroyoshi , Togashi Yosuke
Published: April 2023

Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs’ characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti–PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.
Significance:
Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.
Data from GLS1 is a Protective Factor in Patients with Ovarian Clear Cell Carcinoma and its Expression Does Not Correlate with ARID1A-mutated Tumors
Authors: Clemente Valentino , Hoshino Asumi , Shetty Mihir , Nelson Andrew , Erickson Britt K. , Baker Ruth , Rubin Nathan , Khalifa Mahmoud , Weroha S. John , Lou Emil , Bazzaro Martina
Published: April 2023

Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant patients with ovarian cancer is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for patients with OCCC with tumors harboring ARID1A mutations. Here, we investigated whether GLS1 is differentially expressed between patients with OCCC whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1.
Significance:
GLS1 differential expression in patients with OCCC with or without ARID1A mutations is significant because a clinical trial with a GLS1 inhibitor is forthcoming. Tumors without ARID1A have low levels of GLS1 and GLS1 expression is associated to better outcome. Thus, blockade of GLS1 could be counterproductive for patients with OCCC.
Data from Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge
Authors: van der Westhuizen Andre , Lyle Megan , Graves Moira C. , Zhu Xiaoqiang , Wong Jason W. H. , Cornall Kerrie , Ren Shu , Pugliese Leanna , Levy Richard , Majid Adeeb , Vilain Ricardo E. , Bowden Nikola A.
Published: April 2023

Purpose:
Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma.
Experimental Design:
A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB rechallenge. Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA sequencing, and reduced representation bisulfite sequencing of biopsies at baseline, after priming and after six cycles of avelmuab was performed.
Results:
The overall response rate (ORR) determined after azacitidine and carboplatin priming was 10% (2/20) with two partial responses (PR). The ORR determined after priming followed by six cycles of avelumab (week 22) was 10%, with 2 of 20 participants achieving immune partial response (iPR). The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by six cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks [95% confidence interval (CI): 14.87–21.13 weeks] and the median OS was 47.86 weeks (95% CI: 9.67–86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T cells, in particular CD8+, showed the greatest increase in infiltration.
Conclusions:
Priming with azacitidine and carboplatin can induce disease stabilization and resensitization to ICB for metastatic melanoma.
Significance:
There are limited treatments for melanoma once resistance to ICB occurs. Chemotherapy induces immune-related responses and may be repurposed to reinstate the response to ICB. This study provides the first evidence that chemotherapy can provide clinical benefit and increase OS for ICB-resistant melanoma.
Data from STAG2 Expression is Associated with Adverse Survival Outcomes and Regulates Cell Phenotype in Muscle-invasive Bladder Cancer
Authors: Athans Sarah R. , Krishnan Nithya , Ramakrishnan Swathi , Cortes Gomez Eduardo , Lage-Vickers Sofía , Rak Monika , Kazmierczak Zara I. , Ohm Joyce Ellen , Attwood Kristopher , Wang Jianmin , Woloszynska Anna
Published: April 2023

Stromal antigen 2 (STAG2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle-invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n = 119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n = 346) revealed that decreased STAG2 protein expression is associated with improved overall and progression-free survival for patients with MIBC. In mouse xenograft studies, STAG2 knockdown (KD) decelerated MIBC tumor growth, whereas STAG2 overexpression accelerated tumor growth. In cell line studies, STAG2 loss augmented treatment with cisplatin, a first-line therapy for MIBC. STAG2 KD or overexpression did not alter degree of aneuploidy, copy-number variations, or cell-cycle distribution. However, unbiased RNA-sequencing analysis revealed that STAG2 KD altered gene expression. STAG2 KD led to significant downregulation of several gene sets, such as collagen containing extracellular matrix, external encapsulating structure organization, and regulation of chemotaxis. Therefore, we investigated the effect of STAG2 KD on cell migration and invasion in vitro. We found that STAG2 KD minimized cell speed, displacement, and invasion. Altogether, our results present a noncanonical function of STAG2 in promoting cell motility and invasion of MIBC cells. This work forms the basis for additional investigation into the role of STAG2 in transcriptional regulation and how it becomes dysregulated in STAG2-mutant MIBC.
Significance:
The cohesin component STAG2 regulates cell motility and invasion. STAG2 expression is associated with decreased MIBC survival and may be a useful biomarker to guide bladder cancer treatment.
Data from A Phase II Study Investigating Cabozantinib in Patients with Refractory Metastatic Colorectal Cancer (AGICC 17CRC01)
Authors: Scott Aaron J. , Basu Mallick Atrayee , Dotan Efrat , Cohen Steven J. , Gold Philip J. , Hochster Howard S. , Subramaniam Somasundaram , Barzi Afsaneh , Watts George S. , Blatchford Patrick J. , Messersmith Wells A.
Published: April 2023

Purpose:
Multi-tyrosine kinase inhibitors (TKI) have shown clinical activity in patients with metastatic colorectal cancer. Cabozantinib, a multi-TKI, exhibited potent antitumor activity superior to regorafenib in preclinical colorectal cancer patient-derived tumor xenograft models. This phase II study aimed to investigate cabozantinib, a multi-TKI, in patients with refractory, metastatic colorectal cancer (mCRC).
Experimental Design:
A nonrandomized, two-stage, phase II clinical trial evaluating 12-week progression-free survival (PFS) was conducted in eight cancer centers across the United States between May 2018 and July 2020.
Results:
A total of 44 patients were enrolled between May 2018 and May 2019, 40 of which were response evaluable. Of the total 769 reported adverse events (AE), 93 (12%) were ≥ grade 3. Five grade 5 AEs were reported of which four were unrelated to study drug and one was reported as possibly related due to bowel perforation. Eighteen patients (45%) achieved 12-week PFS with stable disease or better (confidence interval, 0.29–0.62; P < 0.001). One patient (3%) had a partial response, and 27 other patients achieved stable disease as best response per RECISTv1.1. Median PFS was 3.0 months, and median overall survival was 8.3 months. Of the 18 patients who achieved 12-week PFS, 12 had left-sided primary tumors, 11 were RAS wild type, 11 were PIK3CA wild type, and 6 had previous regorafenib therapy. The 12-week PFS rate was higher in RAS wild-type tumors compared with RAS mutant tumors (0.61 vs. 0.32; P = 0.11).
Conclusions:
This phase II study demonstrated clinical activity of cabozantinib in heavily pretreated, patients with refractory mCRC, and supports further investigation.
Significance:
Targeting angiogenesis through VEGF axis blockade provides incremental survival benefit in patients with mCRC. The hepatocyte growth factor/MET signal transduction pathway has been observed as a mechanism for acquired resistance. Dual inhibition of VEGF plus MET is an attractive therapeutic strategy. This phase II trial demonstrated clinical activity with cabozantinib, a multi-TKI targeting VEGFR2 and MET, in patients with refractory, mCRC.