bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S6 from Pathway-based Approach Reveals Differential Sensitivity to E2F1 Inhibition in Glioblastoma
Authors: Alvarado Alvaro G. , Tessema Kaleab , Muthukrishnan Sree Deepthi , Sober Mackenzie , Kawaguchi Riki , Laks Dan R. , Bhaduri Aparna , Swarup Vivek , Nathanson David A. , Geschwind Daniel H. , Goldman Steven A. , Kornblum Harley I.
Published: April 2023

Validation of genelists in additional gliomasphere dataset
Supplemental Table S3 from Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer
Authors: Graf Ryon P. , Fisher Virginia , Creeden James , Schrock Alexa B. , Ross Jeffrey S. , Nimeiri Halla , Oxnard Geoffrey R. , Klempner Samuel J.
Published: April 2023

Patient demographics in 1st Line Cohort
Supplemental Table S2 from Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer
Authors: Graf Ryon P. , Fisher Virginia , Creeden James , Schrock Alexa B. , Ross Jeffrey S. , Nimeiri Halla , Oxnard Geoffrey R. , Klempner Samuel J.
Published: April 2023

Patient demographics in Sequential Cohort
Figure S1 from Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer
Authors: Graf Ryon P. , Fisher Virginia , Creeden James , Schrock Alexa B. , Ross Jeffrey S. , Nimeiri Halla , Oxnard Geoffrey R. , Klempner Samuel J.
Published: April 2023

Propensity Weighting and Balance Adjustment: TMB. The pre- and post-adjustment balance for (A) 2nd line cohort with TMB < 10, (B) 2nd line cohort with TMB 10 or greater, (C) 1st line cohort with TMB < 10, (D) 1st line cohort with TMB 10 or greater.
Table TS1 from Targeting Lymphoma-associated Macrophage Expansion via CSF1R/JAK Inhibition is a Therapeutic Vulnerability in Peripheral T-cell Lymphomas
Authors: Gao Xin , Kady Nermin , Wang Chenguang , Abdelrahman Suhaib , Gann Peter , Sverdlov Maria , Wolfe Ashley , Brown Noah , Reneau John , Robida Aaron M. , Murga-Zamalloa Carlos , Wilcox Ryan A.
Published: April 2023

Antibodies used
Table TS2 from A Phase I Trial of VEGF-A Inhibition Combined with PD-L1 Blockade for Recurrent Glioblastoma
Authors: Chiu Daniel , Qi Jingjing , Thin Tin Htwe , Garcia-Barros Monica , Lee Brian , Hahn Mary , Mandeli John , Belani Puneet , Nael Kambiz , Rashidipour Omid , Ghatan Saadi , Hadjipanayis Constantinos G. , Yong Raymund L. , Germano Isabelle M. , Brody Rachel , Tsankova Nadejda M. , Gnjatic Sacha , Kim-Schulze Seunghee , Hormigo Adília
Published: April 2023

Table S2. Key Antibodies Resource
Fig. S1 from Targeting Lymphoma-associated Macrophage Expansion via CSF1R/JAK Inhibition is a Therapeutic Vulnerability in Peripheral T-cell Lymphomas
Authors: Gao Xin , Kady Nermin , Wang Chenguang , Abdelrahman Suhaib , Gann Peter , Sverdlov Maria , Wolfe Ashley , Brown Noah , Reneau John , Robida Aaron M. , Murga-Zamalloa Carlos , Wilcox Ryan A.
Published: April 2023

The microenvironmental ecosystem in lymphoma-bearing mice
Data File DS2 from Targeting Lymphoma-associated Macrophage Expansion via CSF1R/JAK Inhibition is a Therapeutic Vulnerability in Peripheral T-cell Lymphomas
Authors: Gao Xin , Kady Nermin , Wang Chenguang , Abdelrahman Suhaib , Gann Peter , Sverdlov Maria , Wolfe Ashley , Brown Noah , Reneau John , Robida Aaron M. , Murga-Zamalloa Carlos , Wilcox Ryan A.
Published: April 2023

RNA-seq demonstrates transcriptional reprogramming of LAM
Supplementary Figure S8 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy
Authors: Paillasse Michael R. , Esquerré Michael , Bertrand Florie A. , Poussereau-Pomié Céline , Pichery Mélanie , Visentin Virgile , Gueguen-Dorbes Geneviève , Gaujarengues Florence , Barron Pauline , Badet Gaelle , Briaux Anne , Ancey Pierre-Benoit , Sibrac David , Erdociain Eric , Özcelik Dennis , Meneyrol Jérôme , Martin Valérie , Gomez-Brouchet Anne , Selves Janik , Rochaix Philippe , Battistella Maxime , Lebbé Céleste , Delord Jean-Pierre , Dol-Gleizes Frédérique , Bono Françoise , Blanc Isabelle , Alam Antoine , Hunneyball Ian , Whittaker Mark , Fons Pierre
Published: April 2023

Supplementary Figure S8 shows that EVT801 doesn’t modify blood pressure in rat while sorafenib increases it
Supplementary Figure S4 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy
Authors: Paillasse Michael R. , Esquerré Michael , Bertrand Florie A. , Poussereau-Pomié Céline , Pichery Mélanie , Visentin Virgile , Gueguen-Dorbes Geneviève , Gaujarengues Florence , Barron Pauline , Badet Gaelle , Briaux Anne , Ancey Pierre-Benoit , Sibrac David , Erdociain Eric , Özcelik Dennis , Meneyrol Jérôme , Martin Valérie , Gomez-Brouchet Anne , Selves Janik , Rochaix Philippe , Battistella Maxime , Lebbé Céleste , Delord Jean-Pierre , Dol-Gleizes Frédérique , Bono Françoise , Blanc Isabelle , Alam Antoine , Hunneyball Ian , Whittaker Mark , Fons Pierre
Published: April 2023

Supplementary Figure S4 shows the evaluation of EVT801’s pharmacokinetics and pharmacodynamics
Supplementary Figure S2 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy
Authors: Paillasse Michael R. , Esquerré Michael , Bertrand Florie A. , Poussereau-Pomié Céline , Pichery Mélanie , Visentin Virgile , Gueguen-Dorbes Geneviève , Gaujarengues Florence , Barron Pauline , Badet Gaelle , Briaux Anne , Ancey Pierre-Benoit , Sibrac David , Erdociain Eric , Özcelik Dennis , Meneyrol Jérôme , Martin Valérie , Gomez-Brouchet Anne , Selves Janik , Rochaix Philippe , Battistella Maxime , Lebbé Céleste , Delord Jean-Pierre , Dol-Gleizes Frédérique , Bono Françoise , Blanc Isabelle , Alam Antoine , Hunneyball Ian , Whittaker Mark , Fons Pierre
Published: April 2023

Supplementary Figure S2 shows that EVT801 inhibits tubule formation
Table S4 from Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity
Authors: Steinkamp Mara P. , Lagutina Irina , Brayer Kathryn J. , Schultz Fred , Burke Danielle , Pankratz Vernon S. , Adams Sarah F. , Hudson Laurie G. , Ness Scott A. , Wandinger-Ness Angela
Published: April 2023

Human cytokines with significantly higher levels in PDX ascites samples compared to plasma samples
Figure S4 from Nanoparticle STING Agonist Reprograms the Bone Marrow to an Antitumor Phenotype and Protects Against Bone Destruction
Authors: Florian David C. , Bennett Natalie E. , Odziomek Mateusz , Baljon Jessalyn J. , Wehbe Mohamed , Merkel Alyssa R. , Fischer Melissa A. , Savona Michael R. , Rhoades Julie A. , Guelcher Scott A. , Wilson John T.
Published: April 2023

Supplementary Figure 4: Effects of STING-NP on mouse weights.
Figure S3 from Nanoparticle STING Agonist Reprograms the Bone Marrow to an Antitumor Phenotype and Protects Against Bone Destruction
Authors: Florian David C. , Bennett Natalie E. , Odziomek Mateusz , Baljon Jessalyn J. , Wehbe Mohamed , Merkel Alyssa R. , Fischer Melissa A. , Savona Michael R. , Rhoades Julie A. , Guelcher Scott A. , Wilson John T.
Published: April 2023

Supplementary Figure 3: Gating scheme for Regulatory T Cell flow panel.
Supplementary Figure 7 from The Splicing Factor PTBP1 Represses TP63 γ Isoform Production in Squamous Cell Carcinoma
Authors: Taylor William , Deschamps Stéphane , Reboutier David , Paillard Luc , Méreau Agnès , Audic Yann
Published: April 2023

RIP controls and EMSA
Figure S2 from Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy
Authors: Zhu Zhouting , Tang Rachel , Huff Sarah , Kummetha Indrasena Reddy , Wang Lingling , Li Na , Rana Tariq M.
Published: April 2023

Supplementary Figure S2
Supplementary Table ST1 from The WAVE2/miR-29/Integrin-β1 Oncogenic Signaling Axis Promotes Tumor Growth and Metastasis in Triple-negative Breast Cancer
Authors: Rana Priyanka S. , Wang Wei , Markovic Vesna , Szpendyk Justin , Chan Ernest Ricky , Sossey-Alaoui Khalid
Published: April 2023

Supplementary Table containing primer sequences
Supplementary Figure S7 from The WAVE2/miR-29/Integrin-β1 Oncogenic Signaling Axis Promotes Tumor Growth and Metastasis in Triple-negative Breast Cancer
Authors: Rana Priyanka S. , Wang Wei , Markovic Vesna , Szpendyk Justin , Chan Ernest Ricky , Sossey-Alaoui Khalid
Published: April 2023

Target Scan prediction of micoRNA target sites in the 3'UTR of ITGB1.
Supplementary Table ST2 from Incorporating RNA-based Risk Scores for Genomic Instability to Predict Breast Cancer Recurrence and Immunogenicity in a Diverse Population
Authors: Hamilton Alina M. , Van Alsten Sarah C. , Gao Xiaohua , Nsonwu-Farley Joseph , Calhoun Benjamin C. , Love Michael I. , Troester Melissa A. , Hoadley Katherine A.
Published: April 2023

Beta values and p-values for immune associations
Table TS1 from Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy
Authors: Groeneveldt Christianne , van Ginkel Jurriaan Q. , Kinderman Priscilla , Sluijter Marjolein , Griffioen Lisa , Labrie Camilla , van den Wollenberg Diana J.M. , Hoeben Rob C. , van der Burg Sjoerd H. , ten Dijke Peter , Hawinkels Lukas J.A.C. , van Hall Thorbald , van Montfoort Nadine
Published: April 2023

Table S1. List of antibodies used for flow cytometric analysis.
Figure S5 from Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy
Authors: Groeneveldt Christianne , van Ginkel Jurriaan Q. , Kinderman Priscilla , Sluijter Marjolein , Griffioen Lisa , Labrie Camilla , van den Wollenberg Diana J.M. , Hoeben Rob C. , van der Burg Sjoerd H. , ten Dijke Peter , Hawinkels Lukas J.A.C. , van Hall Thorbald , van Montfoort Nadine
Published: April 2023

Figure S5. CD8-specific TGF-β blockade does not impair the efficacy of Reo&CD3-bsAb therapy.
Figure S8 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

Figure S8. Schedule of HL60 cell xenograft experiments using NOG mice. NOG mice were injected intravenously with HL60 cells. Mice were then treated with OR21 (5.4 mg/kg), Ven (25 mg/kg), and OR21 plus Ven (OR21+Ven) for 21 days since day 7 after transplantation (A). Average mouse body weights (error bars represent standard deviation) for the treatment groups were measured two times per weeks. No weight loss nor severe toxicity were observed in any group during the treatment period (B). Flow cytometric analysis showed tumor burden of human CD45+ (hCD45) leukemic cells in peripheral blood on day 28. The proportion of human CD45-positive cells in the peripheral blood of OR21 plus Ven-treated mice was not lower than that in OR21 or Ven-treated mice (C). Kaplan–Meier analysis showed OR21 plus Ven-treated mice did not exhibit prolonged survival compared to OR21 or Ven-treated mice (p = 0.308 vs. Ven; p = 1.0 vs. OR21; D).
Figure S6 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

Figure S6. Flowcytometric analysis for ROS detection following 48 h vehicle treated (cont), 0.1 μM of azacitidine treated (A 0.1), 1.0 μM of azacitidine treated (A 1.0), 0.1 μM of venetoclax treated (V 0.1), 0.5 μM of venetoclax treated (V 0.5), 0.1 μM of azacitidine and 0.1 μM of venetoclax (A 0.1+V 0.1), 1.0 μM of azacitidine and 0.1 μM of venetoclax (A 1.0 + V 0.1), 0.1 μM of azacitidine and 0.5 μM of venetoclax (A 0.1 + V 0.5) and 1.0 μM of azacitidine and 0.5 μM of venetoclax (A 1.0 + V 0.5).
Table S2 from Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity
Authors: Steinkamp Mara P. , Lagutina Irina , Brayer Kathryn J. , Schultz Fred , Burke Danielle , Pankratz Vernon S. , Adams Sarah F. , Hudson Laurie G. , Ness Scott A. , Wandinger-Ness Angela
Published: April 2023

Patient characteristics for the three PDX models
Figure S4 from Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity
Authors: Steinkamp Mara P. , Lagutina Irina , Brayer Kathryn J. , Schultz Fred , Burke Danielle , Pankratz Vernon S. , Adams Sarah F. , Hudson Laurie G. , Ness Scott A. , Wandinger-Ness Angela
Published: April 2023

Levels of human M-CSF detected in patient ascites fluid
Figure S3 from Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity
Authors: Steinkamp Mara P. , Lagutina Irina , Brayer Kathryn J. , Schultz Fred , Burke Danielle , Pankratz Vernon S. , Adams Sarah F. , Hudson Laurie G. , Ness Scott A. , Wandinger-Ness Angela
Published: April 2023

Levels of human factors in the plasma of a non-tumor bearing humanized NBSGW and a non-humanized non-tumor bearing NBSGW control.
Supplemental Table 8 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 8 reported stratified analysis for obesity and normal weight/overweight.
Supplemental Table 5 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 5 reports the association without adjusting BMI as a sensitivity analysis.
Table TS1 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

Clinicopathologic characteristics of patients in cohort 3.
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
Supplemental Table 14 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 14 reported stratified analysis for ER+ tumors and ER- tumors.
Supplementary Figure S3 from The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8
Authors: Li Yanping , Carey Timothy S. , Feng Catherine H. , Zhu Hong-Ming , Sun Xiao-Xin , Dai Mu-Shui
Published: April 2023

Supplementary Fig. S3 shows that the knockdown of Drosha does not affect USP36 interaction with DGCR8 and the knockdown of DGCR8 does not affect USP36 interaction with Drosha.
Supplementary Figure S1 from The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8
Authors: Li Yanping , Carey Timothy S. , Feng Catherine H. , Zhu Hong-Ming , Sun Xiao-Xin , Dai Mu-Shui
Published: April 2023

Supplementary Fig. S1 shows that knockdown of USP36 decreases the levels of mature miRNAs in HeLa and IMR-90 cells.
Figure S2 from Tumor-derived GCSF Alters Tumor and Systemic Immune System Cell Subset Composition and Signaling
Authors: Matos Israel , Barvalia Maunish , Chehal Manreet K. , Robertson A. Gordon , Kulic Iva , Silva Jessica A.F.D. , Ranganathan Abhinandan , Short Amy , Huang Yu-Hsuan , Long Erin , Priatel John J. , Dhanji Salim , Nelson Brad H. , Krebs Danielle L. , Harder Kenneth W.
Published: April 2023

Supplementary Figure S2 compares the immune cell content in peripheral blood and spleens from immunocompetent, immunocompromised and G-CSFR-/- mice harboring MT or MTG-CSF-/- tumors.
Supplemental Table 1 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

clinical characteristics of discovery (Athens) and validation (Yale) cohorts
Table S3 from IOA-244 is a non-ATP-competitive, highly selective, tolerable phosphoinositide 3-kinase delta inhibitor that targets solid tumors and breaks immune tolerance
Authors: Johnson Zoë , Tarantelli Chiara , Civanelli Elisa , Cascione Luciano , Spriano Filippo , Fraser Amy , Shah Pritom , Nomanbhoy Tyzoon , Napoli Sara , Rinaldi Andrea , Niewola-Staszkowska Karolina , Lahn Michael , Perrin Dominique , Wenes Mathias , Migliorini Denis , Bertoni Francesco , van der Veen Lars , Di Conza Giusy
Published: April 2023

Table showing the raw data of the AUC value of figure 2A
Supplementary Figure 6 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

Extendend analysis of PARP7 expression in prostate cancer
Supplementary Figure 4 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

RBN2397 inhibition of prostate cancer cell growth requires PARP7 over-expression
Supplementary Figure 3 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

The growth inhibitory effect of RBN2397 in prostate cells is not dependent on TBK1 and JAK1/2 kinase activity
Table S3 from Predicting Cancer Risk from Germline Whole-exome Sequencing Data Using a Novel Context-based Variant Aggregation Approach
Authors: Guan Zoe , Begg Colin B. , Shen Ronglai
Published: April 2023

Table S3: AUCs of benchmark WES models using loss-of-function and missense variants.
Supplementary Data S4 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

Data for gene expression signatures.
Supplementary Figure S1 from The GPER agonist LNS8801 induces mitotic arrest and apoptosis in uveal melanoma cells
Authors: Ambrosini Grazia , Natale Christopher A , Musi Elgilda , Garyantes Tina K , Schwartz Gary K.
Published: April 2023

The mitotic effect of LNS8801 is GPER-independent
Table S2 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 S2 shows the patient characteristics OpACIN-neo
Supplemental Figure 5 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 5. Overall survival, disease-specific survival and disease-free survival by age group and treatment type in early-stage rectal cancers.
Figure S2 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 S2 shows a flowchart of patients PRADO study
Supplemental Figure 3 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 3. Kaplan Meier curves for locoregional recurrence (LRR) in (A) early-onset and average-onset patients, (B) early-onset decile groups, and (C) early-onset and average-onset patients that received long-course chemoradiotherapy or (D) short-course radiotherapy.
Supplemental Figure 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 Figure 1. Consort diagram showing patient inclusion at each stage of analysis. Patient groups used in each stage of analysis are adjacent to the indicated analyses. Patients excluded at each stage of analysis are also indicated.
Supplementary Video SV3 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 MyD88−/−
Table ST1 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 age of mice and weight of primary tumours
Supplementary Figure S6 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−/− show similar expression of cell membrane receptors in vitro
Supplementary Figure S1 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

Validation of MSCs TLR4−/−
Supplementary Figure S5 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

Fraction of altered genome density plots
Supplementary Figure S4 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

Proportion of identically assigned SCNAs between samples
Table TS2 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

Summary of MET status tested by NGS, MET inhibitors with clinical outcome and dynamic changes in gene alterations in cohort 3
Figure S2 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

The detection process using NGS of the study.
Data from Multiple germline events contribute to cancer development in patients with Li-Fraumeni syndrome
Authors: Subasri Vallijah , Light Nicholas , Kanwar Nisha , Brzezinski Jack , Luo Ping , Hansford Jordan R , Cairney Elizabeth , Portwine Carol , Elser Christine , Finlay Jonathan L. , Nichols Kim E. , Alon Noa , Brunga Ledia , Anson Jo , Kohlmann Wendy , de Andrade Kelvin C. , Khincha Payal P. , Savage Sharon A. , Schiffman Joshua D , Weksberg Rosanna , Pugh Trevor J. , Villani Anita , Shlien Adam , Goldenberg Anna , Malkin David
Published: April 2023

Abstract
Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbour a pathogenic germline variant in the TP53 tumour suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumour detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of LFS patients (n=396) with variant (n=374) or wildtype TP53 (n=22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harboured a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the non-coding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6 and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in LFS patients with an AUROC of 0.725 [0.633-0.810].
Data from Inhibitor of the Nuclear Transport Protein XPO1 Enhances the Anticancer Efficacy of KRAS G12C Inhibitors in Preclinical Models of KRAS G12C–Mutant Cancers
Authors: Khan Husain Yar , Nagasaka Misako , Li Yiwei , Aboukameel Amro , Uddin Md. Hafiz , Sexton Rachel , Bannoura Sahar , Mzannar Yousef , Al-Hallak Mohammed Najeeb , Kim Steve , Beydoun Rafic , Landesman Yosef , Mamdani Hirva , Uprety Dipesh , Philip Philip A. , Mohammad Ramzi M. , Shields Anthony F. , Azmi Asfar S.
Published: April 2023

The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C–mutated non–small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor–resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin 1 (XPO1), as a single agent. KRAS G12C inhibitors in combination with selinexor suppressed the proliferation of KRAS G12C–mutant cancer cell lines in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C-mutant cancer cells. Mechanistically, the combination of selinexor with KRAS G12C inhibitors suppressed cell growth signaling and downregulated the expression of cell-cycle markers, KRAS and NF-κB as well as increased nuclear accumulation of tumor suppressor protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models.
Significance:
In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for patients with cancer that do not respond or develop resistance to KRAS G12C inhibitor treatment.
Data from Comprehensive Assessment of Anaplastic Lymphoma Kinase in Localized and Metastatic Prostate Cancer Reveals Targetable Alterations
Authors: Patel Radhika A. , Coleman Ilsa , Roudier Martine P. , Konnick Eric Q. , Hanratty Brian , Dumpit Ruth , Lucas Jared M. , Ang Lisa S. , Low Jin-Yih , Tretiakova Maria S. , Ha Gavin , Lee John K. , True Lawrence D. , De Marzo Angelo M. , Nelson Peter S. , Morrissey Colm , Pritchard Colin C. , Haffner Michael C.
Published: April 2023

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is the first-line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by IHC and RNA sequencing, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacologic ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases, we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a novel SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5 of 52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacologic ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Furthermore, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer.
Significance:
Anaplastic lymphoma kinase (ALK) is a validated drug target in cancer. Here we delineate the spectrum of ALK alterations in prostate cancer. We show that ALK overexpression is present in advanced prostate cancers, in particular in cases with features of neuroendocrine carcinoma. Furthermore, ALK expression is associated with responses to pharmacologic ALK inhibition. Our study demonstrates that ALK-directed therapies should be considered in selected prostate cancer cases.
Data from Repurposing Itraconazole and Hydroxychloroquine to Target Lysosomal Homeostasis in Epithelial Ovarian Cancer
Authors: Marastoni Stefano , Madariaga Ainhoa , Pesic Aleksandra , Nair Sree Narayanan , Li Zhu Juan , Shalev Zvi , Ketela Troy , Colombo Ilaria , Mandilaras Victoria , Cabanero Michael , Bruce Jeff P. , Li Xuan , Garg Swati , Wang Lisa , Chen Eric X. , Gill Sarbjot , Dhani Neesha C. , Zhang Wenjiang , Pintilie Melania , Bowering Valerie , Koritzinsky Marianne , Rottapel Robert , Wouters Bradly G. , Oza Amit M. , Joshua Anthony M. , Lheureux Stephanie
Published: April 2023

Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes; similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. In vitro, itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation.
Significance:
The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer.
Data from Development of an Automated Liquid Biopsy Assay for Methylated Markers in Advanced Breast Cancer
Authors: Fackler Mary Jo , Tulac Suzana , Venkatesan Neesha , Aslam Adam J. , de Guzman Timothy N. , Mercado-Rodriguez Claudia , Cope Leslie M. , Downs Bradley M. , Vali Abdul Hussain , Ding Wanjun , Lehman Jennifer , Denbow Rita , Reynolds Jeffrey , Buckley Morgan E. , Visvanathan Kala , Umbricht Christopher B. , Wolff Antonio C. , Stearns Vered , Bates Michael , Lai Edwin W. , Sukumar Saraswati
Published: April 2023

Current molecular liquid biopsy assays to detect recurrence or monitor response to treatment require sophisticated technology, highly trained personnel, and a turnaround time of weeks. We describe the development and technical validation of an automated Liquid Biopsy for Breast Cancer Methylation (LBx-BCM) prototype, a DNA methylation detection cartridge assay that is simple to perform and quantitatively detects nine methylated markers within 4.5 hours. LBx-BCM demonstrated high interassay reproducibility when analyzing exogenous methylated DNA (75–300 DNA copies) spiked into plasma (coefficient of variation, CV = 7.1%–10.9%) and serum (CV = 19.1%–36.1%). It also demonstrated high interuser reproducibility (Spearman r = 0.887, P < 0.0001) when samples of metastatic breast cancer (MBC, N = 11) and normal control (N = 4) were evaluated independently by two users. Analyses of interplatform reproducibility indicated very high concordance between LBx-BCM and the reference assay, cMethDNA, among 66 paired plasma samples [MBC N = 40, controls N = 26; Spearman r = 0.891; 95% confidence interval (CI) = 0.825–0.933, P < 0.0001]. LBx-BCM achieved a ROC AUC = 0.909 (95% CI = 0.836–0.982), 83% sensitivity and 92% specificity; cMethDNA achieved a ROC AUC = 0.896 (95% CI = 0.817–0.974), 83% sensitivity and 92% specificity in test set samples. The automated LBx-BCM cartridge prototype is fast, with performance levels equivalent to the highly sensitive, manual cMethDNA method. Future prospective clinical studies will evaluate LBx-BCM detection sensitivity and its ability to monitor therapeutic response during treatment for advanced breast cancer.
Significance:
We technically validated an automated, cartridge-based, liquid biopsy prototype assay, to quantitatively measure breast cancer methylation in serum or plasma of patients with MBC, that demonstrated high sensitivity and specificity.
Data from Neoantigen Presentation and IFNγ Signaling on the Same Tumor-associated Macrophage are Necessary for CD4 T Cell–mediated Antitumor Activity in Mice
Authors: Perez-Diez Ainhoa , Liu Xiangdong , Matzinger Polly
Published: April 2023

Tumor-associated macrophages (TAM) promote tumor survival, angiogenesis, and metastases. Although they express MHC class II molecules, little is known about their ability to present tumor antigens to tumor-infiltrating CD4 T cells, and the consequences of such presentation. To answer these questions, we used a C57/BL10 mouse tumor model where we subcutaneously implant a bladder carcinoma cell line naturally expressing the H-Y male antigen into female mice, making the H-Y antigen a de facto neoantigen. We found that TAMs indeed present tumor antigens to effector CD4 T cells and that such presentation is necessary for tumor rejection. As a consequence of this interaction, TAMs are reeducated to produce lower amounts of tumor-promoting proteins and greater amounts of inflammatory proteins. The reeducation process of the TAMs is transcriptionally characterized by an IFNγ signature, including genes of known antiviral and antibacterial functions. CD4 production of IFNγ, and not TNFα or CD40L, is required for the reeducation process and tumor rejection. Furthermore, IFNγ signaling on antigen-presenting TAMs and not on bystander TAMs, is necessary for the antitumor effect. These data identify critical mechanisms of tumor rejection by CD4 T cells and underscores the importance of effector CD4 T cell–tissue macrophage interactions not only at the tumors site but potentially in other tissues.
Significance:
In the tumor microenvironment, TAMs are capable of presenting tumor antigens to effector CD4 T cells. Upon antigen recognition, the CD4 cells transform transcriptionally, phenotypically, and functionally the TAMs inducing tumor rejection. This reeducation process requires both cognate interaction and IFNγ signaling on the same macrophage.
Data from Proteome Analysis of Pancreatic Tumors Implicates Extracellular Matrix in Patient Outcome
Authors: Silwal-Pandit Laxmi , Stålberg Stina M. , Johansson Henrik J. , Mermelekas Georgios , Lothe Inger Marie B. , Skrede Martina L. , Dalsgaard Astrid Marie , Nebdal Daniel J. H. , Helland Åslaug , Lingjærde Ole Christian , Labori Knut Jørgen , Skålhegg Bjørn S. , Lehtiö Janne , Kure Elin H.
Published: April 2023

Pancreatic cancer remains a disease with unmet clinical needs and inadequate diagnostic, prognostic, and predictive biomarkers. In-depth characterization of the disease proteome is limited. This study thus aims to define and describe protein networks underlying pancreatic cancer and identify protein centric subtypes with clinical relevance. Mass spectrometry–based proteomics was used to identify and quantify the proteome in tumor tissue, tumor-adjacent tissue, and patient-derived xenografts (PDX)-derived cell lines from patients with pancreatic cancer, and tissues from patients with chronic pancreatitis. We identified, quantified, and characterized 11,634 proteins from 72 pancreatic tissue samples. Network focused analysis of the proteomics data led to identification of a tumor epithelium–specific module and an extracellular matrix (ECM)-associated module that discriminated pancreatic tumor tissue from both tumor adjacent tissue and pancreatitis tissue. On the basis of the ECM module, we defined an ECM-high and an ECM-low subgroup, where the ECM-high subgroup was associated with poor prognosis (median survival months: 15.3 vs. 22.9 months; log-rank test, P = 0.02). The ECM-high tumors were characterized by elevated epithelial–mesenchymal transition and glycolytic activities, and low oxidative phosphorylation, E2F, and DNA repair pathway activities. This study offers novel insights into the protein network underlying pancreatic cancer opening up for proteome precision medicine development.
Significance:
Pancreatic cancer lacks reliable biomarkers for prognostication and treatment of patients. We analyzed the proteome of pancreatic tumors, nonmalignant tissues of the pancreas and PDX-derived cell lines, and identified proteins that discriminate between patients with good and poor survival. The proteomics data also unraveled potential novel drug targets.
Data from Enhanced Costimulatory Signaling Improves CAR T-cell Effector Responses in CLL
Authors: Collins McKensie A. , Jung In-Young , Zhao Ziran , Apodaca Kimberly , Kong Weimin , Lundh Stefan , Fraietta Joseph A. , Kater Arnon P. , Sun Clare , Wiestner Adrian , Melenhorst J. Joseph
Published: April 2023

CD19-redirected chimeric antigen receptor (CAR) T cells have shown remarkable activity against B-cell cancers. While second-generation CARs induce complete remission in >80% of patients with acute lymphoblastic leukemia, similar monotherapy induces long-term remissions in only 26% of patients with chronic lymphocytic leukemia (CLL). This disparity is attributed to cell-intrinsic effector defects in autologous CLL-derived T cells. However, the mechanisms by which leukemic cells impact CAR T-cell potency are poorly understood. Herein we describe an in vitro assay that recapitulates endogenous CLL-mediated T-cell defects in healthy donor CAR T cells. Contact with CLL cells insufficiently activates, but does not irreversibly impair, CAR T-cell function. This state is rescuable by strong antigenic stimulation or IL2, and is not driven by immune suppression. Rather, this activation defect is attributable to low levels of costimulatory molecules on CLL cells, and exogenous costimulation enhanced CAR T-cell activation. We next assessed the stimulatory phenotype of CLL cells derived from different niches within the same patient. Lymph node (LN)-derived CLL cells had a strong costimulatory phenotype and promoted better CAR T-cell degranulation and cytokine production than matched peripheral blood CLL cells. Finally, in vitro CD40L-activated CLL cells acquired a costimulatory phenotype similar to the LN-derived tumor and stimulated improved CAR T-cell proliferation, cytokine production, and cytotoxicity. Together, these data identify insufficient activation as a driver of poor CAR T-cell responses in CLL. The costimulatory phenotype of CLL cells drives differential CAR T-cell responses, and can be augmented by improving costimulatory signaling.
Significance:
CLL cells insufficiently activate CAR T cells, driven by low levels of costimulatory molecules on the tumor. LN-derived CLL cells are more costimulatory and mediate enhanced CAR T-cell killing. This costimulatory phenotype can be modeled via CD40 L activation, and the activated tumor promotes stronger CAR T-cell responses.
Data from A Ketogenic Diet in Combination with Gemcitabine Increases Survival in Pancreatic Cancer KPC Mice
Authors: Cortez Natalia E. , Rodriguez Lanzi Cecilia , Hong Brian V. , Xu Jihao , Wang Fangyi , Chen Shuai , Ramsey Jon J. , Pontifex Matthew G. , Müller Michael , Vauzour David , Vahmani Payam , Hwang Chang-il , Matsukuma Karen , Mackenzie Gerardo G.
Published: April 2023

Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its antitumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 65% carb, 15% protein, 20% fat), a KD (%kcal: 1% carb, 15% protein, 84% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared with mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared with KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data were disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.
Significance:
This article is the first preclinical study to comprehensively evaluate the effect of a KD alongside chemotherapy using a standard autochthonous genetically modified mouse model (in both male and female KPC mice).