bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table S7 from Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor–Positive Primary Human Breast Tumors
Authors: Kim Hyunsoo , Whitman Austin A. , Wisniewska Kamila , Kakati Rasha T. , Garcia-Recio Susana , Calhoun Benjamin C. , Franco Hector L. , Perou Charles M. , Spanheimer Philip M.
Published: December 2023

Comparison of upregulated and downregulated genes in resistant cell subpopulations compared to cluster 2
Supplementary Table S5 from Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor–Positive Primary Human Breast Tumors
Authors: Kim Hyunsoo , Whitman Austin A. , Wisniewska Kamila , Kakati Rasha T. , Garcia-Recio Susana , Calhoun Benjamin C. , Franco Hector L. , Perou Charles M. , Spanheimer Philip M.
Published: December 2023

Response to tamoxifen in InferCNV+ malignant cells within the selected 4 pairs of ER+/HER2- tumors.
Supplementary Table S4 from Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor–Positive Primary Human Breast Tumors
Authors: Kim Hyunsoo , Whitman Austin A. , Wisniewska Kamila , Kakati Rasha T. , Garcia-Recio Susana , Calhoun Benjamin C. , Franco Hector L. , Perou Charles M. , Spanheimer Philip M.
Published: December 2023

T47D response to tamoxifen
Table S1,Table S2 from Near-Infrared Spectral Tomography for Predicting Residual Cancer Burden during Early-Stage Neoadjuvant Chemotherapy for Breast Cancer
Authors: Cao Xu , Muller Kristen E. , Chamberlin Mary D. , Gui Jiang , Kaufman Peter A. , Schwartz Gary N. , diFlorio-Alexander Roberta M. , Pogue Brian W. , Paulsen Keith D. , Jiang Shudong
Published: December 2023

Supplementary Table 1;Supplementary Table 2
Supplementary Table S9 from Differential Benefit of Metronomic Chemotherapy Among Triple-Negative Breast Cancer Subtypes Treated in the IBCSG Trial 22–00
Authors: Joaquin Garcia Andrea , Rediti Mattia , Venet David , Majjaj Samira , Kammler Roswitha , Munzone Elisabetta , Gianni Lorenzo , Thürlimann Beat , Laáng István , Colleoni Marco , Loi Sherene , Viale Giuseppe , Regan Meredith M. , Buisseret Laurence , Rothé Françoise , Sotiriou Christos
Published: December 2023

Clinic-pathologic characteristics across the TIME subtypes.
Supplementary Table 1 from Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up
Authors: Lindskrog Sia V. , Birkenkamp-Demtröder Karin , Nordentoft Iver , Laliotis George , Lamy Philippe , Christensen Emil , Renner Derrick , Andreasen Tine G. , Lange Naja , Sharma Shruti , ElNaggar Adam C. , Liu Minetta C. , Sethi Himanshu , Aleshin Alexey , Agerbæk Mads , Jensen Jørgen B. , Dyrskjøt Lars
Published: December 2023

Univariate- and multivariable cox regression analysis
Supplementary Figure S9 from Differential Benefit of Metronomic Chemotherapy Among Triple-Negative Breast Cancer Subtypes Treated in the IBCSG Trial 22–00
Authors: Joaquin Garcia Andrea , Rediti Mattia , Venet David , Majjaj Samira , Kammler Roswitha , Munzone Elisabetta , Gianni Lorenzo , Thürlimann Beat , Laáng István , Colleoni Marco , Loi Sherene , Viale Giuseppe , Regan Meredith M. , Buisseret Laurence , Rothé Françoise , Sotiriou Christos
Published: December 2023

Boxplot showing the distribution of TILs levels across the different TNBC classifications.
Supplementary Figure S4 from Differential Benefit of Metronomic Chemotherapy Among Triple-Negative Breast Cancer Subtypes Treated in the IBCSG Trial 22–00
Authors: Joaquin Garcia Andrea , Rediti Mattia , Venet David , Majjaj Samira , Kammler Roswitha , Munzone Elisabetta , Gianni Lorenzo , Thürlimann Beat , Laáng István , Colleoni Marco , Loi Sherene , Viale Giuseppe , Regan Meredith M. , Buisseret Laurence , Rothé Françoise , Sotiriou Christos
Published: December 2023

Kaplan-Meier estimates for OS, DRFI and BCFI measures between CM and no-CM cohorts across the Burstein TNBC molecular subtypes.
Supplementary Figure S1 from Upregulation of Indoleamine 2,3-Dioxygenase 1 in Tumor Cells and Tertiary Lymphoid Structures is a Hallmark of Inflamed Non–Small Cell Lung Cancer
Authors: Bessede Alban , Peyraud Florent , Le Moulec Sylvestre , Cousin Sophie , Cabart Mathilde , Chomy François , Rey Christophe , Lara Oren , Odin Ophélie , Nafia Imane , Guegan Jean-Philippe , Italiano Antoine
Published: December 2023

PDL1 expression, TLS status and histological subtypes are associated with improved survivals upon atezolizumab treatment in NSCLC.
Supplementary Table S3 from Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)
Authors: Ring Alistair , Kilburn Lucy S. , Pearson Alex , Moretti Laura , Afshari-Mehr Angelica , Wardley Andrew M. , Gurel Bora , Macpherson Iain R. , Riisnaes Ruth , Baird Richard D. , Martin Sue , Roylance Rebecca , Johnson Hannah , Ferreira Ana , Winter Matthew C. , Dunne Kathryn , Copson Ellen , Hickish Tamas , Burcombe Russell , Randle Kat , Serra Violeta , Llop-Guevara Alba , Bliss Judith M. , Turner Nicolas C.
Published: December 2023

Table S3. List of centres and recruitment
Supplementary Table S2 from Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)
Authors: Ring Alistair , Kilburn Lucy S. , Pearson Alex , Moretti Laura , Afshari-Mehr Angelica , Wardley Andrew M. , Gurel Bora , Macpherson Iain R. , Riisnaes Ruth , Baird Richard D. , Martin Sue , Roylance Rebecca , Johnson Hannah , Ferreira Ana , Winter Matthew C. , Dunne Kathryn , Copson Ellen , Hickish Tamas , Burcombe Russell , Randle Kat , Serra Violeta , Llop-Guevara Alba , Bliss Judith M. , Turner Nicolas C.
Published: December 2023

Table S2.Representativeness of Study Participants
Supplementary Figure S3 from Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)
Authors: Ring Alistair , Kilburn Lucy S. , Pearson Alex , Moretti Laura , Afshari-Mehr Angelica , Wardley Andrew M. , Gurel Bora , Macpherson Iain R. , Riisnaes Ruth , Baird Richard D. , Martin Sue , Roylance Rebecca , Johnson Hannah , Ferreira Ana , Winter Matthew C. , Dunne Kathryn , Copson Ellen , Hickish Tamas , Burcombe Russell , Randle Kat , Serra Violeta , Llop-Guevara Alba , Bliss Judith M. , Turner Nicolas C.
Published: December 2023

Figure S3. Best percentage change from baseline for sum of the target lesions (n=70) by BRCA mutation status
Figure 4 from Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)
Authors: Ring Alistair , Kilburn Lucy S. , Pearson Alex , Moretti Laura , Afshari-Mehr Angelica , Wardley Andrew M. , Gurel Bora , Macpherson Iain R. , Riisnaes Ruth , Baird Richard D. , Martin Sue , Roylance Rebecca , Johnson Hannah , Ferreira Ana , Winter Matthew C. , Dunne Kathryn , Copson Ellen , Hickish Tamas , Burcombe Russell , Randle Kat , Serra Violeta , Llop-Guevara Alba , Bliss Judith M. , Turner Nicolas C.
Published: December 2023

Treatment-emergent AEs more than 10% incidence.
Figure 2 from Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)
Authors: Ring Alistair , Kilburn Lucy S. , Pearson Alex , Moretti Laura , Afshari-Mehr Angelica , Wardley Andrew M. , Gurel Bora , Macpherson Iain R. , Riisnaes Ruth , Baird Richard D. , Martin Sue , Roylance Rebecca , Johnson Hannah , Ferreira Ana , Winter Matthew C. , Dunne Kathryn , Copson Ellen , Hickish Tamas , Burcombe Russell , Randle Kat , Serra Violeta , Llop-Guevara Alba , Bliss Judith M. , Turner Nicolas C.
Published: December 2023

Swimmer plots for evaluable population with (A) germline BRCA mutations (n = 10) and (B) no germline or somatic BRCA mutations (n = 55).
Supplementary Table S1 from Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers
Authors: Tang Tin-Yun , Nichetti Federico , Kaplan Ben , Lonardi Sara , Pietrantonio Filippo , Salvatore Lisa , Vivaldi Caterina , Rimassa Lorenza , de Braud Filippo , Rizzato Mario Domenico , Pavlick Dean , Chu Randy , Danner De Armas Anaemy , Sharaf Radwa , Sokol Ethan , Rodon Ahnert Jordi , Ross Jeffrey S. , Javle Milind , Niger Monica
Published: December 2023

Supplemental Table S1: Extended data on the clinicodemographics for the Genomics Cohort
Figure S1 from Randomized Phase II Trial of Dendritic Cell/Myeloma Fusion Vaccine with Lenalidomide Maintenance after Upfront Autologous Hematopoietic Cell Transplantation for Multiple Myeloma: BMT CTN 1401
Authors: Chung David J. , Shah Nina , Wu Juan , Logan Brent , Bisharat Lina , Callander Natalie , Cheloni Giulia , Anderson Kenneth , Chodon Thinle , Dhakal Binod , Devine Steve , Somaiya Dutt Poorvi , Efebera Yvonne , Geller Nancy , Ghiasuddin Haider , Hematti Peiman , Holmberg Leona , Howard Alan , Johnson Bryon , Karagkouni Dimitra , Lazarus Hillard M. , Malek Ehsan , McCarthy Philip , McKenna David , Mendizabal Adam , Nooka Ajay , Munshi Nikhil , O'Donnell Lynn , Rapoport Aaron P. , Reese Jane , Rosenblatt Jacalyn , Soiffer Robert , Stroopinsky Dina , Uhl Lynne , Vlachos Ioannis S. , Waller Edmund K. , Young James W. , Pasquini Marcelo C. , Avigan David
Published: December 2023

Supplemental Figure 1: (A) Progression Free Survival Kaplan Meier Curve. (B) Overall Survival Kaplan Meier Curve.
Supplementary Figure S1 from Clinical Behavior and Molecular Landscape of Stage I p53-Abnormal Low-Grade Endometrioid Endometrial Carcinomas
Authors: Jamieson Amy , Vermij Lisa , Kramer Claire J.H. , Jobsen Jan J. , Jürgemlienk-Schulz Ina , Lutgens Ludy , Mens Jan Willem , Haverkort Marie A.D. , Slot Annerie , Nout Remi A. , Oosting Jan , Carlson Joseph , Howitt Brooke E. , Ip Philip P.C. , Lax Sigurd F. , McCluggage W. Glenn , Singh Naveena , McAlpine Jessica N. , Creutzberg Carien L. , Horeweg Nanda , Gilks C. Blake , Bosse Tjalling
Published: December 2023

Representative relative copy number plots.
Supplementary Data 2 from Tumor-Infiltrating Normal B Cells Revealed by Immunoglobulin Repertoire Clonotype Analysis Are Highly Prognostic and Crucial for Antitumor Immune Responses in DLBCL
Authors: Xu-Monette Zijun Y. , Li Yong , Snyder Thomas , Yu Tiantian , Lu Tingxun , Tzankov Alexandar , Visco Carlo , Bhagat Govind , Qian Wenbin , Dybkaer Karen , Chiu April , Tam Wayne , Zu Youli , Hsi Eric D. , Hagemeister Fredrick B. , Wang Yingjun , Go Heounjeong , Ponzoni Maurilio , Ferreri Andrés J.M. , Møller Michael B. , Parsons Benjamin M. , Fan Xiangshan , van Krieken J. Han , Piris Miguel A. , Winter Jane N. , Au Qingyan , Kirsch Ilan , Zhang Mingzhi , Shaughnessy John , Xu Bing , Young Ken H.
Published: December 2023

List of top 10 sequences in the individual IGH repertoires of 138 DLBCL cases with a diagnostic IGH clonotype identified
Data from A Prospective Study Exploring the Safety and Efficacy of Lenvatinib for Patients with Advanced Hepatocellular Carcinoma and High Tumor Burden: The LAUNCH Study
Authors: Kobayashi Kazufumi , Ogasawara Sadahisa , Maruta Susumu , Okubo Tomomi , Itokawa Norio , Haga Yuki , Seko Yuya , Moriguchi Michihisa , Watanabe Shunji , Shiko Yuki , Takatsuka Hirokazu , Kanzaki Hiroaki , Koroki Keisuke , Inoue Masanori , Nakamura Masato , Kiyono Soichiro , Kanogawa Naoya , Kondo Takayuki , Suzuki Eiichiro , Ooka Yoshihiko , Nakamoto Shingo , Inaba Yosuke , Ikeda Masafumi , Okabe Shinichiro , Morimoto Naoki , Itoh Yoshito , Nakamura Kazuyoshi , Ito Kenji , Azemoto Ryosaku , Atsukawa Masanori , Itobayashi Ei , Kato Naoya
Published: December 2023

AbstractPurpose:
This study aimed to investigate the safety and efficacy of lenvatinib in real-world settings, including patients excluded from the REFLECT trial, a phase III trial that compared lenvatinib with sorafenib.
Patients and Methods:
This multicenter, nonrandomized, open-label prospective study was conducted at 10 medical facilities in Japan (jRCTs031190017). Eligible patients had advanced hepatocellular carcinoma (HCC) and were suitable for lenvatinib therapy. The study included patients with high tumor burden (with >50% intrahepatic tumor volume, main portal vein invasion, or bile duct invasion), Child-Pugh B status, and receiving lenvatinib as second-line therapy following atezolizumab plus bevacizumab.
Results:
From December 2019 to September 2021, 59 patients were analyzed (47 and 12 patients with Child-Pugh A and B, respectively). In patients with Child-Pugh A, the frequency of aspartate aminotransferase elevation was high (72.7%) in the high-burden group. No other significant ad verse events (AE) were observed even in second-line treatment. However, patients with Child-Pugh B had high incidence of grade ≥3 AE (100.0%) and high discontinuation rates caused by AE (33.3%) compared with patients with Child-Pugh A (80.9% and 17.0%, respectively). Median progression-free survival was 6.4 and 2.5 months and median overall survival was 19.7 and 4.1 months in Child-Pugh A and B, respectively. Lenvatinib plasma concentration was higher in patients with Child-Pugh B on days 8 and 15 and correlated with dose modifications and lower relative dose intensity.
Conclusions:
Lenvatinib is safe and effective for advanced HCC in patients with Child-Pugh A, even with high tumor burden. However, it carries a higher risk of AE and may not provide adequate efficacy for patients with Child-Pugh B status.
Data from Genetic Predictors of Ibrutinib-related Cardiovascular Side Effects in Patients with Chronic Lymphocytic Leukemia
Authors: Hamadeh Issam S. , Patel Jai N. , Jacobs Ryan , Zeng Hang , He Jiaxian , Hu Bei , Moyo Tamara Kay , Soni Amy , Park Steven , Copelan Ed , Avalos Belinda , Hamilton Alicia , Steuerwald Nury , Ghosh Nilanjan
Published: December 2023

AbstractPurpose:
Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib are at risk of developing cardiovascular side effects (CVSE). The molecular determinants of CVSEs have not been fully elucidated. We interrogated genetic polymorphisms in the Bruton tyrosine kinase (BTK) signaling pathway for their association with ibrutinib-related CVSEs.
Experimental Design:
We conducted a retrospective/prospective observational pharmacogenetic study of 50 patients with newly diagnosed or relapsed CLL who received ibrutinib at a starting daily dose of 420 mg for at least 6 months. CVSEs, primarily atrial fibrillation and hypertension, occurred in 10 patients (20%), of whom 4 discontinued therapy. DNA was isolated from buccal swabs of all 50 patients and genotyped for 40 SNPs in GATA4, SGK1, KCNQ1, KCNA4, NPPA, and SCN5A using a customized next-generation sequencing panel. Univariate and multivariate logistic regression analysis were performed to determine genetic and clinical factors associated with the incidence of ibrutinib-related CVSEs.
Results:
GATA4 rs804280 AA (P = 0.043), KCNQ1 rs163182 GG (P = 0.036), and KCNQ1 rs2237895 AA (P = 0.023) genotypes were univariately associated with ibrutinib-related CVSEs. On the basis of multivariate analysis, a high genetic risk score, defined as the presence of at least two of these genotypes, was associated with 11.5-fold increased odds of CVSEs (P = 0.019; 95% confidence interval, 1.79–119.73).
Conclusions:
Our findings suggest possible genetic determinants of ibrutinib-related CVSEs in CLL. If replicated in a larger study, pretreatment pharmacogenetic testing for GATA4 and KCNQ1 polymorphisms may be a useful clinical tool for personalizing treatment selection for CLL and/or instituting early risk mitigation strategies.
Data from Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor–Positive Primary Human Breast Tumors
Authors: Kim Hyunsoo , Whitman Austin A. , Wisniewska Kamila , Kakati Rasha T. , Garcia-Recio Susana , Calhoun Benjamin C. , Franco Hector L. , Perou Charles M. , Spanheimer Philip M.
Published: December 2023

AbstractPurpose:
In estrogen receptor–positive (ER+)/HER2− breast cancer, multiple measures of intratumor heterogeneity are associated with a worse response to endocrine therapy. We sought to develop a novel experimental model to measure heterogeneity in response to tamoxifen treatment in primary breast tumors.
Experimental Design:
To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live normal breast specimens and human tumors immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. Live primary cell suspensions were treated ex vivo with tamoxifen (10 μmol/L) or control media for 12 hours, and single-cell RNA libraries were generated using the 10X Genomics droplet-based kit.
Results:
In total, we obtained and processed normal breast tissue from two women undergoing reduction mammoplasty and tumor tissue from 10 women with ER+/HER2− invasive breast carcinoma. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from resistant subpopulations predict poor outcomes in two large cohorts of ER+ breast cancer patients and are enriched in endocrine therapy–resistant tumors.
Conclusions:
This novel ex vivo model system now provides the foundation to define responsive and resistant subpopulations within heterogeneous human tumors, which can be used to develop precise single cell–based predictors of response to therapy and to identify genes and pathways driving therapeutic resistance.
Data from Fibroblast Activation Protein-Targeted Radioligand Therapy with 177Lu-EB-FAPI for Metastatic Radioiodine-Refractory Thyroid Cancer: First-in-Human, Dose-Escalation Study
Authors: Fu Hao , Huang Jingxiong , Zhao Tianzhi , Wang Hongjian , Chen Yuhang , Xu Weizhi , Pang Yizhen , Guo Wei , Sun Long , Wu Hua , Xu Pengfei , Su Bishan , Zhang Jingjing , Chen Xiaoyuan , Chen Haojun
Published: December 2023

AbstractPurpose:
Fibroblast activation protein (FAP) is a promising target for tumor treatment. In this study, we aimed to investigate the safety and efficacy of the albumin binder-conjugated FAP-targeted radiopharmaceutical, 177Lu-EB-FAPI (177Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC).
Patients and Methods:
This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week 177Lu-LNC1004 treatment cycle in patients with mRAIR-TC at 2.22 GBq initially, with subsequent cohorts receiving an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed.
Results:
177Lu-LNC1004 administration was well tolerated, with no life-threatening adverse events observed. No patients experienced DLT in Group A (2.22 GBq/cycle). One patient experienced grade 4 thrombocytopenia in Group B (3.33 GBq/cycle); hence, another three patients were enrolled, none of whom experienced DLT. Two patients experienced grade 3 and 4 hematotoxicity in Group C (4.99 GBq/cycle). The mean whole-body effective dose was 0.17 ± 0.04 mSv/MBq. Intense 177Lu-LNC1004 uptake and prolonged tumor retention resulted in high mean absorbed tumor doses (8.50 ± 12.36 Gy/GBq). The mean effective half-lives for the whole-body and tumor lesions were 90.20 ± 7.68 and 92.46 ± 9.66 hours, respectively. According to RECIST, partial response, stable disease, and progressive disease were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively. The objective response and disease control rates were 25% and 83%, respectively.
Conclusions:
FAP-targeted radioligand therapy with 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated in patients with advanced mRAIR-TC, with high radiation dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects.
Data from Differential Benefit of Metronomic Chemotherapy Among Triple-Negative Breast Cancer Subtypes Treated in the IBCSG Trial 22–00
Authors: Joaquin Garcia Andrea , Rediti Mattia , Venet David , Majjaj Samira , Kammler Roswitha , Munzone Elisabetta , Gianni Lorenzo , Thürlimann Beat , Laáng István , Colleoni Marco , Loi Sherene , Viale Giuseppe , Regan Meredith M. , Buisseret Laurence , Rothé Françoise , Sotiriou Christos
Published: December 2023

AbstractPurpose:
To explore whether specific triple-negative breast cancer (TNBC) molecular subtypes are predictive for a benefit from maintenance low-dose cyclophosphamide and methotrexate (CM) in the adjuvant IBCSG 22–00 phase III clinical trial.
Experimental Design:
RNA sequencing was performed on a selection of 347 TNBC formalin-fixed paraffin-embedded (FFPE) tumor samples following a case–cohort-like sampling. TNBC subtypes were computed on gene expression data. The association between TNBC subtypes and treatment outcome was assessed using a Cox proportional-hazards interaction test.
Results:
Immunomodulatory (IM) and basal-like/immune activated (BLIA) molecular subtypes showed a significant survival benefit when treated with low-dose CM [disease-free survival (DFS): HR, 0.5; 95% confidence interval (CI), 0.28–0.89; Pinteraction = 0.018 and HR, 0.49; 95% CI, 0.27–0.9; Pinteraction = 0.021]. Moreover, a high expression of regulatory T-cell immune signature was associated with a better prognosis in the CM arm, in line with a potential immunomodulating role of cyclophosphamide. In contrast, a worse outcome was observed in tumors with a mesenchymal (M) subtype treated with low-dose CM (DFS: HR, 1.9; 95% CI, 1.2–3; Pinteraction = 0.0044).
Conclusions:
Our results show a differential benefit of low-dose CM therapy across different TNBC subtypes. Low-dose CM therapy could be considered as a potential strategy for TNBC tumors with IM subtype in the early-disease setting.
Data from Upregulation of Indoleamine 2,3-Dioxygenase 1 in Tumor Cells and Tertiary Lymphoid Structures is a Hallmark of Inflamed Non–Small Cell Lung Cancer
Authors: Bessede Alban , Peyraud Florent , Le Moulec Sylvestre , Cousin Sophie , Cabart Mathilde , Chomy François , Rey Christophe , Lara Oren , Odin Ophélie , Nafia Imane , Guegan Jean-Philippe , Italiano Antoine
Published: December 2023

AbstractPurpose:
Overexpression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) has been reported in several tumor types, including non–small cell lung cancer (NSCLC), and has been shown to promote tumor-immune evasion and inhibit T-cell activation through increased tryptophan degradation and the production of several immunosuppressive metabolites collectively known as kynurenines. However, it remains unclear whether IDO1 expression by tumor cells is detrimental specifically in the context of programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis blockade.
Experimental Design:
We analyzed the transcriptome of 891 NSCLC tumor samples from patients enrolled in two large randomized clinical trials investigating the safety and activity of atezolizumab, a humanized IgG1 mAb that targets PD-L1, versus docetaxel in patients with advanced NSCLC. We complemented these transcriptomics results at the protein level by using multiplex immunofluorescence and at the functional level with in vitro experiments.
Results:
The increased expression of the tryptophan-catabolizing enzyme IDO1 was significantly associated with improved objective response, progression-free survival, and overall survival in patients treated with PD-L1 inhibitors, but not in those treated with chemotherapy. Strikingly, inflamed tumors had higher levels of IDO1, and IDO1 was also expressed in tertiary lymphoid structures (TLS) by mature follicular dendritic cells. L-kynurenine impaired the differentiation of antibody-producing B cells induced by follicular helper T (Tfh)/B-cell interactions, a hallmark process within TLS.
Conclusions:
IDO1 pathway in NSCLC is driven by the immune system rather than by tumor cells. Targeting IDO1 in combination with anti–PD-1/PD-L1 might be beneficial only in patients with inflamed tumors and particularly in those bearing TLS.
Data from PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors
Authors: Stokes Michael E. , Calvo Veronica , Fujisawa Sho , Dudgeon Crissy , Huang Sharon , Ballal Nupur , Shen Leyi , Gasparek Jennifer , Betzenhauser Matthew , Taylor Simon J. , Staschke Kirk A. , Rigby Alan C. , Mulvihill Mark J. , Bose Nandita , Lightcap Eric S. , Surguladze David
Published: December 2023

AbstractPurpose:
Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).
Experimental Design:
HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.
Results:
VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group.
Conclusions:
By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.
Data from Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers
Authors: Tang Tin-Yun , Nichetti Federico , Kaplan Ben , Lonardi Sara , Pietrantonio Filippo , Salvatore Lisa , Vivaldi Caterina , Rimassa Lorenza , de Braud Filippo , Rizzato Mario Domenico , Pavlick Dean , Chu Randy , Danner De Armas Anaemy , Sharaf Radwa , Sokol Ethan , Rodon Ahnert Jordi , Ross Jeffrey S. , Javle Milind , Niger Monica
Published: December 2023

AbstractPurpose:
BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC.
Experimental Design:
We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a “genomic cohort” [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional “clinical cohort” of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT).
Results:
In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS.
Conclusions:
In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.
Data from Suppression of Tumor Cell Lactate-generating Signaling Pathways Eradicates Murine PTEN/p53-deficient Aggressive-variant Prostate Cancer via Macrophage Phagocytosis
Authors: Chaudagar Kiranj , Hieromnimon Hanna M. , Kelley Anne , Labadie Brian , Shafran Jordan , Rameshbabu Srikrishnan , Drovetsky Catherine , Bynoe Kaela , Solanki Ani , Markiewicz Erica , Fan Xiaobing , Loda Massimo , Patnaik Akash
Published: December 2023

AbstractPurpose:
Phosphatase and tensin homolog (PTEN) loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy/PI3K inhibitor (PI3Ki)/programmed cell death protein 1 (PD-1) antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM. Here, we targeted immunometabolic mechanism(s) of PI3Ki resistance, with the goal of durable tumor control in AVPC.
Experimental Design:
Pb-Cre;PTENfl/flTrp53fl/fl GEM were treated with PI3Ki (copanlisib), MEK inhibitor (trametinib) or Porcupine inhibitor (LGK'974) singly or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo coculture mechanistic studies were performed on GEM tumors or corresponding tumor-derived cell lines.
Results:
Given our proteomic profiling showing persistent MEK signaling within tumors of PI3Ki-resistant GEM, we tested whether addition of trametinib to copanlisib enhances tumor control in GEM, and we observed 80% overall response rate via additive suppression of lactate within TME and H3K18lac within TAM, relative to copanlisib (37.5%) monotherapy. The 20% resistant mice demonstrated feedback Wnt/β-catenin activation, resulting in restoration of lactate secretion by tumor cells and H3K18lac within TAM. Cotargeting Wnt/β-catenin signaling with LGK'974 in combination with PI3Ki/MEKi, demonstrated durable tumor control in 100% mice via H3K18lac suppression and complete TAM activation.
Conclusions:
Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.
Data from ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V.
Published: December 2023

AbstractPurpose:
Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non–small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated.
Experimental Design:
Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of ATM loss on STING signaling and chemotherapy sensitivity in preclinical models.
Results:
Nonsynonymous mutations in ATM were observed in 11.2% of samples (2,980/26,587) and were significantly associated with mutations in KRAS, but mutually exclusive with EGFR (q < 0.1). KRAS mutational status constrained the ATM co-mutation landscape, with strong mutual exclusivity with TP53 and KEAP1 within KRAS-mutated samples. Those ATM mutations that co-occurred with TP53 were more likely to be missense mutations and associate with high mutational burden, suggestive of non-functional passenger mutations. In the CGDB cohort, dysfunctional ATM mutations associated with improved OS only in patients treated with ICI-chemotherapy, and not ICI alone. In vitro analyses demonstrated enhanced upregulation of STING signaling in ATM knockout cells with the addition of chemotherapy.
Conclusions:
ATM mutations define a distinct subset of NSCLC associated with KRAS mutations, increased TMB, decreased TP53 and EGFR co-occurrence, and potential increased sensitivity to ICIs in the context of DNA-damaging chemotherapy.
Pancreatic Cancer's PD1-Roadblock: When T-Cell Reinvigoration Is Not Enough
Authors: Lander Varintra E. , DeNardo David G.
Published: December 2023

PD1-blockade combinations in pancreatic ductal adenocarcinoma have been poorly effective, and the underlying reasons for this are unknown. A recent study revealed that chemoradiation plus PD1-blockade reinvigorates tumor-specific T cells; however, this T-cell activation is accompanied with exaggerated NFκB signaling, which may limit productive tumor-controlling immunity.

See related article by Ali et al., p. 542
Supplementary Data from EGFR Inhibition Overcomes Resistance to FGFR4 Inhibition and Potentiates FGFR4 Inhibitor Therapy in Hepatocellular Carcinoma
Authors: Shen Bin , Shi Jue-Ping , Zhu Zhi-Xuan , He Zhi-Dong , Liu Shen-Yan , Shi Wan , Zhang Yong-Xian , Ying Hai-Yan , Wang Jie , Xu Rui-Feng , Fang Fei , Chang Harrison Xuesong , Chen Zhui , Zhang Nan-Nan
Published: December 2023

Supplementary Data
Supplementary Table S4 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Mean Tumor volumes and mouse body weights from cell line xenograft studies treated with CLDN18.2-207-mAb (Figure 4A)
Supplementary Methodology from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

All supplementary methodologies are desribed
Supplemental Figure S7 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Expression of CLDN18.2 is normal tissues.
Supplemental Figure S6 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Expression of CLDN18.2 in different human cancer types.
Supplemental Figure S5 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

CLDN18.2 expression in human pancreas PDX models.
Supplemental Figure S4 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Selective efficacy of CLDN18.2-307-ADC compared to non-targeting control ADC in CLDN18.2 positive cell line xenografts.
Supplemental Figure S2 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

CLDN18.2-307-ADC binds with high affinity to CLDN18.2 but not CLDN18.1.
Supplemental Figure S1 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Selectivity of IHC antibody (AB222512) for CLDN18.2.
Supplementary Fig S6 from Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers
Authors: Khan Husain Yar , Nagasaka Misako , Aboukameel Amro , Alkhalili Osama , Uddin Md. Hafiz , Bannoura Sahar F. , Mzannar Yousef , Azar Ibrahim , Beal Eliza W. , Tobon Miguel E. , Kim Steve H. , Beydoun Rafic , Baloglu Erkan , Senapedis William , El-Rayes Bassel F. , Philip Philip A. , Mohammad Ramzi M. , Shields Anthony F. , Al Hallak Mohammed Najeeb , Azmi Asfar S.
Published: December 2023

Suppl Fig S6 shows colony counts from the colony formation assay data shown in Figure 3A
Supplementary Fig S2 from Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers
Authors: Khan Husain Yar , Nagasaka Misako , Aboukameel Amro , Alkhalili Osama , Uddin Md. Hafiz , Bannoura Sahar F. , Mzannar Yousef , Azar Ibrahim , Beal Eliza W. , Tobon Miguel E. , Kim Steve H. , Beydoun Rafic , Baloglu Erkan , Senapedis William , El-Rayes Bassel F. , Philip Philip A. , Mohammad Ramzi M. , Shields Anthony F. , Al Hallak Mohammed Najeeb , Azmi Asfar S.
Published: December 2023

Suppl Fig S2 shows PAK4-KRAS synthetic lethal interaction identified using the Slorth database
Supplementary Figure 6 C_D from Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition
Authors: Noonepalle Satish Kumar R. , Grindrod Scott , Aghdam Nima , Li Xintang , Gracia-Hernandez Maria , Zevallos-Delgado Christian , Jung Mira , Villagra Alejandro , Dritschilo Anatoly
Published: December 2023

Supplementary Figure 6 C_D
Supplementary Figure 6 A_B from Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition
Authors: Noonepalle Satish Kumar R. , Grindrod Scott , Aghdam Nima , Li Xintang , Gracia-Hernandez Maria , Zevallos-Delgado Christian , Jung Mira , Villagra Alejandro , Dritschilo Anatoly
Published: December 2023

Supplementary Figure 6 A_B
Supplementary Figure 4 from Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition
Authors: Noonepalle Satish Kumar R. , Grindrod Scott , Aghdam Nima , Li Xintang , Gracia-Hernandez Maria , Zevallos-Delgado Christian , Jung Mira , Villagra Alejandro , Dritschilo Anatoly
Published: December 2023

Supplementary Figure 4
Supplementary Data from RYZ101 (Ac-225 DOTATATE) Opportunity beyond Gastroenteropancreatic Neuroendocrine Tumors: Preclinical Efficacy in Small-Cell Lung Cancer
Authors: Han Guangzhou , Hwang Eunmi , Lin Fanching , Clift Renee , Kim Daniel , Guest Matt , Bischoff Eric , Moran Susan , Li Gary
Published: December 2023

Tables S1-S4; Figures S1-S3
Supplementary Figure 3 from Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition
Authors: Noonepalle Satish Kumar R. , Grindrod Scott , Aghdam Nima , Li Xintang , Gracia-Hernandez Maria , Zevallos-Delgado Christian , Jung Mira , Villagra Alejandro , Dritschilo Anatoly
Published: December 2023

Supplementary Figure 3
Table S1 from Novel Thienoduocarmycin–Trastuzumab ADC Demonstrates Strong Antitumor Efficacy with Favorable Safety Profile in Preclinical Studies
Authors: Valsasina Barbara , Orsini Paolo , Caruso Michele , Albanese Clara , Ciavolella Antonella , Cucchi Ulisse , Fraietta Ivan , Melillo Nicola , Fiorentini Francesco , Rizzi Simona , Salsa Matteo , Isacchi Antonella , Gasparri Fabio
Published: December 2023

Cell lines used in the study with providers, date of master banking and growth media compositions
Figure S2 from Novel Thienoduocarmycin–Trastuzumab ADC Demonstrates Strong Antitumor Efficacy with Favorable Safety Profile in Preclinical Studies
Authors: Valsasina Barbara , Orsini Paolo , Caruso Michele , Albanese Clara , Ciavolella Antonella , Cucchi Ulisse , Fraietta Ivan , Melillo Nicola , Fiorentini Francesco , Rizzi Simona , Salsa Matteo , Isacchi Antonella , Gasparri Fabio
Published: December 2023

Half-life determination of NMS-P528 +self immolative spacer at different pH and timepoints
Supplementary Data from Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor
Authors: Lemberg Kathryn M. , Ali Eunus S. , Krecmerova Marcela , Aguilar Joanna Marie H. , Alt Jesse , Peters Diane E. , Zhao Liang , Wu Ying , Nuha Naziba , Asara John M. , Staedtke Verena , Pratilas Christine A. , Majer Pavel , Rais Rana , Ben-Sahra Issam , Slusher Barbara S.
Published: December 2023

Supplementary Materials and Figures
Supplementary Table S4 from C-X-C Motif Chemokine Ligand 9 Correlates with Favorable Prognosis in Triple-Negative Breast Cancer by Promoting Immune Cell Infiltration
Authors: Cao Xi , Song Yu , Wu Huanwen , Ren Xinyu , Sun Qiang , Liang Zhiyong
Published: December 2023

Supplementary Table S4 shows the infiltration of different immune cells between the low- and high- CXCL9 mRNA groups in basal-like subtype of TCGA BRCA cohort (n=140).
Supplementary Table S2 from C-X-C Motif Chemokine Ligand 9 Correlates with Favorable Prognosis in Triple-Negative Breast Cancer by Promoting Immune Cell Infiltration
Authors: Cao Xi , Song Yu , Wu Huanwen , Ren Xinyu , Sun Qiang , Liang Zhiyong
Published: December 2023

Supplementary Table S2 shows the CXCL9 mRNA expression level and clinicopathological features in the basal-like subtype of TCGA BRCA cohort (n=138).
Supplementary Table S1 from C-X-C Motif Chemokine Ligand 9 Correlates with Favorable Prognosis in Triple-Negative Breast Cancer by Promoting Immune Cell Infiltration
Authors: Cao Xi , Song Yu , Wu Huanwen , Ren Xinyu , Sun Qiang , Liang Zhiyong
Published: December 2023

Supplementary Table S1 shows the spearman correlation analyses between CXCL9 expression and other immune markers in the PUMCH TNBC cohort (n=268). Abbreviations: TNBC, triple-negative breast cancer; IC, immune cell; TC, tumor cell; TILs, tumor-infiltrating lymphocytes.
Supplementary Figure 5 from Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas
Authors: Ehteda Anahid , Khan Aaminah , Rajakumar Gayathiri , Vanniasinghe Anne S. , Gopalakrishnan Anjana , Liu Jie , Tsoli Maria , Ziegler David S.
Published: December 2023

Combination of TRX-E-009-1 and SAHA is synergistic against DIPG.
Data from EGFR Inhibition Overcomes Resistance to FGFR4 Inhibition and Potentiates FGFR4 Inhibitor Therapy in Hepatocellular Carcinoma
Authors: Shen Bin , Shi Jue-Ping , Zhu Zhi-Xuan , He Zhi-Dong , Liu Shen-Yan , Shi Wan , Zhang Yong-Xian , Ying Hai-Yan , Wang Jie , Xu Rui-Feng , Fang Fei , Chang Harrison Xuesong , Chen Zhui , Zhang Nan-Nan
Published: December 2023

Abstract
Aberrant activation of the FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of hepatocellular carcinoma (HCC). As such, FGFR4 inhibition has emerged as a novel therapeutic option for the treatment of HCC and has shown preliminary efficacy in recent clinical trials for patients exhibiting aberrant FGF19 expression. Resistance to kinase inhibitors is common in oncology, presenting a major challenge in the clinical treatment process. Hence, we investigated the potential mechanisms mediating and causing resistance to FGFR4 inhibition in HCC. Upon the successful establishment of a battery of cellular models developing resistance to FGFR4 inhibitors, we have identified the activation of EGFR, MAPK, and AKT signaling as the primary mechanisms mediating the acquired resistance. Combination of inhibitors against EGFR or its downstream components restored sensitivity to FGFR4 inhibitors. In parental HCC cell lines, EGF treatment also resulted in resistance to FGFR4 inhibitors. This resistance was effectively reverted by inhibitors of the EGFR signaling pathway, suggesting that EGFR activation is a potential cause of intrinsic resistance. We further confirmed the above findings in vivo in mouse xenograft tumor models. Genomic analysis of patient samples from The Cancer Genome Atlas confirmed that a segment of patients with HCC harboring FGF19 overexpression indeed exhibited increased activation of EGFR signaling. These findings conclusively indicate that both induced and innate activation of EGFR could mediate resistance to FGFR4 inhibition, suggesting that dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for the treatment of FGF19-FGFR4 altered HCC.