bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S6 from The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor Resistance in Homologous Recombination–Deficient Tumors
Authors: Cadzow Louise , Brenneman Jehrod , Tobin Erica , Sullivan Pamela , Nayak Sumeet , Ali Janid A. , Shenker Sol , Griffith Jim , McGuire Michael , Grasberger Paula , Mishina Yuji , Murray Morgan , Dodson Anne E. , Gannon Hugh , Krall Elsa , Hixon Jeff , Chipumuro Edmond , Sinkevicius Kerstin , Gokhale Prafulla C. , Ganapathy Suthakar , Matulonis Ursula A. , Liu Joyce F. , Olaharski Andrew , Sangurdekar Dipen , Liu Hanlan , Wilt Jeremy , Schlabach Michael , Stegmeier Frank , Wylie Andrew A.
Published: October 2024

Western blot analysis of sensitive and insensitive cell lines to USP1 inhibition
Figure S3 from The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor Resistance in Homologous Recombination–Deficient Tumors
Authors: Cadzow Louise , Brenneman Jehrod , Tobin Erica , Sullivan Pamela , Nayak Sumeet , Ali Janid A. , Shenker Sol , Griffith Jim , McGuire Michael , Grasberger Paula , Mishina Yuji , Murray Morgan , Dodson Anne E. , Gannon Hugh , Krall Elsa , Hixon Jeff , Chipumuro Edmond , Sinkevicius Kerstin , Gokhale Prafulla C. , Ganapathy Suthakar , Matulonis Ursula A. , Liu Joyce F. , Olaharski Andrew , Sangurdekar Dipen , Liu Hanlan , Wilt Jeremy , Schlabach Michael , Stegmeier Frank , Wylie Andrew A.
Published: October 2024

KSQ-4279 CryoEM data collection
Data from Targeting the Sodium–Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia
Authors: Schneider Constanze , Spaink Hermes , Alexe Gabriela , Dharia Neekesh V. , Meyer Ashleigh , Merickel Lucy A. , Khalid Delan , Scheich Sebastian , Häupl Björn , Staudt Louis M. , Oellerich Thomas , Stegmaier Kimberly
Published: October 2024

Abstract
Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein–protein interactions, paralog relationships, and gene expression in cancer models. In this study, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the β-subunit of the sodium–potassium pump (Na/K-ATP pump), interacts with the α-subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3’s paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. Thus, ATP1B3 is a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1.

Significance: ATP1B3 is a lethal selective paralog dependency in acute myeloid leukemia that can be eliminated to destabilize the sodium–potassium pump, inducing cell death.
Data from Chromosome 7 Gain Compensates for Chromosome 10 Loss in Glioma
Authors: Nair Nishanth Ulhas , Schäffer Alejandro A. , Gertz E. Michael , Cheng Kuoyuan , Zerbib Johanna , Sahu Avinash Das , Leor Gil , Shulman Eldad D. , Aldape Kenneth D. , Ben-David Uri , Ruppin Eytan
Published: October 2024

Abstract
The co-occurrence of chromosome 10 loss and chromosome 7 gain in gliomas is the most frequent loss–gain co-aneuploidy pair in human cancers. This phenomenon has been investigated since the late 1980s without resolution. Expanding beyond previous gene-centric studies, we investigated the co-occurrence in a genome-wide manner, taking an evolutionary perspective. Mining of large-scale tumor aneuploidy data confirmed the previous finding of a small-scale longitudinal study that the most likely order is chromosome 10 loss, followed by chromosome 7 gain. Extensive analysis of genomic and transcriptomic data from both patients and cell lines revealed that this co-occurrence can be explained by functional rescue interactions that are highly enriched on chromosome 7, which could potentially compensate for any detrimental consequences arising from the loss of chromosome 10. Transcriptomic data from various normal, noncancerous human brain tissues were analyzed to assess which tissues may be most predisposed to tolerate compensation of chromosome 10 loss by chromosome 7 gain. The analysis indicated that the preexisting transcriptomic states in the cortex and frontal cortex, where gliomas arise, are more favorable than other brain regions for compensation by rescuer genes that are active on chromosome 7. Collectively, these findings suggest that the phenomenon of chromosome 10 loss and chromosome 7 gain in gliomas is orchestrated by a complex interaction of many genes residing within these two chromosomes and provide a plausible reason why this co-occurrence happens preferentially in cancers originating in certain regions of the brain.

 Significance: Increased expression of multiple rescuer genes on the gained chromosome 7 could compensate for the downregulation of several vulnerable genes on the lost chromosome 10, resolving the long-standing mystery of this frequent co-occurrence in gliomas.
Data from Targeting YAP Activity and Glutamine Metabolism Cooperatively Suppresses Tumor Progression by Preventing Extracellular Matrix Accumulation
Authors: Park Mihyang , Jin Jonghwa , An Da Young , Kim Dong-Ho , Lee Jaebon , Yun Jae Won , Hwang Ilseon , Park Jae Seok , Kim Mi Kyung , Lee You Mie , Byun Jun-Kyu , Choi Yeon-Kyung , Park Keun-Gyu
Published: October 2024

Abstract
Cancer cells use multiple mechanisms to evade the effects of glutamine metabolism inhibitors. The pathways that govern responses to alterations in glutamine availability within the tumor may represent therapeutic targets for combinatorial strategies with these inhibitors. Here, we showed that targeting glutamine utilization stimulated Yes-associated protein (YAP) signaling in cancer cells by reducing cyclic adenosine monophosphate/protein kinase A (PKA)–dependent phosphorylation of large tumor suppressor (LATS). Elevated YAP activation induced extracellular matrix (ECM) deposition by increasing the secretion of connective tissue growth factor that promoted the production of fibronectin and collagen by surrounding fibroblasts. Consequently, inhibiting YAP synergized with inhibition of glutamine utilization to effectively suppress tumor growth in vivo, along with a concurrent decrease in ECM deposition. Blocking ECM remodeling also augmented the tumor suppressive effects of the glutamine utilization inhibitor. Collectively, these data reveal mechanisms by which targeting glutamine utilization increases ECM accumulation and identify potential strategies to reduce ECM levels and increase the efficacy of glutamine metabolism inhibitors.

Significance: Blocking glutamine utilization activates YAP to promote ECM deposition by fibroblasts, highlighting the potential of YAP inhibitors and antifibrotic strategies as promising approaches for effective combination metabolic therapies in cancer.
Data from Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer
Authors: Wang Huijuan , Chen Jiaxin , Chen Xiaoyu , Liu Yingqiang , Wang Jiawei , Meng Qing , Wang Huogang , He Ying , Song Yujia , Li Jingyun , Ju Zhenyu , Xiao Peng , Qian Junbin , Song Zhangfa
Published: October 2024

Abstract
Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAF) are a major component of the tumor stroma. Identifying the key molecular determinants for the protumor properties of CAFs could enable the development of more effective treatment strategies. In this study, through analyses of single-cell sequencing data, we identified a population of CAFs expressing high levels of sulfatase 1 (SULF1), which was associated with poor prognosis in patients with colorectal cancer. Colorectal cancer models using mice with conditional SULF1 knockout in fibroblasts revealed the tumor-supportive function of SULF1+ CAFs. Mechanistically, SULF1+ CAFs enhanced the release of VEGFA from heparan sulfate proteoglycan. The increased bioavailability of VEGFA initiated the deposition of extracellular matrix and enhanced angiogenesis. In addition, intestinal microbiota–produced butyrate suppressed SULF1 expression in CAFs through its histone deacetylase (HDAC) inhibitory activity. The insufficient butyrate production in patients with colorectal cancer increased the abundance of SULF1+ CAFs, thereby promoting tumor progression. Importantly, tumor growth inhibition by HDAC was dependent on SULF1 expression in CAFs, and patients with colorectal cancer with more SULF1+ CAFs were more responsive to treatment with the HDAC inhibitor chidamide. Collectively, these findings unveil the critical role of SULF1+ CAFs in colorectal cancer and provide a strategy to stratify patients with colorectal cancer for HDAC inhibitor treatment.

 Significance: SULF1+ cancer-associated fibroblasts play a tumor-promoting role in colorectal cancer by stimulating extracellular matrix deposition and angiogenesis and can serve as a biomarker for the therapeutic response to HDAC inhibitors in patients.
Supplementary Data1 from Artificial Intelligence-Powered Spatial Analysis of Tumor-Infiltrating Lymphocytes as a Potential Biomarker for Immune Checkpoint Inhibitors in Patients with Biliary Tract Cancer
Authors: Bang Yeong Hak , Lee Choong-kun , Bang Kyunghye , Kim Hyung-Don , Kim Kyu-pyo , Jeong Jae Ho , Park Inkeun , Ryoo Baek-Yeol , Lee Dong Ki , Choi Hye Jin , Chung Taek , Jeon Seung Hyuck , Shin Eui-Cheol , Oum Chiyoon , Kim Seulki , Lim Yoojoo , Park Gahee , Ahn Chang Ho , Lee Taebum , Finn Richard S. , Ock Chan-Young , Shin Jinho , Yoo Changhoon
Published: October 2024

Supplementary Methods; Supplementary Figs. 1-6; Supplementary Tables 1-4.
Supplementary Table S3 from Pembrolizumab and Cabozantinib in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Long-term Survival Update with a Biomarker Analysis
Authors: Saba Nabil F. , Chaudhary Ritu , Kirtane Kedar , Marra Angelo , Ekpenyong Asari , McCook-Veal Ashley , Schmitt Nicole C. , Gross Jennifer H. , Patel Mihir R. , Remick Jill , Bates James E. , McDonald Mark W. , Rudra Soumon F. , Stokes William A. , Biernacki Maria , Song Xiaofei , Slebos Robbert J.C. , Liu Yuan , Steuer Conor E. , Shin Dong M. , Teng Yong , Chung Christine H.
Published: October 2024

Supplementary Table S3. OS versus myeloid markers.
Supplementary Figure S3 from YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities
Authors: Stewart C. Allison , Diao Lixia , Xi Yuanxin , Wang Runsheng , Ramkumar Kavya , Serrano Alejandra G. , Tanimoto Azusa , Rodriguez B. Leticia , Morris Benjamin B. , Shen Li , Zhang Bingnan , Yang Yan , Hamad Samera H. , Cardnell Robert J. , Duarte Alberto , Sahu Moushumi , Novegil Veronica Y. , Weissman Bernard E. , Frumovitz Michael , Kalhor Neda , Solis Soto Luisa , da Rocha Pedro , Vokes Natalie , Gibbons Don L. , Wang Jing , Heymach John V. , Glisson Bonnie , Byers Lauren Averett , Gay Carl M.
Published: October 2024

Supplementary Figure S3. Unique features of YAP1-high LCNEC.
Supplementary Table S6 from Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies
Authors: Jovanović Bojana , Church Sarah E. , Gorman Kara M. , North Khrystyna , Richardson Edward T. , DiLullo Molly , Attaya Victoria , Kasparian Julie , Mohammed-Abreu Ayesha , Kirkner Gregory , Hughes Melissa E. , Lin Nancy U. , Mittendorf Elizabeth A. , Schnitt Stuart J. , Tolaney Sara M. , Goel Shom
Published: October 2024

Supplementary Table S6. Differential genes and signature for PDL1 positive tumors.
Supplementary Table S4 from Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies
Authors: Jovanović Bojana , Church Sarah E. , Gorman Kara M. , North Khrystyna , Richardson Edward T. , DiLullo Molly , Attaya Victoria , Kasparian Julie , Mohammed-Abreu Ayesha , Kirkner Gregory , Hughes Melissa E. , Lin Nancy U. , Mittendorf Elizabeth A. , Schnitt Stuart J. , Tolaney Sara M. , Goel Shom
Published: October 2024

Supplementary Table S4. Differential genes and signature for AR tumors.
Supplementary Table S3 from Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies
Authors: Jovanović Bojana , Church Sarah E. , Gorman Kara M. , North Khrystyna , Richardson Edward T. , DiLullo Molly , Attaya Victoria , Kasparian Julie , Mohammed-Abreu Ayesha , Kirkner Gregory , Hughes Melissa E. , Lin Nancy U. , Mittendorf Elizabeth A. , Schnitt Stuart J. , Tolaney Sara M. , Goel Shom
Published: October 2024

Supplementary Table S3. Differential genes and signature for RB tumors.
Supplementary Table S1 from Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies
Authors: Jovanović Bojana , Church Sarah E. , Gorman Kara M. , North Khrystyna , Richardson Edward T. , DiLullo Molly , Attaya Victoria , Kasparian Julie , Mohammed-Abreu Ayesha , Kirkner Gregory , Hughes Melissa E. , Lin Nancy U. , Mittendorf Elizabeth A. , Schnitt Stuart J. , Tolaney Sara M. , Goel Shom
Published: October 2024

Supplementary Table S1. Representativeness of Study Part icipants.
Supplementary Results S1 from A Phase Ib/II Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma
Authors: Coveler Andrew L. , Reilley Matthew J. , Zalupski Mark , Macarulla Teresa , Fountzilas Christos , Ponz-Sarvisé Mariano , Nagrial Adnan , Uboha Nataliya V. , Frentzas Sophia , Overman Michael , Noonan Anne , Messersmith Wells A. , Pavlakis Nick , Mettu Niharika B. , Bisha Ina , Wang Ying , Smith Paul , Murtomaki Elina , Bielska Agata A. , Bragulat Veronique , Cooper Zachary A. , Kumar Rakesh , Spigel David R.
Published: October 2024

Supplementary Results
Supplementary Figure S7 from Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies
Authors: Jovanović Bojana , Church Sarah E. , Gorman Kara M. , North Khrystyna , Richardson Edward T. , DiLullo Molly , Attaya Victoria , Kasparian Julie , Mohammed-Abreu Ayesha , Kirkner Gregory , Hughes Melissa E. , Lin Nancy U. , Mittendorf Elizabeth A. , Schnitt Stuart J. , Tolaney Sara M. , Goel Shom
Published: October 2024

Supplementary Figure S7. Overall survival and differential signatures.
Supplementary Methods S1 from A Phase Ib/II Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma
Authors: Coveler Andrew L. , Reilley Matthew J. , Zalupski Mark , Macarulla Teresa , Fountzilas Christos , Ponz-Sarvisé Mariano , Nagrial Adnan , Uboha Nataliya V. , Frentzas Sophia , Overman Michael , Noonan Anne , Messersmith Wells A. , Pavlakis Nick , Mettu Niharika B. , Bisha Ina , Wang Ying , Smith Paul , Murtomaki Elina , Bielska Agata A. , Bragulat Veronique , Cooper Zachary A. , Kumar Rakesh , Spigel David R.
Published: October 2024

Supplementary Methods
Supplementary Figure S5 from Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies
Authors: Jovanović Bojana , Church Sarah E. , Gorman Kara M. , North Khrystyna , Richardson Edward T. , DiLullo Molly , Attaya Victoria , Kasparian Julie , Mohammed-Abreu Ayesha , Kirkner Gregory , Hughes Melissa E. , Lin Nancy U. , Mittendorf Elizabeth A. , Schnitt Stuart J. , Tolaney Sara M. , Goel Shom
Published: October 2024

Supplementary Figure S5. Biological profiles for TNBC based on RB, AR, PD-L1 status in primary versus metastatic tumors.
Supplementary Figure S4 from Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies
Authors: Jovanović Bojana , Church Sarah E. , Gorman Kara M. , North Khrystyna , Richardson Edward T. , DiLullo Molly , Attaya Victoria , Kasparian Julie , Mohammed-Abreu Ayesha , Kirkner Gregory , Hughes Melissa E. , Lin Nancy U. , Mittendorf Elizabeth A. , Schnitt Stuart J. , Tolaney Sara M. , Goel Shom
Published: October 2024

Supplementary Figure S4. Biological profiles and clinical outcomes for TNBC based on PD-L1 status.
Figure 2 from A Phase Ib/II Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma
Authors: Coveler Andrew L. , Reilley Matthew J. , Zalupski Mark , Macarulla Teresa , Fountzilas Christos , Ponz-Sarvisé Mariano , Nagrial Adnan , Uboha Nataliya V. , Frentzas Sophia , Overman Michael , Noonan Anne , Messersmith Wells A. , Pavlakis Nick , Mettu Niharika B. , Bisha Ina , Wang Ying , Smith Paul , Murtomaki Elina , Bielska Agata A. , Bragulat Veronique , Cooper Zachary A. , Kumar Rakesh , Spigel David R.
Published: October 2024

A, PFS and (B) OS in the dose-expansion phase overall (ITT) population; (C) PFS and (D) OS in patients with low CD73 levels, and (E) PFS and (F) OS in patients with high CD73 levels. ITT, intent-to-treat; NC, not calculable.
Supplementary Figure S7 from Second Primary Malignancies after CAR T-Cell Therapy: A Systematic Review and Meta-analysis of 5,517 Lymphoma and Myeloma Patients
Authors: Tix Tobias , Alhomoud Mohammad , Shouval Roni , Cliff Edward R. Scheffer , Perales Miguel-Angel , Cordas dos Santos David M. , Rejeski Kai
Published: October 2024

Subgroup analysis of SPM point estimates stratified by age.
Figure 4 from Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome
Authors: Bartos Laura M. , Quach Stefanie , Zenatti Valerio , Kirchleitner Sabrina V. , Blobner Jens , Wind-Mark Karin , Kolabas Zeynep Ilgin , Ulukaya Selin , Holzgreve Adrien , Ruf Viktoria C. , Kunze Lea H. , Kunte Sebastian T. , Hoermann Leonie , Härtel Marlies , Park Ha Eun , Groß Mattes , Franzmeier Nicolai , Zatcepin Artem , Zounek Adrian , Kaiser Lena , Riemenschneider Markus J. , Perneczky Robert , Rauchmann Boris-Stephan , Stöcklein Sophia , Ziegler Sibylle , Herms Jochen , Ertürk Ali , Tonn Joerg C. , Thon Niklas , von Baumgarten Louisa , Prestel Matthias , Tahirovic Sabina , Albert Nathalie L. , Brendel Matthias
Published: October 2024

Back-translation into a glioblastoma mouse model pinpoints myeloid cells as the cellular source of contralateral TSPO-PET signal elevations. A, Glioblastoma mice (n = 15) show higher TSPO-PET signal in the contralateral hemisphere compared to sham injected animals (n = 14). B, Coronal slices of group average TSPO-PET images of SB28 glioblastoma mice (top row; n = 15) and sham injected mice (bottom row; n = 14). Analyzed planes are indicated upon a CT template. Arrows point to the PET signal elevation in the contralateral hemisphere of SB28 mice. Tumor hemisphere is blurred. C, Whole brain tumor seed correlation analysis shows dependency of contralateral TSPO-PET signals (white arrows) from tumor TSPO-PET signals in SB28 mice (n = 15). Tumor TSPO-PET signals were extracted using a spherical volume of interest with 1.5 mm diameter and included as a seed in a voxel-wise statistical parametric mapping regression model. D, CD11b positive myeloid cells of the contralateral hemisphere of glioblastoma mice (n = 13) show higher single-cell TSPO tracer uptake than myeloid cells of sham injected (n = 14) or healthy control mice (n = 8; left). Non-myeloid cells show no difference in TSPO tracer uptake between the three conditions (right). E and F, Immunohistochemistry shows higher myeloid cell abundance and increased TSPO in IBA1 positive myeloid cells in contralateral hemispheres of SB28 glioblastoma mice (n = 3) compared to sham (n = 4). G, qPCR was used to exclude infiltration of SB28 glioblastoma cells into the contralateral hemispheres in SB28 glioblastoma mice (n = 8; left). Tumor tissue was used as a positive control. While tumor cells could only be detected in the tumor tissue, TSPO expression was observed in contralateral hemispheres of SB28 glioblastoma mice and exceeded TSPO expression in sham injected (n = 4) and healthy control mice (n = 4, right). (Adapted from an image created with BioRender.com.)
Supplementary Figure S1 from Second Primary Malignancies after CAR T-Cell Therapy: A Systematic Review and Meta-analysis of 5,517 Lymphoma and Myeloma Patients
Authors: Tix Tobias , Alhomoud Mohammad , Shouval Roni , Cliff Edward R. Scheffer , Perales Miguel-Angel , Cordas dos Santos David M. , Rejeski Kai
Published: October 2024

Funnel plots.
Supplementary Data and methods 4 from Metabolomic Prediction of Breast Cancer Treatment–Induced Neurologic and Metabolic Toxicities
Authors: Piffoux Max , Jacquemin Jérémie , Pétéra Mélanie , Durand Stéphanie , Abila Angélique , Centeno Delphine , Joly Charlotte , Lyan Bernard , Martin Anne-Laure , Everhard Sibille , Boyault Sandrine , Pistilli Barbara , Fournier Marion , Rouanet Philippe , Havas Julie , Sauterey Baptiste , Campone Mario , Tarpin Carole , Mouret-Reynier Marie-Ange , Rigal Olivier , Petit Thierry , Lasset Christine , Bertaut Aurélie , Cottu Paul , André Fabrice , Vaz-Luis Ines , Pujos-Guillot Estelle , Drouet Youenn , Trédan Olivier
Published: October 2024

Supplementary Data and methods
Supplementary Table S2 from Proportional Hazards Violations in Phase III Cancer Clinical Trials: A Potential Source of Trial Misinterpretation
Authors: Lin Timothy A. , McCaw Zachary R. , Koong Alex , Lin Christine , Abi Jaoude Joseph , Patel Roshal , Kouzy Ramez , El Alam Molly B. , Sherry Alexander D. , Noticewala Sonal S. , Fuller Clifton D. , Thomas Charles R. , Sun Ryan , Lee J. Jack , Lin Ruitao , Yuan Ying , Shyr Yu , Meirson Tomer , Ludmir Ethan B.
Published: October 2024

Table S2: Sensitivity analyses of univariable and multivariable logistic regressions using only progression-free survival (PFS) comparisons for trials with co-primary endpoints (PEPs).
Supplementary Table S9 from Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial
Authors: Grivas Petros , Garralda Elena , Meric-Bernstam Funda , Mellinghoff Ingo K. , Goyal Lipika , Harding James J. , Dees E. Claire , Bahleda Rastislav , Azad Nilofer S. , Karippot Asha , Kurzrock Razelle , Tabernero Josep , Kononen Juha , Ng Matthew C.H. , Mehta Rutika , Uboha Nataliya V. , Bigot Frédéric , Boni Valentina , Bowyer Samantha E. , Breder Valeriy , Cervantes Andrés , Chan Nancy , Cleary James M. , Dhawan Mallika , Eefsen Rikke L. , Ewing James , Graham Donna M. , Guren Tormod K. , Won Kim Jin , Koynov Krassimir , Oh Do-Youn , Redman Rebecca , Yen Chia-Jui , Spetzler David , Roubaudi-Fraschini Marie-Claude , Nicolas-Metral Valerie , Ait-Sarkouh Rafik , Zanna Claudio , Ennaji Abdallah , Pokorska-Bocci Anna , Flaherty Keith T.
Published: October 2024

Supplementary Table S9. Summary of adverse events (safety population).
Supplementary Table S3 from Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial
Authors: Grivas Petros , Garralda Elena , Meric-Bernstam Funda , Mellinghoff Ingo K. , Goyal Lipika , Harding James J. , Dees E. Claire , Bahleda Rastislav , Azad Nilofer S. , Karippot Asha , Kurzrock Razelle , Tabernero Josep , Kononen Juha , Ng Matthew C.H. , Mehta Rutika , Uboha Nataliya V. , Bigot Frédéric , Boni Valentina , Bowyer Samantha E. , Breder Valeriy , Cervantes Andrés , Chan Nancy , Cleary James M. , Dhawan Mallika , Eefsen Rikke L. , Ewing James , Graham Donna M. , Guren Tormod K. , Won Kim Jin , Koynov Krassimir , Oh Do-Youn , Redman Rebecca , Yen Chia-Jui , Spetzler David , Roubaudi-Fraschini Marie-Claude , Nicolas-Metral Valerie , Ait-Sarkouh Rafik , Zanna Claudio , Ennaji Abdallah , Pokorska-Bocci Anna , Flaherty Keith T.
Published: October 2024

Supplementary Table S3. FGFR1–3 fusions partners detected in a large pan-tumor database of Caris Life Sciences (Phoenix, AZ) using whole-transcriptome sequencing.
Supplementary Data S3 from Proportional Hazards Violations in Phase III Cancer Clinical Trials: A Potential Source of Trial Misinterpretation
Authors: Lin Timothy A. , McCaw Zachary R. , Koong Alex , Lin Christine , Abi Jaoude Joseph , Patel Roshal , Kouzy Ramez , El Alam Molly B. , Sherry Alexander D. , Noticewala Sonal S. , Fuller Clifton D. , Thomas Charles R. , Sun Ryan , Lee J. Jack , Lin Ruitao , Yuan Ying , Shyr Yu , Meirson Tomer , Ludmir Ethan B.
Published: October 2024

Data Supplement S3: Framework for implementation of proportional hazards violation assessment and alternative assessments that do not depend upon the assumption of proportional hazards.
Supplementary Table S12 from Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial
Authors: Grivas Petros , Garralda Elena , Meric-Bernstam Funda , Mellinghoff Ingo K. , Goyal Lipika , Harding James J. , Dees E. Claire , Bahleda Rastislav , Azad Nilofer S. , Karippot Asha , Kurzrock Razelle , Tabernero Josep , Kononen Juha , Ng Matthew C.H. , Mehta Rutika , Uboha Nataliya V. , Bigot Frédéric , Boni Valentina , Bowyer Samantha E. , Breder Valeriy , Cervantes Andrés , Chan Nancy , Cleary James M. , Dhawan Mallika , Eefsen Rikke L. , Ewing James , Graham Donna M. , Guren Tormod K. , Won Kim Jin , Koynov Krassimir , Oh Do-Youn , Redman Rebecca , Yen Chia-Jui , Spetzler David , Roubaudi-Fraschini Marie-Claude , Nicolas-Metral Valerie , Ait-Sarkouh Rafik , Zanna Claudio , Ennaji Abdallah , Pokorska-Bocci Anna , Flaherty Keith T.
Published: October 2024

Supplementary Table S12. Grade ≥3 treatment-emergent adverse events considered by the investigator to be related to the study drug (safety population).
Supplementary Table S11 from Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial
Authors: Grivas Petros , Garralda Elena , Meric-Bernstam Funda , Mellinghoff Ingo K. , Goyal Lipika , Harding James J. , Dees E. Claire , Bahleda Rastislav , Azad Nilofer S. , Karippot Asha , Kurzrock Razelle , Tabernero Josep , Kononen Juha , Ng Matthew C.H. , Mehta Rutika , Uboha Nataliya V. , Bigot Frédéric , Boni Valentina , Bowyer Samantha E. , Breder Valeriy , Cervantes Andrés , Chan Nancy , Cleary James M. , Dhawan Mallika , Eefsen Rikke L. , Ewing James , Graham Donna M. , Guren Tormod K. , Won Kim Jin , Koynov Krassimir , Oh Do-Youn , Redman Rebecca , Yen Chia-Jui , Spetzler David , Roubaudi-Fraschini Marie-Claude , Nicolas-Metral Valerie , Ait-Sarkouh Rafik , Zanna Claudio , Ennaji Abdallah , Pokorska-Bocci Anna , Flaherty Keith T.
Published: October 2024

Supplementary Table S11. Treatment-emergent adverse events occurring at grade ≥3 in ≥2 patients (safety population).
Supplementary Table S4 from Clinical and Molecular Risk Factors in Extracranial Malignant Rhabdoid Tumors: Toward an Integrated Model of High-Risk Tumors
Authors: Fincke Victoria E. , Steinbügl Mona , Chun Hye-Jung E. , Nemes Karolina , Mucha Marlena , Loßner Maurice , Dorn Felix , Gastberger Katharina , Bühner Sebastian , Sill Martin , Kröncke Thomas , Siebert Reiner , Melchior Patrick , Furtwängler Rhoikos , Schlesner Matthias , Vokuhl Christian , Röcken Christoph , Johann Pascal D. , Frühwald Michael C.
Published: October 2024

Relapse therapy overview
Supplementary Table S3 from Clinical and Molecular Risk Factors in Extracranial Malignant Rhabdoid Tumors: Toward an Integrated Model of High-Risk Tumors
Authors: Fincke Victoria E. , Steinbügl Mona , Chun Hye-Jung E. , Nemes Karolina , Mucha Marlena , Loßner Maurice , Dorn Felix , Gastberger Katharina , Bühner Sebastian , Sill Martin , Kröncke Thomas , Siebert Reiner , Melchior Patrick , Furtwängler Rhoikos , Schlesner Matthias , Vokuhl Christian , Röcken Christoph , Johann Pascal D. , Frühwald Michael C.
Published: October 2024

Cox-Regression model
Supplementary Figure S5 from Clinical and Molecular Risk Factors in Extracranial Malignant Rhabdoid Tumors: Toward an Integrated Model of High-Risk Tumors
Authors: Fincke Victoria E. , Steinbügl Mona , Chun Hye-Jung E. , Nemes Karolina , Mucha Marlena , Loßner Maurice , Dorn Felix , Gastberger Katharina , Bühner Sebastian , Sill Martin , Kröncke Thomas , Siebert Reiner , Melchior Patrick , Furtwängler Rhoikos , Schlesner Matthias , Vokuhl Christian , Röcken Christoph , Johann Pascal D. , Frühwald Michael C.
Published: October 2024

Random forest predictor for eMRT subgroups based on DNA methylation-an example
Supplementary Table S7 from Transcriptomic Heterogeneity of EGFR-Mutant Non–Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer
Authors: Oh Songji , Koh Jaemoon , Kim Tae Min , Kim Soyeon , Youk Jeonghwan , Kim Miso , Keam Bhumsuk , Jeon Yoon Kyung , Ku Ja-Lok , Kim Dong-Wan , Chung Doo Hyun , Heo Dae Seog
Published: October 2024

Supplementary Table S7. Screening of multiple drugs including previously proposed classical SCLC therapeutic targets in two t-SCLC cell lines.
Supplementary Figure S7 from Transcriptomic Heterogeneity of EGFR-Mutant Non–Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer
Authors: Oh Songji , Koh Jaemoon , Kim Tae Min , Kim Soyeon , Youk Jeonghwan , Kim Miso , Keam Bhumsuk , Jeon Yoon Kyung , Ku Ja-Lok , Kim Dong-Wan , Chung Doo Hyun , Heo Dae Seog
Published: October 2024

Supplementary Figure S7. Immune-related signatures in our datasets.
Supplementary Figure S5 from Transcriptomic Heterogeneity of EGFR-Mutant Non–Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer
Authors: Oh Songji , Koh Jaemoon , Kim Tae Min , Kim Soyeon , Youk Jeonghwan , Kim Miso , Keam Bhumsuk , Jeon Yoon Kyung , Ku Ja-Lok , Kim Dong-Wan , Chung Doo Hyun , Heo Dae Seog
Published: October 2024

Supplementary Figure S5. Reduction of cMyc and activation of caspase signaling upon BET inhibitors treatment.
Supplementary Figure S2 from The Impact of Li‐Fraumeni and Germline Retinoblastoma Mutations on Leiomyosarcoma Initiation, Outcomes, and Genetic Testing Recommendations
Authors: Dermawan Josephine K. , Abramson David H. , Chiang Sarah , Hensley Martee L. , Tap William D. , Movva Sujana , Maki Robert G. , Mandelker Diana , Antonescu Cristina R.
Published: October 2024

Supplementary Figure S2. Outcome of germline vs sporadic soft tissue leiomyosarcoma (STLMS) patients.
Supplementary Table S1 from Tumor-Secreted Extracellular Vesicles Counteract Therapy Response by Triggering Inflammatory Mesenchymal Stem Cell Development
Authors: Massaro Crescenzo , Sensoy Hilal N. , Mulders Manon , De Schrijver Celine , Gómez-Martín Cristina , Simon Nieto Juan , Lagerweij Tonny , Atmopawiro Alisha , Pérez-Boza Jennifer , Bebelman Maarten , Bosch Leontien , Foderaro Simone , Neves Ferreira Mafalda , van Eijndhoven Monique A.J. , van Weering Jan R.T. , Dell’Aversana Carmela , Altucci Lucia , Savci-Heijink Cemile Dilara , van de Donk Niels W.C.J. , Giorgio Cristina , Brandolini Laura , Allegretti Marcello , Pegtel Dirk Michiel , Baglio Serena Rubina
Published: October 2024

qPCR primers
Supplementary Figure S4 from Tumor-Secreted Extracellular Vesicles Counteract Therapy Response by Triggering Inflammatory Mesenchymal Stem Cell Development
Authors: Massaro Crescenzo , Sensoy Hilal N. , Mulders Manon , De Schrijver Celine , Gómez-Martín Cristina , Simon Nieto Juan , Lagerweij Tonny , Atmopawiro Alisha , Pérez-Boza Jennifer , Bebelman Maarten , Bosch Leontien , Foderaro Simone , Neves Ferreira Mafalda , van Eijndhoven Monique A.J. , van Weering Jan R.T. , Dell’Aversana Carmela , Altucci Lucia , Savci-Heijink Cemile Dilara , van de Donk Niels W.C.J. , Giorgio Cristina , Brandolini Laura , Allegretti Marcello , Pegtel Dirk Michiel , Baglio Serena Rubina
Published: October 2024

Suppl. Figure 4. a-b) scRNA-seq mapping of human osteosarcoma tumors. MSC and other indicated clusters were identified through the UMAP (a) and marker gene expression analysis (b).
Supplementary Figure S2 from Tumor-Secreted Extracellular Vesicles Counteract Therapy Response by Triggering Inflammatory Mesenchymal Stem Cell Development
Authors: Massaro Crescenzo , Sensoy Hilal N. , Mulders Manon , De Schrijver Celine , Gómez-Martín Cristina , Simon Nieto Juan , Lagerweij Tonny , Atmopawiro Alisha , Pérez-Boza Jennifer , Bebelman Maarten , Bosch Leontien , Foderaro Simone , Neves Ferreira Mafalda , van Eijndhoven Monique A.J. , van Weering Jan R.T. , Dell’Aversana Carmela , Altucci Lucia , Savci-Heijink Cemile Dilara , van de Donk Niels W.C.J. , Giorgio Cristina , Brandolini Laura , Allegretti Marcello , Pegtel Dirk Michiel , Baglio Serena Rubina
Published: October 2024

Suppl. Figure 2. a-b) scRNA-seq mapping of the non-hematopoietic mononuclear cell fraction from bone marrow aspirates of MM patients and non-cancer control individuals. UMAP plot (a) and violin plots (b) of marker gene expression in the identified clusters. c) UMAP plot split into control and MM datasets. d-i) Density plots of differentially expressed cytokines and chemokine in control and MM samples.
Supplementary Figure S1 from Tumor-Secreted Extracellular Vesicles Counteract Therapy Response by Triggering Inflammatory Mesenchymal Stem Cell Development
Authors: Massaro Crescenzo , Sensoy Hilal N. , Mulders Manon , De Schrijver Celine , Gómez-Martín Cristina , Simon Nieto Juan , Lagerweij Tonny , Atmopawiro Alisha , Pérez-Boza Jennifer , Bebelman Maarten , Bosch Leontien , Foderaro Simone , Neves Ferreira Mafalda , van Eijndhoven Monique A.J. , van Weering Jan R.T. , Dell’Aversana Carmela , Altucci Lucia , Savci-Heijink Cemile Dilara , van de Donk Niels W.C.J. , Giorgio Cristina , Brandolini Laura , Allegretti Marcello , Pegtel Dirk Michiel , Baglio Serena Rubina
Published: October 2024

Suppl. Figure 1. a-b) Tumor growth measured by caliper (a) and BLI (b) in osteosarcoma-bearing mice receiving the TGFBR1 inhibitor EW-7197 and injected or not with 143B EV-educated MSCs. c) Western blot for CD63 and CD81 in EVs released by human fibroblasts (hF) and 143B, MDA-MB-231, PC3, HOS and MCF7 cell lines. d) GSEA enrichment plot for gene set ‘TNFα signaling via NFKB’ in 143B EV-exposed MSC compared to hF EV-exposed (ctrl) MSCs. e) List of gene sets enriched in 143B EV-exposed MSCs compared to hF EV-exposed (ctrl) MSCs.
Data from YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities
Authors: Stewart C. Allison , Diao Lixia , Xi Yuanxin , Wang Runsheng , Ramkumar Kavya , Serrano Alejandra G. , Tanimoto Azusa , Rodriguez B. Leticia , Morris Benjamin B. , Shen Li , Zhang Bingnan , Yang Yan , Hamad Samera H. , Cardnell Robert J. , Duarte Alberto , Sahu Moushumi , Novegil Veronica Y. , Weissman Bernard E. , Frumovitz Michael , Kalhor Neda , Solis Soto Luisa , da Rocha Pedro , Vokes Natalie , Gibbons Don L. , Wang Jing , Heymach John V. , Glisson Bonnie , Byers Lauren Averett , Gay Carl M.
Published: October 2024

AbstractPurpose:
Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non–small cell lung cancer approaches.
Experimental Design:
To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models.
Results:
In this study, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and is characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK- and AXL-targeting strategies, including a novel preclinical AXL chimeric antigen receptor–expressing T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by the expression of SCLC subtype–defining transcription factors, especially ASCL1 and NEUROD1, and as expected, given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including delta-like ligand 3 and CD56 targeting, as is with novel preclinical delta-like ligand 3 and CD56 chimeric antigen receptor–expressing T cells, and DNA damage repair inhibition.
Conclusions:
YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.
Data from Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial
Authors: Grivas Petros , Garralda Elena , Meric-Bernstam Funda , Mellinghoff Ingo K. , Goyal Lipika , Harding James J. , Dees E. Claire , Bahleda Rastislav , Azad Nilofer S. , Karippot Asha , Kurzrock Razelle , Tabernero Josep , Kononen Juha , Ng Matthew C.H. , Mehta Rutika , Uboha Nataliya V. , Bigot Frédéric , Boni Valentina , Bowyer Samantha E. , Breder Valeriy , Cervantes Andrés , Chan Nancy , Cleary James M. , Dhawan Mallika , Eefsen Rikke L. , Ewing James , Graham Donna M. , Guren Tormod K. , Won Kim Jin , Koynov Krassimir , Oh Do-Youn , Redman Rebecca , Yen Chia-Jui , Spetzler David , Roubaudi-Fraschini Marie-Claude , Nicolas-Metral Valerie , Ait-Sarkouh Rafik , Zanna Claudio , Ennaji Abdallah , Pokorska-Bocci Anna , Flaherty Keith T.
Published: October 2024

AbstractPurpose:
This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1–3, in patients with solid tumors harboring a functional FGFR1–3 fusion.
Patients and Methods:
Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events.
Results:
Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events.
Conclusions:
Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.

See related commentary by Hage Chehade et al., p. 4549
Data from HER2 Antibody–Drug Conjugates Are Active against Desmoplastic Small Round Cell Tumor
Authors: Zhang Tom , Febres-Aldana Christopher A. , Liu Zebing , Dix Jenna-Marie , Cheng Ryan , Dematteo Raymond G. , Lui Allan J.W. , Khodos Inna , Gili Leo , Mattar Marissa S. , Lisanti Jeanine , Kwong Charlene , Linkov Irina , Tipping Murray J. , de Stanchina Elisa , Odintsov Igor , Ladanyi Marc , Somwar Romel
Published: October 2024

AbstractPurpose:
Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target.
Experimental Design:
ERBB2/HER2 expression was assessed in clinical samples and patient-derived xenografts (PDX) using RNA sequencing, RT-qPCR, and a newly developed HER2 IHC assay (clone 29D8). Responses to HER2 antibody–drug conjugates (ADC)—trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine—were evaluated in DSRCT PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays.
Results:
ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity RNA assays and improved IHC detectability using clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or trastuzumab emtansine resulted in tumor regression. This therapeutic response was long-lasting in T-DXd–treated xenografts and was mediated by rapid HER2 ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status.
Conclusions:
ERBB2/HER2 is a therapeutic target in DSRCT. HER2 ADCs may represent novel options for managing this exceptionally aggressive sarcoma, possibly fulfilling an urgent and historically unmet need for more effective clinical therapy.
Data from Tumor-Secreted Extracellular Vesicles Counteract Therapy Response by Triggering Inflammatory Mesenchymal Stem Cell Development
Authors: Massaro Crescenzo , Sensoy Hilal N. , Mulders Manon , De Schrijver Celine , Gómez-Martín Cristina , Simon Nieto Juan , Lagerweij Tonny , Atmopawiro Alisha , Pérez-Boza Jennifer , Bebelman Maarten , Bosch Leontien , Foderaro Simone , Neves Ferreira Mafalda , van Eijndhoven Monique A.J. , van Weering Jan R.T. , Dell’Aversana Carmela , Altucci Lucia , Savci-Heijink Cemile Dilara , van de Donk Niels W.C.J. , Giorgio Cristina , Brandolini Laura , Allegretti Marcello , Pegtel Dirk Michiel , Baglio Serena Rubina
Published: October 2024

AbstractPurpose:
Therapy resistance is a major clinical hurdle in bone cancer treatment and seems to be largely driven by poorly understood microenvironmental factors. Recent evidence suggests a critical role for a unique subpopulation of mesenchymal stem cells with inflammatory features (iMSC), though their origin and function remained unexplored. We demonstrate that cancer-secreted extracellular vesicles (EV) trigger the development of iMSCs, which hinder therapy response in vivo, and set out to identify strategies to counteract their function.
Experimental Design:
The role of iMSCs in therapy resistance was evaluated in an orthotopic xenograft mouse model of osteosarcoma. EV-induced alterations of the MSC transcriptome were analyzed and compared with single-cell RNA sequencing data of biopsies from patients with osteosarcoma and multiple myeloma. Functional assays identified EV components driving iMSC development. We assessed the efficacy of clinical drugs in blocking iMSC-induced resistance in vivo.
Results:
We found that iMSCs are induced by interaction with cancer EVs and completely abrogate the antimetastatic effect of TGFβ signaling inhibition. Importantly, EV-induced iMSCs faithfully recapitulate the inflammatory single-cell RNA signature of stromal cells enriched in biopsies from patients with multiple myeloma and osteosarcoma. Mechanistically, cancer EVs act through two distinct mechanisms. EV-associated TGFβ induces IL6 production, whereas the EV-RNA cargo enhances TLR3-mediated chemokine production. We reveal that simultaneous blockade of downstream EV-activated pathways with ladarixin and tocilizumab disrupts metastasis formation and overcomes iMSC-induced resistance.
Conclusions:
Our observations establish iMSCs as major contributors to drug resistance, reveal EVs as triggers of iMSC development, and highlight a promising combination strategy to improve therapy response in patients with bone cancer.
Histology-Specific Clinical Trial of Lenvatinib and Pembrolizumab in Patients with Sarcoma
Authors: Movva Sujana , Seier Kenneth , Avutu Viswatej , Banks Lauren B. , Chan Jason , Chi Ping , Dickson Mark A. , Gounder Mrinal M. , Kelly Ciara M. , Keohan Mary L. , Maki Robert , Rosenbaum Evan , Salcito Tiffany , Rodriguez Kaithleen , Dempsey Rebecca , Meyers Paul A. , Cohen Seth M. , Hensley Martee L. , Konner Jason A. , Schram Alison M. , Lefkowitz Robert A. , Erinjeri Joseph P. , Qin Li-Xuan , Tap William D. , D’Angelo Sandra P.
Published: October 2024

Purpose:

Survival of patients with metastatic sarcoma remains poor, and there is a pressing need for new therapies. Most sarcoma subtypes are not responsive to immune checkpoint inhibition alone. Lenvatinib, a multireceptor tyrosine kinase inhibitor targeting tumor vasculature, has an immunomodulatory activity that contributes to its antitumor effects. Therefore, we hypothesized that a combination of lenvatinib and pembrolizumab would lead to improved clinical outcomes in patients with sarcoma.

Patients and Methods:

This was an open-label, single-arm study of lenvatinib and pembrolizumab in the following cohorts: (A) leiomyosarcoma, (B) undifferentiated pleomorphic sarcoma (UPS), (C) vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), (D) synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST), and (E) bone sarcomas (osteosarcoma and chondrosarcoma). The primary endpoint was the best overall response (BOR) rate documented by RECIST v1.1 by 27 weeks in each cohort, with a threshold of ≥2 responses among 10 patients. Secondary endpoints included progression-free survival, overall survival, duration of response, and safety.

Results:

Forty-six patients were evaluable for the primary endpoint, which was met in the UPS and MPNST/synovial cohorts (BOR rates by 27 weeks of 25% and 30%, respectively). There were seven partial responses overall with additional responses noted in angiosarcoma and osteosarcoma. Treatment-related adverse events of any grade and grade 3 or higher occurred in 50/51 (98%) and 29/51 (57%) of patients, respectively.

Conclusions:

We observed durable responses in MPNST, synovial sarcoma, and osteosarcoma. Patients with UPS and angiosarcoma also responded. Further exploration of this approach is warranted to confirm activity and determine optimal dosing schedules.
Figure S5 from Oncogenic Mutant p53 Sensitizes Non–Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress–Dependent Induction of Mitochondrial Apoptosis
Authors: Chougoni Kranthi Kumar , Neely Victoria , Ding Boxiao , Oduah Eziafa , Lam Vianna T. , Hu Bin , Koblinski Jennifer E. , Windle Bradford E. , Palit Deb Swati , Deb Sumitra , Nieva Jorge J. , Radhakrishnan Senthil K. , Harada Hisashi , Grossman Steven R.
Published: October 2024

Figure S5
Figure S1 from Oncogenic Mutant p53 Sensitizes Non–Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress–Dependent Induction of Mitochondrial Apoptosis
Authors: Chougoni Kranthi Kumar , Neely Victoria , Ding Boxiao , Oduah Eziafa , Lam Vianna T. , Hu Bin , Koblinski Jennifer E. , Windle Bradford E. , Palit Deb Swati , Deb Sumitra , Nieva Jorge J. , Radhakrishnan Senthil K. , Harada Hisashi , Grossman Steven R.
Published: October 2024

Figure S1