bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammasome-Activating Nanovaccine for Cancer Immunotherapy
Authors: Zhen Wenyao , Chen Xiaoyuan
Published: November 2024

A range of advanced nanovaccines (NV) combined with immunotherapies has recently emerged for treating malignant tumors and has demonstrated promising tumor-suppressive effects. Nevertheless, their effectiveness is often limited by immunosuppression within the tumor microenvironment. To overcome this challenge, new approaches for NV development are required to improve antigen cross-presentation and to remodel the tumor microenvironment. In this issue of Cancer Research, Zhou and colleagues have developed a photo-enhanceable inflammasome-activating nanovaccine (PIN) designed for precise, in situ delivery of a tumor antigen and a hydrophobic small molecule that activates the NLRP3 inflammasome pathway. Near infrared light exposure enables the accumulation of PINs at tumor sites by inducing a photo-triggered charge reversal in the BODIPY-modified PAMAM nanocarrier. Systemic administration of PINs resulted in effective intratumoral activation of the NLRP3 inflammasome and antigen cross-presentation in antigen-presenting cells upon light exposure, leading to enhanced immune responses through increased proinflammatory cytokine production without significant systemic toxicity. Importantly, PINs also enhanced the efficacy of immune checkpoint blockade and promoted the development of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Overall, inflammasome-activating NVs represent a cancer immunotherapy strategy by harnessing the innate immune system to achieve robust responses against tumors. Ongoing research and development are crucial to addressing current limitations and advancing this innovative technology toward clinical application.

See related article by Zhou et al., p. 3834
Supplementary Table S4 from Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology
Authors: Ercan Caner , Renne Salvatore Lorenzo , Di Tommaso Luca , Ng Charlotte K.Y. , Piscuoglio Salvatore , Terracciano Luigi M.
Published: November 2024

Supplementary Table S4. Comparison of clinicopathological features between homogeneous and heterogeneous tumors.
Supplementary Table S2 from Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology
Authors: Ercan Caner , Renne Salvatore Lorenzo , Di Tommaso Luca , Ng Charlotte K.Y. , Piscuoglio Salvatore , Terracciano Luigi M.
Published: November 2024

Supplementary Table S2. Training hyperparameters for the tumor/stroma/necrosis segmentation model.
Supplementary Fig. S5 from Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology
Authors: Ercan Caner , Renne Salvatore Lorenzo , Di Tommaso Luca , Ng Charlotte K.Y. , Piscuoglio Salvatore , Terracciano Luigi M.
Published: November 2024

Supplementary Fig. S5. The effect of biopsy procedure on the concordance of immunophenotype classifications between needle biopsy and resection.
Supplementary Fig. S4 from Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology
Authors: Ercan Caner , Renne Salvatore Lorenzo , Di Tommaso Luca , Ng Charlotte K.Y. , Piscuoglio Salvatore , Terracciano Luigi M.
Published: November 2024

Supplementary Fig. S4. Inflamed immunophenotype is predictor for better patient outcome.
Supplementary Fig. S1 from Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology
Authors: Ercan Caner , Renne Salvatore Lorenzo , Di Tommaso Luca , Ng Charlotte K.Y. , Piscuoglio Salvatore , Terracciano Luigi M.
Published: November 2024

Supplementary Fig. S1. Sample selection and utilisation.
Supplementary Table S4 from MEK Inhibitors Lead to PDGFR Pathway Upregulation and Sensitize Tumors to RAF Dimer Inhibitors in NF1-Deficient Malignant Peripheral Nerve Sheath Tumor
Authors: Miranda-Román Miguel A. , Lee Cindy J. , Fishinevich Eve , Ran Leili , Patel Amish J. , Yan Juan , Khudoynazarova Makhzuna N. , Warda Sarah , Pachai Mohini R. , Chen Yu , Chi Ping
Published: November 2024

Supplementary Table S4. Primers used for RT-qPCR.
Supplementary Figure S6 from MEK Inhibitors Lead to PDGFR Pathway Upregulation and Sensitize Tumors to RAF Dimer Inhibitors in NF1-Deficient Malignant Peripheral Nerve Sheath Tumor
Authors: Miranda-Román Miguel A. , Lee Cindy J. , Fishinevich Eve , Ran Leili , Patel Amish J. , Yan Juan , Khudoynazarova Makhzuna N. , Warda Sarah , Pachai Mohini R. , Chen Yu , Chi Ping
Published: November 2024

Supplementary Figure S6. Different MEKi synergize with RAFi in MPNST.
Supplementary Figure S1 from MEK Inhibitors Lead to PDGFR Pathway Upregulation and Sensitize Tumors to RAF Dimer Inhibitors in NF1-Deficient Malignant Peripheral Nerve Sheath Tumor
Authors: Miranda-Román Miguel A. , Lee Cindy J. , Fishinevich Eve , Ran Leili , Patel Amish J. , Yan Juan , Khudoynazarova Makhzuna N. , Warda Sarah , Pachai Mohini R. , Chen Yu , Chi Ping
Published: November 2024

Supplementary Figure S1. MPNST cell lines response to MEKi treatment.
Supplementary Figure S2 from High Mechanical Conditioning by Tumor Extracellular Matrix Stiffness Is a Predictive Biomarker for Antifibrotic Therapy in HER2-Negative Breast Cancer
Authors: Quintela-Fandino Miguel , Bermejo Begoña , Zamora Esther , Moreno Fernando , García-Saenz José Ángel , Pernas Sonia , Martínez-Jañez Noelia , Jiménez Desirée , Adrover Encarna , de Andrés Raquel , Mourón Silvana , Bueno Maria J. , Manso Luis , Viñas Gemma , Alba Emilio , Llombart-Cussac Antonio , Cortés Javier , Tebar Cristina , Roe Denise J. , Grant Adam , Watson Adam , Colomer Ramon , Mouneimne Ghassan
Published: November 2024

EFS in the basal-like subset.
Supplementary Table 4 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Supplementary Table 4. Drug schedules and tumor responses in the EHE PDX model.
Supplementary Table 2 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Supplementary Table 2. Quantification of band intensities for blot reported in Figure 3E.
Supplementary Table S6 from A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6–Targeting Antibody–Drug Conjugate, in Patients with Small Cell Lung Cancer
Authors: Morgensztern Daniel , Ready Neal , Johnson Melissa L. , Dowlati Afshin , Choudhury Noura , Carbone David P. , Schaefer Eric , Arnold Susanne M. , Puri Sonam , Piotrowska Zofia , Hegde Aparna , Chiang Anne C. , Iams Wade , Tolcher Anthony , Nosaki Kaname , Kozuki Toshiyuki , Li Tianhong , Santana-Davila Rafael , Akamatsu Hiroaki , Murakami Haruyasu , Yokouchi Hiroshi , Wang Song , Zha Jiuhong , Li Rui , Robinson Randy R. , Hingorani Pooja , Jeng Edwin E. , Furqan Muhammad
Published: November 2024

Overview of Treatment Response by Line of Treatment and Platinum Sensitivity
Supplementary Table 1 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Supplementary Table 1. Quantification of band intensities for blot reported in Figure 2D.
Supplementary Material 1 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Supplementary Material 1. Patient and human tumor characterization and prospective study.
Supplementary Figure 9 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Supplementary Figure 9. Representative images of H&E-stained EHE PDX tissue sections at the appropriate magnification to exhibit the different presence of sclerojalinosis (S) and necrotic (N) areas induced by Sirolimus at different doses.
Supplementary Table S3 from A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6–Targeting Antibody–Drug Conjugate, in Patients with Small Cell Lung Cancer
Authors: Morgensztern Daniel , Ready Neal , Johnson Melissa L. , Dowlati Afshin , Choudhury Noura , Carbone David P. , Schaefer Eric , Arnold Susanne M. , Puri Sonam , Piotrowska Zofia , Hegde Aparna , Chiang Anne C. , Iams Wade , Tolcher Anthony , Nosaki Kaname , Kozuki Toshiyuki , Li Tianhong , Santana-Davila Rafael , Akamatsu Hiroaki , Murakami Haruyasu , Yokouchi Hiroshi , Wang Song , Zha Jiuhong , Li Rui , Robinson Randy R. , Hingorani Pooja , Jeng Edwin E. , Furqan Muhammad
Published: November 2024

Time to Onset of First Hepatotoxicity Event
Supplementary Table S2 from A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6–Targeting Antibody–Drug Conjugate, in Patients with Small Cell Lung Cancer
Authors: Morgensztern Daniel , Ready Neal , Johnson Melissa L. , Dowlati Afshin , Choudhury Noura , Carbone David P. , Schaefer Eric , Arnold Susanne M. , Puri Sonam , Piotrowska Zofia , Hegde Aparna , Chiang Anne C. , Iams Wade , Tolcher Anthony , Nosaki Kaname , Kozuki Toshiyuki , Li Tianhong , Santana-Davila Rafael , Akamatsu Hiroaki , Murakami Haruyasu , Yokouchi Hiroshi , Wang Song , Zha Jiuhong , Li Rui , Robinson Randy R. , Hingorani Pooja , Jeng Edwin E. , Furqan Muhammad
Published: November 2024

Representativeness of Study Participants
Supplementary Figure 7 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Supplementary Figure 7. Volcano plot of genes differentially expressed between EHE cells transfected with GDF-15 siRNA or control (NEG) siRNA.
Supplementary Table S1 from A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6–Targeting Antibody–Drug Conjugate, in Patients with Small Cell Lung Cancer
Authors: Morgensztern Daniel , Ready Neal , Johnson Melissa L. , Dowlati Afshin , Choudhury Noura , Carbone David P. , Schaefer Eric , Arnold Susanne M. , Puri Sonam , Piotrowska Zofia , Hegde Aparna , Chiang Anne C. , Iams Wade , Tolcher Anthony , Nosaki Kaname , Kozuki Toshiyuki , Li Tianhong , Santana-Davila Rafael , Akamatsu Hiroaki , Murakami Haruyasu , Yokouchi Hiroshi , Wang Song , Zha Jiuhong , Li Rui , Robinson Randy R. , Hingorani Pooja , Jeng Edwin E. , Furqan Muhammad
Published: November 2024

Patient Disposition
Supplementary Figure 4 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Supplementary Figure 4. Transcriptomic profiles of EHE clinical tumor and PDX.
Supplementary Figure S1 from A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6–Targeting Antibody–Drug Conjugate, in Patients with Small Cell Lung Cancer
Authors: Morgensztern Daniel , Ready Neal , Johnson Melissa L. , Dowlati Afshin , Choudhury Noura , Carbone David P. , Schaefer Eric , Arnold Susanne M. , Puri Sonam , Piotrowska Zofia , Hegde Aparna , Chiang Anne C. , Iams Wade , Tolcher Anthony , Nosaki Kaname , Kozuki Toshiyuki , Li Tianhong , Santana-Davila Rafael , Akamatsu Hiroaki , Murakami Haruyasu , Yokouchi Hiroshi , Wang Song , Zha Jiuhong , Li Rui , Robinson Randy R. , Hingorani Pooja , Jeng Edwin E. , Furqan Muhammad
Published: November 2024

Preclinical efficacy study with xenograft models derived from patients with SCLC
Supplementary Table S4 from Long-Term Follow-up of Levonorgestrel Intrauterine Device for Atypical Hyperplasia and Early Endometrial Cancer Reveals Relapse Characterized by Immune Exhaustion
Authors: Bowen Mikayla B. , Melendez Brenda , Zhang Qian , Yang Richard K. , Fellman Bryan M. , Lawson Barrett C. , Adjei Naomi N. , Celestino Joseph , Wani Khalida M. , Singh Bhavana , Urbauer Diana L. , Lazar Alexander J. , Lu Karen H. , Wargo Jennifer A. , Westin Shannon N. , Yates Melinda S.
Published: November 2024

Supplementary Table S4. Gene set variation analyses of DSP data with FDR<0.05.
Supplementary Table S2 from Long-Term Follow-up of Levonorgestrel Intrauterine Device for Atypical Hyperplasia and Early Endometrial Cancer Reveals Relapse Characterized by Immune Exhaustion
Authors: Bowen Mikayla B. , Melendez Brenda , Zhang Qian , Yang Richard K. , Fellman Bryan M. , Lawson Barrett C. , Adjei Naomi N. , Celestino Joseph , Wani Khalida M. , Singh Bhavana , Urbauer Diana L. , Lazar Alexander J. , Lu Karen H. , Wargo Jennifer A. , Westin Shannon N. , Yates Melinda S.
Published: November 2024

Supplementary Table S2. Digital spatial profiling metadata.
Supplementary Figure 1 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Supplementary Figure 1. Representative growth curves of the EHE PDX at different passages in mice.
Supplementary Figure S1 from Long-Term Follow-up of Levonorgestrel Intrauterine Device for Atypical Hyperplasia and Early Endometrial Cancer Reveals Relapse Characterized by Immune Exhaustion
Authors: Bowen Mikayla B. , Melendez Brenda , Zhang Qian , Yang Richard K. , Fellman Bryan M. , Lawson Barrett C. , Adjei Naomi N. , Celestino Joseph , Wani Khalida M. , Singh Bhavana , Urbauer Diana L. , Lazar Alexander J. , Lu Karen H. , Wargo Jennifer A. , Westin Shannon N. , Yates Melinda S.
Published: November 2024

Supplementary Figure S1. Digital spatial profiling quality control.
Figure 4 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Sirolimus downmodulated GDF-15 release in patient-derived models of EHE through the inhibition of ATF4 and ATF5. A, GDF-15 released in culture medium of control cells and cells exposed for 3 days to doxorubicin or different sirolimus concentrations as detected by ELISA. Data were normalized as amount (pg) of released GDF-15 to total released (mg) proteins and reported as mean ± SD of three independent experiments. B, GDF-15 released in the blood collected from untreated mice and after the end of treatment with doxorubicin or different sirolimus doses. Data were normalized as amount (pg) of released GDF-15 to tumor weight (g) and reported as mean ± SD of three mice/experimental group. C, Western blot analysis of GDF-15, ATF4, and ATF5 expression in untreated cells (−) and cells treated with different sirolimus concentrations for 3 days (left) and in tumors removed from untreated (−) and sirolimus-treated mice after the first round of treatment with different drug doses (right). Western blot data of GDF-15 expression obtained on tumors from three untreated mice (−) and three mice exposed to 2.5 mg/kg sirolimus. Cropped images of selected proteins are shown. D, siRNA-mediated downregulation of ATF4 (left) and ATF5 (right) in the EHE cell line as detected at the mRNA level by RT-qPCR. E, Effects of ATF4 and ATF5 downregulation on GDF-15 protein expression as detected by level by Western blotting (left) and on cytokine release in cell culture medium as measured by ELISA (right). ELISA data were normalized as amount (pg) of released GDF-15 to total released (mg) proteins and reported as mean ± SD of three independent experiments. Cropped images of selected proteins are shown. F, The working model of sirolimus-induced GDF-15 downregulation. Sirolimus-induced mTORC1 inhibition led to reduced 4E-BP1 phosphorylation/activation followed by decreased ATF4 and ATF5 expression, thus resulting in GDF-15 downregulation. (F, Created with BioRender.com.)
Figure 2 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

GDF-15 was released by tumor cells in patient-derived models of EHE. A, Assessment of released cytokines in the culture medium of EHE cells using the Human XL Cytokine Array. Detection of GDF-15 by ELISA in culture medium of EHE cell lines and cell lines of PLPS and DDLPS-1 and -2. B, Data were normalized as amount (pg) of released GDF-15 to total released (mg) proteins. RT-qPCR and ELISA results are reported as mean ± SD of three independent experiments. C, Detection of GDF-15 by ELISA in the plasma of healthy mice and mice carrying EHE PDX or PLPS PDX. D, siRNA-mediated downregulation of GDF-15 in the EHE cell line as detected at the mRNA level by RT-qPCR (left), protein level by Western blotting (middle), and as cytokine released in cell culture medium by ELISA 3 days after transfection (right). ELISA data were normalized as amount (pg) of released GDF-15 to total released (mg) proteins and reported as mean ± SD of three independent experiments. E, GSEA (RRID: SCR_003199) was employed on Hallmark (H) collection of the Molecular Signature Database, showing a limited number of modulated pathways following GDF-15 knockdown. DDLPS, dedifferentiated liposarcoma; PLPS, pleomorphic liposarcoma.
Figure 1 from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

Characterization of EHE PDX and paired cell line. Representative pictures of the EHE clinical sample and corresponding EHE PDX model. A, The histology was assessed on hematoxylin and eosin–stained slides. Scale bar, 100 µm. WWTR1::CAMTA1 dual-color dual-fusion FISH pattern in diploid tumor cells showing one single fusion, consistently with the genomic profile. B, Genomic profile of EHE clinical tumor (left) and PDX (right). C, Loss (blue) and gain (red) were depicted in the top. LOH (green) was reported in the bottom (scale bar, 10 µm). D, Scatter plot of significant correlation between the transcriptome of the clinical tumor and the paired PDX (Spearman correlation, rs = 0.916; P < 0.001). E, Morphology of the EHE cell line derived from the PDX growing as monolayer (left, scale bar, 250 µm) and confirmation of WWTR1::CAMTA1 translocation at FISH analysis (right, scale bar, 10 µm). H&E, hematoxylin and eosin; LOH, loss of heterozygosity; RNA-seq, RNA sequencing.
Supplementary Table S2 from Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma
Authors: Hubbeling Harper , Leithner Doris , Silverman Emily A. , Flynn Jessica , Devlin Sean , Shah Gunjan , Fregonese Beatrice , Wills Beatriz , Bedmutha Akshay , Alarcon Tomas Ana , Parascondola Allison , Saldia Amethyst , Landego Ivan , Hajj Carla , Boardman Alexander P. , Dahi Parastoo B. , Ghosh Arnab , Giralt Sergio , Lin Richard J. , Park Jae , Scordo Michael , Salles Gilles , Yahalom Joachim , Palomba Maria L. , Schöder Heiko , Perales Miguel-Angel , Shouval Roni , Imber Brandon S.
Published: November 2024

Supplementary Table S2. Radiation characteristics.
Supplementary Table S1 from Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma
Authors: Hubbeling Harper , Leithner Doris , Silverman Emily A. , Flynn Jessica , Devlin Sean , Shah Gunjan , Fregonese Beatrice , Wills Beatriz , Bedmutha Akshay , Alarcon Tomas Ana , Parascondola Allison , Saldia Amethyst , Landego Ivan , Hajj Carla , Boardman Alexander P. , Dahi Parastoo B. , Ghosh Arnab , Giralt Sergio , Lin Richard J. , Park Jae , Scordo Michael , Salles Gilles , Yahalom Joachim , Palomba Maria L. , Schöder Heiko , Perales Miguel-Angel , Shouval Roni , Imber Brandon S.
Published: November 2024

Supplementary Table S1. Systemic bridging regimens.
Supplementary Figure S1 from Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma
Authors: Hubbeling Harper , Leithner Doris , Silverman Emily A. , Flynn Jessica , Devlin Sean , Shah Gunjan , Fregonese Beatrice , Wills Beatriz , Bedmutha Akshay , Alarcon Tomas Ana , Parascondola Allison , Saldia Amethyst , Landego Ivan , Hajj Carla , Boardman Alexander P. , Dahi Parastoo B. , Ghosh Arnab , Giralt Sergio , Lin Richard J. , Park Jae , Scordo Michael , Salles Gilles , Yahalom Joachim , Palomba Maria L. , Schöder Heiko , Perales Miguel-Angel , Shouval Roni , Imber Brandon S.
Published: November 2024

Supplementary Figure S1. Schematic depicting timing of imaging assessment and analytic approach.
Supplementary Figure S5 from Predictive and Dynamic Signature for Antiangiogenics in Combination with a PD1 Inhibitor in Soft-Tissue Sarcoma: Correlative Studies Linked to the IMMUNOSARC Trial
Authors: Moura David S. , Lopez-Marti Jesus M. , Benesova Iva , de Andrea Carlos , di Lernia Davide , Lacerenza Serena , Mondaza-Hernandez Jose L. , Martin-Ruiz Marta , Ramirez-Calvo Marta , Grignani Giovanni , Martinez-Trufero Javier , Redondo Andres , Valverde Claudia , Stacchiotti Silvia , Lopez-Pousa Antonio , Lopez-Guerrero José A. , Gutierrez Antonio , Encinas-Tobajas Victor , Hindi Nadia , Sangiolo Dario , Lopez-Martin Jose A. , Strizova Zuzana Ozaniak , Martin-Broto Javier
Published: November 2024

Supplementary Figure S5. CXCL10 protein expression in cell culture supernatant. The expression levels of CXCL10 soluble protein were measured after anti-CD3/CD28 stimulation and anti-PD-1 treatment in PBMC cultures (A) and tumor multi-cultures (B). Significance was defined as p<0.05 (Students t-test).
Supplemental Figure S5 from Androgen Deprivation Therapy Drives a Distinct Immune Phenotype in Localized Prostate Cancer
Authors: Dallos Matthew C. , Obradovic Aleksandar Z. , McCann Patrick , Chowdhury Nivedita , Pratapa Aditya , Aggen David H. , Gaffney Christopher , Autio Karen A. , Virk Renu K. , De Marzo Angelo M. , Antonarakis Emmanuel S. , Scher Howard I. , Drake Charles G. , Rathkopf Dana E.
Published: November 2024

Supplemental Figure S5. Top differentially expressed genes by expression level and statistical significance.
Supplementary Figure S2 from Epigenome Reprogramming Through H3K27 and H3K4 Trimethylation as a Resistance Mechanism to DNA Methylation Inhibition in BRAFV600E-Mutated Colorectal Cancer
Authors: Lee Hey Min , Saw Ajay Kumar , Morris Van K. , Napolitano Stefania , Bristow Christopher , Srinivasan Sanjana , Peoples Micheal , Sorokin Alexey , Kanikarla Marie Preeti , Schulz Jonathan , Singh Anand K. , Terranova Christopher , Coker Oluwadara , Jain Abhinav , Kopetz Scott , Rai Kunal
Published: November 2024

Limited impact of 5-azacitidine treatment in gene expression changes
Supplementary Table S3 from A First-in-Human Phase I Study of BXQ-350, a First-in-Class Sphingolipid Metabolism Regulator, in Patients with Advanced/Recurrent Solid Tumors or High-Grade Gliomas
Authors: Rixe Olivier , Villano John L. , Wesolowski Robert , Noonan Anne M. , Puduvalli Vinay K. , Wise-Draper Trisha M. , Curry Richard , Yilmaz Emrullah , Cruze Charlie , Ogretmen Besim , Tapolsky Gilles , Takigiku Ray
Published: November 2024

Supplementary Table S3. BXQ-350 PK parameters in Part 2, Day 1 (2.4 mg/kg).
Supplementary Table S2 from A First-in-Human Phase I Study of BXQ-350, a First-in-Class Sphingolipid Metabolism Regulator, in Patients with Advanced/Recurrent Solid Tumors or High-Grade Gliomas
Authors: Rixe Olivier , Villano John L. , Wesolowski Robert , Noonan Anne M. , Puduvalli Vinay K. , Wise-Draper Trisha M. , Curry Richard , Yilmaz Emrullah , Cruze Charlie , Ogretmen Besim , Tapolsky Gilles , Takigiku Ray
Published: November 2024

Supplementary Table S2. Representativeness of study participants.
Supplementary Figure S1 from A First-in-Human Phase I Study of BXQ-350, a First-in-Class Sphingolipid Metabolism Regulator, in Patients with Advanced/Recurrent Solid Tumors or High-Grade Gliomas
Authors: Rixe Olivier , Villano John L. , Wesolowski Robert , Noonan Anne M. , Puduvalli Vinay K. , Wise-Draper Trisha M. , Curry Richard , Yilmaz Emrullah , Cruze Charlie , Ogretmen Besim , Tapolsky Gilles , Takigiku Ray
Published: November 2024

Supplementary Figure S1. Concentration-time profiles of SapC beyond study day 1.
Supplementary Figure S5 from Chemoradiotherapy and Subsequent Immunochemotherapy as Conversion Therapy in Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II NEXUS-1 Trial
Authors: Wang Xin , Kang Xiaozheng , Zhang Ruixiang , Xue Liyan , Xu Jiaqi , Zhao Xiaotian , Ou Qiuxiang , Yu Nuo , Feng Guojie , Li Jiao , Zheng Ziyu , Chen Xiankai , Wang Zhen , Zheng Qingfeng , Li Yong , Qin Jianjun , Bi Nan , Li Yin
Published: November 2024

Supplementary Figure 5. Results of univariate analyses for overall survival
Supplementary Figure S3 from Chemoradiotherapy and Subsequent Immunochemotherapy as Conversion Therapy in Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II NEXUS-1 Trial
Authors: Wang Xin , Kang Xiaozheng , Zhang Ruixiang , Xue Liyan , Xu Jiaqi , Zhao Xiaotian , Ou Qiuxiang , Yu Nuo , Feng Guojie , Li Jiao , Zheng Ziyu , Chen Xiankai , Wang Zhen , Zheng Qingfeng , Li Yong , Qin Jianjun , Bi Nan , Li Yin
Published: November 2024

Supplementary Figure 3. Prognostic analysis of esophageal squamous cell carcinoma in MRD status
Supplementary Figure S1 from Chemoradiotherapy and Subsequent Immunochemotherapy as Conversion Therapy in Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II NEXUS-1 Trial
Authors: Wang Xin , Kang Xiaozheng , Zhang Ruixiang , Xue Liyan , Xu Jiaqi , Zhao Xiaotian , Ou Qiuxiang , Yu Nuo , Feng Guojie , Li Jiao , Zheng Ziyu , Chen Xiankai , Wang Zhen , Zheng Qingfeng , Li Yong , Qin Jianjun , Bi Nan , Li Yin
Published: November 2024

Supplementary Figure 1. Kaplan-Meier estimates of survival in the R0 resection and non-surgery group
Supplementary Table S1 from Cancer in Multilineage Mosaic RASopathies due to Pathogenic Variants in HRAS or KRAS: A Systematic Review and Meta-analysis
Authors: Windrich Jonas , Ney Gina M. , Rosenberg Philip S. , Kim Jung , Zenker Martin , Stewart Douglas R. , Kratz Christian P.
Published: November 2024

Details on each patient
Supplementary Tables S1-S14 from ctDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial
Authors: Soo Ross A. , Dafni Urania , Han Ji-Youn , Cho Byoung Chul , Nadal Ernest , Yeo Chong Ming , Carcereny Enric , de Castro Javier , Sala Maria Angeles , Coate Linda , Provencio Mariano , Britschgi Christian , Vagenknecht Patrick , Dimopoulou Georgia , Kammler Roswitha , Finn Stephen P. , Peters Solange , Stahel Rolf A.
Published: November 2024

Supplementary Tables S1-S14
Supplementary Figure S9 from ctDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial
Authors: Soo Ross A. , Dafni Urania , Han Ji-Youn , Cho Byoung Chul , Nadal Ernest , Yeo Chong Ming , Carcereny Enric , de Castro Javier , Sala Maria Angeles , Coate Linda , Provencio Mariano , Britschgi Christian , Vagenknecht Patrick , Dimopoulou Georgia , Kammler Roswitha , Finn Stephen P. , Peters Solange , Stahel Rolf A.
Published: November 2024

Supplementary Figure S9. Overall survival for the N=136 patients constituting the biomarker analysis cohort, by baseline mutational status of (A) EGFR T790M (B) TP53.
Supplementary Figure S3 from ctDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial
Authors: Soo Ross A. , Dafni Urania , Han Ji-Youn , Cho Byoung Chul , Nadal Ernest , Yeo Chong Ming , Carcereny Enric , de Castro Javier , Sala Maria Angeles , Coate Linda , Provencio Mariano , Britschgi Christian , Vagenknecht Patrick , Dimopoulou Georgia , Kammler Roswitha , Finn Stephen P. , Peters Solange , Stahel Rolf A.
Published: November 2024

Supplementary Figure S3. EGFR T790M mutational status (MD/MND) by treatment arm at baseline (N=136), week 9 (N=110) and progression (N=65).
Supplementary Table S5 from The Epstein–Barr Virus Nuclear Antigen 1 Variant Associated with Nasopharyngeal Carcinoma Defines the Sequence Criteria for Serologic Risk Prediction
Authors: Warner Benjamin E. , Patel Japan , Wang Renwei , Adams-Haduch Jennifer , Gao Yu-Tang , Koh Woon-Puay , Wong Ka Wo , Chiang Alan K.S. , Yuan Jian-Min , Shair Kathy H.Y.
Published: November 2024

Supplementary Table S5. Sensitivity and specificity of IgA to EBNA1 IDE2 amino acid substitution constructs by denaturing immunoblot assay in NPCs <4 years to diagnosis and healthy controls.
Supplementary Table S4 from The Epstein–Barr Virus Nuclear Antigen 1 Variant Associated with Nasopharyngeal Carcinoma Defines the Sequence Criteria for Serologic Risk Prediction
Authors: Warner Benjamin E. , Patel Japan , Wang Renwei , Adams-Haduch Jennifer , Gao Yu-Tang , Koh Woon-Puay , Wong Ka Wo , Chiang Alan K.S. , Yuan Jian-Min , Shair Kathy H.Y.
Published: November 2024

Supplementary Table S4. Tabulated EBNA1 IgA test positives by denaturing immunoblot assay in NPC and healthy sera.
Supplementary Figure S1 from ctDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial
Authors: Soo Ross A. , Dafni Urania , Han Ji-Youn , Cho Byoung Chul , Nadal Ernest , Yeo Chong Ming , Carcereny Enric , de Castro Javier , Sala Maria Angeles , Coate Linda , Provencio Mariano , Britschgi Christian , Vagenknecht Patrick , Dimopoulou Georgia , Kammler Roswitha , Finn Stephen P. , Peters Solange , Stahel Rolf A.
Published: November 2024

Supplementary Figure S1. Consort diagram.
Supplementary Appendix S1 from ctDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial
Authors: Soo Ross A. , Dafni Urania , Han Ji-Youn , Cho Byoung Chul , Nadal Ernest , Yeo Chong Ming , Carcereny Enric , de Castro Javier , Sala Maria Angeles , Coate Linda , Provencio Mariano , Britschgi Christian , Vagenknecht Patrick , Dimopoulou Georgia , Kammler Roswitha , Finn Stephen P. , Peters Solange , Stahel Rolf A.
Published: November 2024

List of ETOP 10-16 BOOSTER collaborators
Supplementary Table S2 from The Epstein–Barr Virus Nuclear Antigen 1 Variant Associated with Nasopharyngeal Carcinoma Defines the Sequence Criteria for Serologic Risk Prediction
Authors: Warner Benjamin E. , Patel Japan , Wang Renwei , Adams-Haduch Jennifer , Gao Yu-Tang , Koh Woon-Puay , Wong Ka Wo , Chiang Alan K.S. , Yuan Jian-Min , Shair Kathy H.Y.
Published: November 2024

Supplementary Table S2. Tabulated data from EBNA1 amino acid sequence conservation in Fig. 1 and Supplementary Fig. S1.
Supplementary Methods S1 from The Epstein–Barr Virus Nuclear Antigen 1 Variant Associated with Nasopharyngeal Carcinoma Defines the Sequence Criteria for Serologic Risk Prediction
Authors: Warner Benjamin E. , Patel Japan , Wang Renwei , Adams-Haduch Jennifer , Gao Yu-Tang , Koh Woon-Puay , Wong Ka Wo , Chiang Alan K.S. , Yuan Jian-Min , Shair Kathy H.Y.
Published: November 2024

Supplementary Methods S1. Slot blot and Mikrogen recomLine EBV immunoassay methods.
Supplementary Figure S2 from The Epstein–Barr Virus Nuclear Antigen 1 Variant Associated with Nasopharyngeal Carcinoma Defines the Sequence Criteria for Serologic Risk Prediction
Authors: Warner Benjamin E. , Patel Japan , Wang Renwei , Adams-Haduch Jennifer , Gao Yu-Tang , Koh Woon-Puay , Wong Ka Wo , Chiang Alan K.S. , Yuan Jian-Min , Shair Kathy H.Y.
Published: November 2024

Supplementary Figure S2. EBNA1 IgG detection by denaturing immunoblot assay in NPC and healthy sera.
Data from Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology
Authors: Ercan Caner , Renne Salvatore Lorenzo , Di Tommaso Luca , Ng Charlotte K.Y. , Piscuoglio Salvatore , Terracciano Luigi M.
Published: November 2024

AbstractPurpose:
The spatial variability and clinical relevance of the tumor immune microenvironment (TIME) are still poorly understood for hepatocellular carcinoma (HCC). In this study, we aim to develop a deep learning (DL)–based image analysis model for the spatial analysis of immune cell biomarkers and microscopically evaluate the distribution of immune infiltration.
Experimental Design:
Ninety-two HCC surgical liver resections and 51 matched needle biopsies were histologically classified according to their immunophenotypes: inflamed, immune-excluded, and immune-desert. To characterize the TIME on immunohistochemistry (IHC)-stained slides, we designed a multistage DL algorithm, IHC-TIME, to automatically detect immune cells and their localization in the TIME in tumor–stroma and center–border segments.
Results:
Two models were trained to detect and localize the immune cells on IHC-stained slides. The framework models (i.e., immune cell detection models and tumor–stroma segmentation) reached 98% and 91% accuracy, respectively. Patients with inflamed tumors showed better recurrence-free survival than those with immune-excluded or immune-desert tumors. Needle biopsies were found to be 75% accurate in representing the immunophenotypes of the main tumor. Finally, we developed an algorithm that defines immunophenotypes automatically based on the IHC-TIME analysis, achieving an accuracy of 80%.
Conclusions:
Our DL-based tool can accurately analyze and quantify immune cells on IHC-stained slides of HCC. Microscopic classification of the TIME can stratify HCC according to the patient prognosis. Needle biopsies can provide valuable insights for TIME-related prognostic prediction, albeit with specific constraints. The computational pathology tool provides a new way to study the HCC TIME.
Data from MEK Inhibitors Lead to PDGFR Pathway Upregulation and Sensitize Tumors to RAF Dimer Inhibitors in NF1-Deficient Malignant Peripheral Nerve Sheath Tumor
Authors: Miranda-Román Miguel A. , Lee Cindy J. , Fishinevich Eve , Ran Leili , Patel Amish J. , Yan Juan , Khudoynazarova Makhzuna N. , Warda Sarah , Pachai Mohini R. , Chen Yu , Chi Ping
Published: November 2024

AbstractPurpose:
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive subtype of soft-tissue sarcoma with a high propensity to metastasize and extremely limited treatment options. Loss of the RAS-GAP NF1 leads to sustained RAF/MEK/ERK signaling in MPNST. However, single-agent MEK inhibitors (MEKi) have failed to elicit a sustained inhibition of the MAPK signaling pathway in MPNST.
Experimental Design:
We used pharmacological, biochemical, and genetic perturbations of the receptor tyrosine kinase and MAPK signaling pathway regulators to investigate the mechanisms of MEKi resistance and evaluated combination therapeutic strategies in various preclinical MPNST models in vitro and in vivo.
Results:
Here, we report that MEKi treatment resistance in MPNST involves two adaptive pathways: direct transcriptional upregulation of the receptor tyrosine kinase PDGFRβ and MEKi-induced increase in RAF dimer formation and activation of downstream signaling. Although the pharmacologic combination of a MEKi with a PDGFRβ-specific inhibitor was more effective than treatment with the MEKi alone, the combination of the MEKi and RAF dimer inhibitors led to a robust inhibition of MAPK pathway signaling. This combination treatment was effective in vitro and in vivo, as demonstrated by the significant increase in drug synergism and its high effectiveness in decreasing MPNST viability.
Conclusions:
Our findings suggest that the combination of MEKis and PDGFR and/or RAF dimer inhibitors can overcome MEKi resistance and may serve as a novel targeted therapeutic strategy for patients with NF1-deficient MPNST, which in turn could impact future clinical investigations for this patient population.
Data from GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression
Authors: Stacchiotti Silvia , Martini Silvia , Pasquali Sandro , Frezza Anna M. , Beretta Alessia , Percio Stefano , Lecchi Mara , Tortoreto Monica , Barisella Marta , Collini Paola , Dagrada Gian Paolo , Merlini Alessandra , Huang Paul H. , Jenks Andrew , Jones Robin L. , Tap William D. , Ingrosso Matilde , Morosi Carlo , Brich Silvia , Giani Claudia , Verderio Paolo , Casali Paolo G. , Leonard Hugh , Gronchi Alessandro , Zuco Valentina , Zaffaroni Nadia
Published: November 2024

AbstractPurpose:
Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness.
Experimental Design:
A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness.
Results:
ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness.
Conclusions:
This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug’s activity in patients.
Data from Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma
Authors: Hubbeling Harper , Leithner Doris , Silverman Emily A. , Flynn Jessica , Devlin Sean , Shah Gunjan , Fregonese Beatrice , Wills Beatriz , Bedmutha Akshay , Alarcon Tomas Ana , Parascondola Allison , Saldia Amethyst , Landego Ivan , Hajj Carla , Boardman Alexander P. , Dahi Parastoo B. , Ghosh Arnab , Giralt Sergio , Lin Richard J. , Park Jae , Scordo Michael , Salles Gilles , Yahalom Joachim , Palomba Maria L. , Schöder Heiko , Perales Miguel-Angel , Shouval Roni , Imber Brandon S.
Published: November 2024

AbstractPurpose:
Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell (CAR T) therapy. Although bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data have evaluated the impact of BT on CAR T outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic.
Experimental Design:
Patients with large B-cell lymphoma treated with CD19-CAR T from 2016 to 2022 were included in the study. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into “High” and “Low” disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression-free survival (PFS).
Results:
Of 191 patients treated with CAR T, 144 (75%) received BT. In the BT cohort, 56% had a reduction in MTV post-BT. On multivariate analysis, the MTV trajectory across the bridging period remained significantly associated with PFS (P < 0.001); however, notably, patients with improved MTV (High->Low) had equivalent PFS compared with those with initially and persistently low MTV (Low->Low; HR for High->Low MTV: 2.74; 95% confidence interval, 0.82–9.18). There was a reduction in any grade immune effector cell–associated neurotoxicity syndrome in the High->Low MTV cohort as compared with the High->High MTV cohort (13% vs. 41%; P = 0.05).
Conclusions:
This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real-world large B-cell lymphoma cohort. We demonstrate that effective BT can enable initially high–disease burden patients to achieve post–CAR T outcomes comparable with low–disease burden patients.
Data from Epigenome Reprogramming Through H3K27 and H3K4 Trimethylation as a Resistance Mechanism to DNA Methylation Inhibition in BRAFV600E-Mutated Colorectal Cancer
Authors: Lee Hey Min , Saw Ajay Kumar , Morris Van K. , Napolitano Stefania , Bristow Christopher , Srinivasan Sanjana , Peoples Micheal , Sorokin Alexey , Kanikarla Marie Preeti , Schulz Jonathan , Singh Anand K. , Terranova Christopher , Coker Oluwadara , Jain Abhinav , Kopetz Scott , Rai Kunal
Published: November 2024

AbstractPurpose:
BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo.
Experimental Design:
We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine–treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.
Results:
A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions, suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor-suppressor genes. Combined inhibition of PRC activity through EZH2 inhibition with 5-azacitidine treatment additively improved efficacies in BRAFV600E colorectal cancer cells.
Conclusions:
In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E colorectal cancer, and simultaneous blockade of DNA methyltransferase and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated colorectal cancer.