bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Multi-scale Pan-cancer Integrative Analyses Identify the STAT3-VSIR Axis as a Key Immunosuppressive Mechanism in Head and Neck Cancer
Authors: Katabathula Ramachandra , Joseph Peronne , Singh Salendra , Zhao Songzhu , Kumar Bhavna , Gaule Patricia , Pan Quintin , Old Matthew , Tuck David P. , Varadan Vinay
Published: April 2023

AbstractPurpose:
VSIR is a novel immune checkpoint protein whose expression on tumor cells across cancers remains largely uncharacterized. Here we purposed to decode the pan-cancer biologic and clinical significance of VSIR overexpression in the tumor compartment.
Experimental Design:
We performed multi-omics integrative analyses of 9,735 tumor samples to identify cancers with non-leukocytic expression of VSIR (VSIR High), followed by association with overall survival and immune cell infiltration levels. Orthogonal assessments of VSIR protein expression and lymphocytic infiltration were performed using quantitative immunofluorescence (QIF).
Results:
Integrative modeling identified a subset of cancer types as being enriched for VSIR High tumors. VSIR High tumors were associated with significantly poorer overall survival in immunogenic ovarian serous adenocarcinoma (SA) and oral cavity squamous cell carcinoma (SCC). QIF assessments in an independent validation cohort confirmed overexpression of VSIR as being associated with poorer overall survival within immunogenic oral cavity SCC. VSIR overexpression was associated with lower CD4 helper T-cell infiltration in both ovarian SA and oral cavity SCC, but did not impact CD8 T-cell infiltration. VSIR overexpressing tumors in both cancer types exhibited significantly higher STAT3 signaling activity. Pharmacologic inhibition of STAT3 signaling resulted in dose-dependent reduction of VSIR expression in ovarian SA and oral cavity SCC cells.
Conclusions:
The STAT3-VSIR axis is a potentially significant immunomodulatory mechanism in oral cavity and ovarian cancers, whose activation is associated with poorer survival and an immune microenvironment marked by decreased CD4 helper T-cell activity. The role of VSIR as a tumor-intrinsic modulator of resistance to immunotherapy warrants further exploration.
Data from Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma
Authors: Esteban-Fabró Roger , Willoughby Catherine E. , Piqué-Gili Marta , Montironi Carla , Abril-Fornaguera Jordi , Peix Judit , Torrens Laura , Mesropian Agavni , Balaseviciute Ugne , Miró-Mur Francesc , Mazzaferro Vincenzo , Pinyol Roser , Llovet Josep M.
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibitors combined with antiangiogenic agents produce benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination.
Experimental Design:
C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumors received cabozantinib, anti-PD1, their combination, or placebo. Tumor and blood samples were analyzed by flow cytometry, IHC, transcriptome, and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer patient-derived xenograft model. Transcriptomic data from three human HCC cohorts (cohort 1: n = 167, cohort 2: n = 57, The Cancer Genome Atlas: n = 319) were used to cluster patients according to neutrophil features, and assess their impact on survival.
Results:
The combination of cabozantinib and anti-PD1 showed increased antitumor efficacy compared with monotherapy and placebo (P < 0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced intratumor CD8+PD1+ T-cell proportions, while the combination with anti-PD1 further stimulated both effects and significantly decreased regulatory T cell (Treg) infiltration (all P < 0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P < 0.01) and memory/effector T cells (P < 0.05), while lowering the neutrophil-to-lymphocyte ratio (P < 0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumor enrichment in neutrophil features observed with the treatment combination was linked to less aggressive tumors with more differentiated and less proliferative phenotypes.
Conclusions:
Cabozantinib in combination with anti-PD1 enhanced antitumor immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favors this approach for HCC treatment.
Data from Unbiased Detection of Driver Mutations in Extramammary Paget Disease
Authors: Ishida Yoshihiro , Kakiuchi Nobuyuki , Yoshida Kenichi , Inoue Yoshikage , Irie Hiroyuki , Kataoka Tatsuki R. , Hirata Masahiro , Funakoshi Takeru , Matsushita Shigeto , Hata Hiroo , Uchi Hiroshi , Yamamoto Yuki , Fujisawa Yasuhiro , Fujimura Taku , Saiki Ryunosuke , Takeuchi Kengo , Shiraishi Yuichi , Chiba Kenichi , Tanaka Hiroko , Otsuka Atsushi , Miyano Satoru , Kabashima Kenji , Ogawa Seishi
Published: April 2023

AbstractPurpose:
Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and PIK3CA. In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing.
Experimental Design:
First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several in silico analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. ERBB2 expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence in situ hybridization.
Results:
A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 as likely driver mutations. Copy-number alteration analysis showed regions spanning CDKN2A as recurrently deleted, and ERBB2 as recurrently amplified. ERBB2, ERBB3, and FGFR1 amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence in situ analysis validated ERBB2 amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of ERBB2 amplification status was observed in some cases.
Conclusions:
Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K–AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.
Data from Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial
Authors: Lee Jung-Min , Moore Richard G. , Ghamande Sharad , Park Min S. , Diaz John P. , Chapman Julia , Kendrick James , Slomovitz Brian M. , Tewari Krishnansu S. , Lowe Elizabeth S. , Milenkova Tsveta , Kumar Sanjeev , Dymond Mike , Brown Jessica , Liu Joyce F.
Published: April 2023

AbstractPurpose:
The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline–BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer.
Patients and Methods:
PARP inhibitor–naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0–2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined.
Results:
Sixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% [4/15; 95% confidence interval (CI), 7.8–55.1], while ORR was 12.5% (4/32; 95% CI, 3.5–29.0) in the low gLOH group.
Conclusions:
Clinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies.
Data from Temporal Muscle Thickness as a Prognostic Marker in Patients with Newly Diagnosed Glioblastoma: Translational Imaging Analysis of the CENTRIC EORTC 26071–22072 and CORE Trials
Authors: Furtner Julia , Weller Michael , Weber Michael , Gorlia Thierry , Nabors Burt , Reardon David A. , Tonn Joerg C. , Stupp Roger , Preusser Matthias
Published: April 2023

AbstractPurpose:
To investigate the prognostic relevance of temporal muscle thickness (TMT) as a surrogate parameter of skeletal muscle status in patients with newly diagnosed glioblastoma.
Experimental Design:
We assessed TMT in cranial MRI of 755 patients enrolled in the CENTRIC EORTC 26071–22072 study (n = 508) and CORE study (n = 247). We used predefined sex-specific TMT cut-off values to categorize “patients at risk of sarcopenia” and “patients with normal muscle status” at baseline. Furthermore, we categorized patients according to the extent of TMT loss over time. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using the Cox model adjusted for other exploratory variables.
Results:
Patients at risk of sarcopenia (CENTRIC; n = 158/508, 31.1%; CORE; n = 87/247, 35.2%) at baseline had significantly higher risk of progression and death than patients with normal muscle status in both study cohorts [CENTRIC: PFS = HR 0.16; 95% confidence interval (CI), 0.12–0.21; P < 0.001; OS = HR 0.341; 95% CI, 0.27–0.44; P < 0.001; CORE: PFS = HR 0.29; 95% CI, 0.21–0.39; P < 0.001; OS = HR, 0.365; 95% CI, 0.27–0.49; P < 0.001]. Similar results were obtained in multivariate Cox models adjusted for other important prognostic parameters. The extent of TMT loss over time showed a significant inverse correlation with median OS times in patients at risk for sarcopenia (CENTRIC: P < 0.001; CORE: P = 0.005), but not in patients with normal baseline muscle mass (CENTRIC: P = 0.538; CORE: P = 0.28).
Conclusions:
TMT identifies ambulatory patients with newly diagnosed glioblastoma at risk for progressive sarcopenia and adverse outcomes. Early intervention may prevent skeletal muscle loss and improve patient outcome.
Data from A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer
Authors: Dylgjeri Emanuela , Kothari Vishal , Shafi Ayesha A. , Semenova Galina , Gallagher Peter T. , Guan Yi F. , Pang Angel , Goodwin Jonathan F. , Irani Swati , McCann Jennifer J. , Mandigo Amy C. , Chand Saswati , McNair Christopher M. , Vasilevskaya Irina , Schiewer Matthew J. , Lallas Costas D. , McCue Peter A. , Gomella Leonard G. , Seifert Erin L. , Carroll Jason S. , Butler Lisa M. , Holst Jeff , Kelly William K. , Knudsen Karen E.
Published: April 2023

AbstractPurpose:
DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes.
Experimental Design:
Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE).
Results:
Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease.
Conclusions:
Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK–mediated aggressive disease phenotypes.
Data from Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma
Authors: Noh Joseph J. , Cho Young-Jae , Ryu Ji-Yoon , Choi Jung-Joo , Hwang Jae Ryoung , Choi Ju-Yeon , Lee Jeong-Won
Published: April 2023

AbstractPurpose:
To evaluate the anticancer effects of cabozantinib, temozolomide, and their combination in uterine sarcoma cell lines and mouse xenograft models.
Experimental Design:
Human uterine sarcoma cell lines (SK-LMS-1, SK-UT-1, MES-SA, and SKN) were used to evaluate the anticancer activity of cabozantinib, temozolomide, and their combination. The optimal dose of each drug was determined by MTT assay. Cell proliferation and apoptosis were assessed 48 and 72 hours after the drug treatments. The tumor weights were measured in an SK-LMS-1 xenograft mouse model and a patient-derived xenograft (PDX) model of leiomyosarcoma treated with cabozantinib, temozolomide, or both.
Results:
Given individually, cabozantinib and temozolomide each significantly decreased the growth and viability of cells. This inhibitory effect was more pronounced when cabozantinib (0.50 μmol/L) and temozolomide (0.25 or 0.50 mmol/L) were co-administered (P < 0.05). The combination of the drugs also significantly increased apoptosis in all cells. Moreover, this effect was consistently observed in patient-derived leiomyosarcoma cells. In vivo studies with SK-LMS-1 cell xenografts and the PDX model with leiomyosarcoma demonstrated that combined treatment with cabozantinib (5 mg/kg/d, per os administration) and temozolomide (5 mg/kg/d, per os administration) synergistically decreased tumor growth (both P < 0.05).
Conclusions:
The addition of cabozantinib to temozolomide offers synergistic anticancer effects in uterine sarcoma cell lines and xenograft mouse models, including PDX. These results warrant further investigation in a clinical trial.
Data from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer
Authors: Lim Joline S.J. , Wong Andrea L.A. , Ow Samuel G.W. , Ngoi Natalie Y.L. , Chan Gloria H.J. , Ang Yvonne L.E. , Chong Wan Qin , Lim Siew Eng , Lim Yi Wan , Lee Matilda , Choo Joan R.E. , Tan Hon Lyn , Yong Wei Peng , Soo Ross A. , Tan David S.P. , Chee Cheng Ean , Sundar Raghav , Yadav Kritika , Jain Supriya , Wang Lingzhi , Tai Bee Choo , Goh Boon Cher , Lee Soo-Chin
Published: April 2023

AbstractPurpose:
RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer.
Patients and Methods:
Patients with advanced ER+/HER2− breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion.
Results:
Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0–11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%–42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%–68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%–40.7%), median DoR 6.9 months (IQR 5.9–13.1), and CBR 52.0% (95% CI, 31.3%–72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index.
Conclusions:
Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.
Data from HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma
Authors: Sasame Jo , Ikegaya Naoki , Kawazu Masahito , Natsumeda Manabu , Hayashi Takahiro , Isoda Masataka , Satomi Kaishi , Tomiyama Arata , Oshima Akito , Honma Hirokuni , Miyake Yohei , Takabayashi Katsuhiro , Nakamura Taishi , Ueno Toshihide , Matsushita Yuko , Iwashita Hiromichi , Kanemaru Yu , Murata Hidetoshi , Ryo Akihide , Terashima Keita , Yamanaka Shoji , Fujii Yukihiko , Mano Hiroyuki , Komori Takashi , Ichimura Koichi , Cahill Daniel P. , Wakimoto Hiroaki , Yamamoto Tetsuya , Tateishi Kensuke
Published: April 2023

AbstractPurpose:
Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E-mutant high-grade gliomas (HGG); however, the therapeutic effect is limited by the emergence of drug resistance.
Experimental Design:
We established multiple paired BRAFV600E-mutant HGG patient-derived xenograft models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment-resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo.
Results:
We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the reactivation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E-mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3β (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular targeted therapy.
Conclusions:
The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E-mutant HGG.
Data from Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer
Authors: Zizzari Ilaria Grazia , Di Filippo Alessandra , Botticelli Andrea , Strigari Lidia , Pernazza Angelina , Rullo Emma , Pignataro Maria Gemma , Ugolini Alessio , Scirocchi Fabio , Di Pietro Francesca Romana , Rossi Ernesto , Gelibter Alain , Schinzari Giovanni , D'Amati Giulia , Rughetti Aurelia , Marchetti Paolo , Nuti Marianna , Napoletano Chiara
Published: April 2023

AbstractPurpose:
CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137+ T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+ T cells in the improvement of patients' selection for immunotherapy treatment.
Experimental Design:
Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137+ T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137+ T cells was also examined in different tumor settings.
Results:
The percentage of CD137+ T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8+CD137+ T cell population. The high frequency of CD137+ and CD8+CD137+ T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3+CD137+PD1+ lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137+ and CD8+ T cells.
Conclusions:
We propose the CD137+ T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.
Data from Interactome of Aiolos/Ikaros Reveals Combination Rationale of Cereblon Modulators with HDAC Inhibitors in DLBCL
Authors: Hagner Patrick R. , Chiu Hsiling , Chopra Vivek S. , Colombo Martino , Patel Nisha , Estevez Maria Ortiz , Waldman Michelle F. , Loos Remco , Towfic Fadi , Gandhi Anita K.
Published: April 2023

AbstractPurpose:
Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the small molecules lenalidomide and avadomide. Upon binding of the drugs, Aiolos and Ikaros are recruited to the E3 ligase, ubiquitylated, and subsequently degraded. In diffuse large B-cell lymphoma (DLBCL) cells, Aiolos and Ikaros are direct transcriptional repressors of interferon-stimulated genes (ISG) and degradation of these substrates results in increased ISG protein levels resulting in decreased proliferation and apoptosis. Herein, we aimed to uncover the mechanism(s) Aiolos and Ikaros use to repress ISG transcription and provide a mechanistic rationale for a combination strategy to enhance cell autonomous activities of CRBN modulators (CELMoD).
Experimental Design:
We conducted paired RNA sequencing with histone modification and Aiolos/Ikaros chromatin immunoprecipitation sequencing to identify genes regulated by these transcription factors and to elucidate correlations to drug sensitivity. We confirmed Aiolos/Ikaros mediated transcriptional complex formation in DLBCL patient samples including those treated with avadomide.
Results:
In DLBCL, the repression of ISG transcription is accomplished in part through recruitment of large transcriptional complexes such as the nucleosome remodeling and deacetylase, which modify the chromatin landscape of these promoters. A rational combination approach of avadomide with a specific histone deacetylase inhibitor leads to a significant increase in ISG transcription compared with either single agent, and synergistic antiproliferative activity in DLBCL cell lines.
Conclusions:
Our results provide a novel role for lineage factors Aiolos and Ikaros in DLBCL as well as further insight into the mechanism(s) of Aiolos and Ikaros–mediated transcriptional repression and unique therapeutic combination strategies.
Data from The Impact of PIK3R1 Mutations and Insulin–PI3K–Glycolytic Pathway Regulation in Prostate Cancer
Authors: Chakraborty Goutam , Nandakumar Subhiksha , Hirani Rahim , Nguyen Bastien , Stopsack Konrad H. , Kreitzer Christoph , Rajanala Sai Harisha , Ghale Romina , Mazzu Ying Z. , Pillarsetty Naga Vara Kishore , Lee Gwo-Shu Mary , Scher Howard I. , Morris Michael J. , Traina Tiffany , Razavi Pedram , Abida Wassim , Durack Jeremy C. , Solomon Stephen B. , Vander Heiden Matthew G. , Mucci Lorelei A. , Wibmer Andreas G. , Schultz Nikolaus , Kantoff Philip W.
Published: April 2023

AbstractPurpose:
Oncogenic alterations of the PI3K/AKT pathway occur in >40% of patients with metastatic castration-resistant prostate cancer, predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown.
Experimental Design:
Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions; copy-number alterations; and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used the siRNA-based knockdown of PIK3R1 for functional studies. FDG‐PET/CT examinations were performed with a hybrid positron emission tomography (PET)/CT scanner for some prostate cancer patients in the MSK-IMPACT cohort.
Results:
Analyzing 1,417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared with primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F‐fluorodeoxyglucose in PET imaging, suggesting increased glycolysis.
Conclusions:
Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin–PI3K–glycolytic pathway regulation in prostate cancer.
Data from Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data
Authors: Fisher Natalie C. , Byrne Ryan M. , Leslie Holly , Wood Colin , Legrini Assya , Cameron Andrew J. , Ahmaderaghi Baharak , Corry Shania M. , Malla Sudhir B. , Amirkhah Raheleh , McCooey Aoife J. , Rogan Emily , Redmond Keara L. , Sakhnevych Svetlana , Domingo Enric , Jackson James , Loughrey Maurice B. , Leedham Simon , Maughan Tim , Lawler Mark , Sansom Owen J. , Lamrock Felicity , Koelzer Viktor H. , Jamieson Nigel B. , Dunne Philip D.
Published: April 2023

AbstractPurpose:
Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling.
Experimental Design:
Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets.
Results:
Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment.
Conclusions:
Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples.
Data from A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma
Authors: Saulnier-Sholler Giselle , Duda Dan G. , Bergendahl Genevieve , Ebb David , Snuderl Matija , Laetsch Theodore W. , Michlitsch Jennifer , Hanson Derek , Isakoff Michael S. , Bielamowicz Kevin , Kraveka Jacqueline M. , Ferguson William , Carmeliet Peter , De Deene A. , Gijsen Lore , Jain Rakesh K.
Published: April 2023

AbstractPurpose:
Placental growth factor (PlGF) and its receptor neuropilin 1 are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation, survival, and metastasis. TB-403 is a blocking monoclonal antibody against PlGF that inhibits tumor growth and increases survival in orthotopic medulloblastoma models.
Patients and Methods:
We conducted a phase I, open-label, multicenter, dose-escalation study of TB-403 in pediatric subjects with relapsed or refractory cancers. The study involved four dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3 + 3 dose-escalation scheme. Subjects received two doses of TB-403 (days 1 and 15) per cycle. After cycle 1, temozolomide or etoposide could be added. The primary objective was to determine the maximum tolerated dose (MTD) of TB-403 monotherapy during a dose-limiting toxicity assessment period. The secondary and exploratory objectives included efficacy, drug pharmacokinetics, and detection of pharmacodynamic biomarkers.
Results:
Fifteen subjects were treated in four dose levels. All subjects received two doses of TB-403 in cycle 1. Five serious treatment-emergent adverse events were reported in 3 subjects, but MTD was not reached. While no complete nor partial responses were observed, 7 of 11 relapsed subjects with medulloblastoma experienced stable disease, which persisted for more than 100 days in 4 of 7 subjects.
Conclusions:
TB-403 was safe and well tolerated at all dose levels. No MTD was reached. The results look encouraging and therefore warrant further evaluation of efficacy in pediatric subjects with medulloblastoma.
Data from Phase II Clinical Trial of Eribulin–Gemcitabine Combination Therapy in Previously Treated Patients With Advanced Liposarcoma or Leiomyosarcoma
Authors: Kim Chang Gon , Sim Nam Suk , Kim Jeong Eun , Yun Kum-Hee , Lee Young Han , Kim Seung Hyun , Baek Wooyeol , Han Yoon Dae , Kim Sang Kyum , Kim Jee Hung , Koh Yoon Woo , Jung Inkyung , Shin Su-Jin , Rha Sun Young , Ahn Jin-Hee , Kim Hyo Song
Published: April 2023

AbstractPurpose:
Monotherapy with eribulin or gemcitabine has been found to be moderately effective in treating soft-tissue sarcomas (STS). In this study, we evaluated the efficacy and safety of eribulin–gemcitabine combination therapy for the two most common histologic types of STS, liposarcoma and leiomyosarcoma.
Patients and Methods:
In this nonrandomized, multicenter, phase II study, we included patients with progressive disease who had received one or two courses of chemotherapy that included doxorubicin. Patients were administered 1.4 mg/m2 eribulin and 1,000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks), with null and alternative hypotheses of PFSR12wks ≤20.0% and ≥40.0%, respectively. Exploratory biomarker analyses with next-generation sequencing (NGS) were performed on pretreatment tumor samples.
Results:
Among the 37 patients included, the overall PFSR12wks was 73.0%, achieving the primary endpoint. The objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 5.6 months, and 31.9 months, respectively, without differences according to histologic type. New safety signals and treatment-related deaths were not documented. NGS-based transcriptome analysis revealed that functional enrichment in the TGFβ pathway was mostly associated with a poor outcome, whereas single genetic alterations largely failed to predict treatment outcome.
Conclusions:
Eribulin–gemcitabine combination therapy showed promising activity and an acceptable safety profile in patients with liposarcoma or leiomyosarcoma. Gene expression profiling with pathway enrichment analysis would have possibilities to have predictive value for survival outcome, necessitating further investigation to confirm.
Data from Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma
Authors: Philip Philip A. , Azar Ibrahim , Xiu Joanne , Hall Michael J. , Hendifar Andrew Eugene , Lou Emil , Hwang Jimmy J. , Gong Jun , Feldman Rebecca , Ellis Michelle , Stafford Phil , Spetzler David , Khushman Moh'd M. , Sohal Davendra , Lockhart A. Craig , Weinberg Benjamin A. , El-Deiry Wafik S. , Marshall John , Shields Anthony F. , Korn W. Michael
Published: April 2023

AbstractPurpose:
KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments.
Experimental Design:
Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination.
Results:
Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden–high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin.
Conclusions:
KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.
Data from The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models
Authors: Hebron Katie E. , Wan Xiaolin , Roth Jacob S. , Liewehr David J. , Sealover Nancy E. , Frye William J.E. , Kim Angela , Stauffer Stacey , Perkins Olivia L. , Sun Wenyue , Isanogle Kristine A. , Robinson Christina M. , James Amy , Awasthi Parirokh , Shankarappa Priya , Luo Xiaoling , Lei Haiyan , Butcher Donna , Smith Roberta , Edmondson Elijah F. , Chen Jin-Qiu , Kedei Noemi , Peer Cody J. , Shern Jack F. , Figg W. Douglas , Chen Lu , Hall Matthew D. , Difilippantonio Simone , Barr Frederic G. , Kortum Robert L. , Robey Robert W. , Vaseva Angelina V. , Khan Javed , Yohe Marielle E.
Published: April 2023

AbstractPurpose:
PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS.
Experimental Design:
Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models.
Results:
Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis.
Conclusions:
We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.
Data from Prognostic Impact of Unsupervised Early Assessment of Bulk and Leukemic Stem Cell Measurable Residual Disease in Acute Myeloid Leukemia
Authors: Canali Alban , Vergnolle Inès , Bertoli Sarah , Largeaud Laetitia , Nicolau Marie-Laure , Rieu Jean-Baptiste , Tavitian Suzanne , Huguet Françoise , Picard Muriel , Bories Pierre , Vial Jean Philippe , Lechevalier Nicolas , Béné Marie Christine , Luquet Isabelle , Mansat-De Mas Véronique , Delabesse Eric , Récher Christian , Vergez François
Published: April 2023

AbstractPurpose:
Acute myeloid leukemias (AML) are clonal diseases that develop from leukemic stem cells (LSC) that carry an independent prognostic impact on the initial response to induction chemotherapy, demonstrating the clinical relevance of LSC abundance in AML. In 2018, the European LeukemiaNet published recommendations for the detection of measurable residual disease (Bulk MRD) and suggested the exploration of LSC MRD and the use of multiparametric displays.
Experimental Design:
We evaluated the performance of unsupervised clustering for the post-induction assessment of bulk and LSC MRD in 155 patients with AML who received intensive conventional chemotherapy treatment.
Results:
The median overall survival (OS) for Bulk+ MRD patients was 16.7 months and was not reached for negative patients (HR, 3.82; P < 0.0001). The median OS of LSC+ MRD patients was 25.0 months and not reached for negative patients (HR, 2.84; P = 0.001). Interestingly, 1-year (y) and 3-y OS were 60% and 39% in Bulk+, 91% and 52% in Bulk-LSC+ and 92% and 88% in Bulk-LSC−.
Conclusions:
In this study, we confirm the prognostic impact of post-induction multiparametric flow cytometry Bulk MRD in patients with AML. Focusing on LSCs, we identified a group of patients with negative Bulk MRD but positive LSC MRD (25.8% of our cohort) with an intermediate prognosis, demonstrating the interest of MRD analysis focusing on leukemic chemoresistant subpopulations.
Data from Serologic Profiling Using an Epstein-Barr Virus Mammalian Expression Library Identifies EBNA1 IgA as a Prediagnostic Marker for Nasopharyngeal Carcinoma
Authors: Paudel Sarita , Warner Benjamin E. , Wang Renwei , Adams-Haduch Jennifer , Reznik Alex S. , Dou Jason , Huang Yufei , Gao Yu-Tang , Koh Woon-Puay , Bäckerholm Alan , Yuan Jian-Min , Shair Kathy H.Y.
Published: April 2023

AbstractPurpose:
The favorable prognosis of stage I and II nasopharyngeal carcinoma (NPC) has motivated a search for biomarkers for the early detection and risk assessment of Epstein-Barr virus (EBV)–associated NPC. Although EBV seropositivity is ubiquitous among adults, a spike in antibodies against select EBV proteins is a harbinger of NPC. A serologic survey would likely reveal which EBV antibodies could discriminate those at risk of developing NPC.
Experimental Design:
Lysates from a new EBV mammalian expression library were used in a denaturing multiplex immunoblot assay to survey antibodies against EBV in sera collected from healthy individuals who later developed NPC (incident cases) in a prospective cohort from Singapore and validated in an independent cohort from Shanghai, P.R. China.
Results:
We show that IgA against EBV nuclear antigen 1 (EBNA1) discriminated incident NPC cases from matched controls with 100% sensitivity and 100% specificity up to 4 years before diagnosis in both Singapore and Shanghai cohorts. Incident NPC cases had a greater IgG repertoire against lytic-classified EBV proteins, and the assortment of IgA against EBV proteins detected by the immunoblot assay increased closer to diagnosis.
Conclusions:
Although NPC tumors consistently harbor latent EBV, the observed heightened systemic and mucosal immunity against lytic-classified antigens years prior to clinical diagnosis is consistent with enhanced lytic transcription. We conclude that an expanding EBV mucosal reservoir (which can be latent and/or lytic) is a risk factor for NPC. This presents an opportunity to identify those at risk of developing NPC using IgA against EBNA1 as a biomarker.
Data from Intraperitoneal Monocytes plus IFNs as a Novel Cellular Immunotherapy for Ovarian Cancer: Mechanistic Characterization and Results from a Phase I Clinical Trial
Authors: Green Daniel S. , Ning Franklin , Duemler Anna , Myers Timothy G. , Trewhitt Kathryn , Ekwede Irene , McCoy Ann , Houston Nicole , Lee Jung-min , Lipkowitz Stanley , Zimmer Alexandra , Pavelova Miroslava , Villanueva Erin N. , Smith Leslie , Blakely Andrew , Casablanca Yovanni , Highfill Steven L. , Stroncek David F. , Collins-Johnson Naoza , Panch Sandhya , Procter JoLynn , Pham Chauha , Korrapati Soumya , Holland Steven M. , Rosen Lindsey B. , Nunes Ana T. , Zoon Kathryn C. , Cole Christopher B. , Annunziata Christina M.
Published: April 2023

AbstractPurpose:
Ovarian cancer is the most lethal gynecologic cancer and intrinsically resistant to checkpoint immunotherapies. We sought to augment innate immunity, building on previous work with IFNs and monocytes.
Patients and Methods:
Preclinical experiments were designed to define the mechanisms of cancer cell death mediated by the combination of IFNs α and γ with monocytes. We translated these preclinical findings into a phase I trial of autologous IFN-activated monocytes administered intraperitoneally to platinum-resistant or -refractory ovarian cancer patients.
Results:
IFN-treated monocytes induced caspase 8–dependent apoptosis by the proapoptotic TRAIL and mediated by the death receptors 4 and 5 (DR4 and DR5, respectively) on cancer cells. Therapy was well tolerated with evidence of clinical activity, as 2 of 9 evaluable patients had a partial response by RECIST criteria, and 1 additional patient had a CA-125 response. Upregulation of monocyte-produced TRAIL and cytokines was confirmed in peripheral blood. Long-term responders had alterations in innate and adaptive immune compartments.
Conclusions:
Given the mechanism of cancer cell death, and the acceptable tolerability of the clinical regimen, this platform presents a possibility for future combination therapies to augment anticancer immunity.

See related commentary by Chow and Dorigo, p. 299
Data from Colorectal Cancer Metastases in the Liver Establish Immunosuppressive Spatial Networking between Tumor-Associated SPP1+ Macrophages and Fibroblasts
Authors: Sathe Anuja , Mason Kaishu , Grimes Susan M. , Zhou Zilu , Lau Billy T. , Bai Xiangqi , Su Andrew , Tan Xiao , Lee HoJoon , Suarez Carlos J. , Nguyen Quan , Poultsides George , Zhang Nancy R. , Ji Hanlee P.
Published: April 2023

AbstractPurpose:
 The liver is the most frequent metastatic site for colorectal cancer. Its microenvironment is modified to provide a niche that is conducive for colorectal cancer cell growth. This study focused on characterizing the cellular changes in the metastatic colorectal cancer (mCRC) liver tumor microenvironment (TME).
Experimental Design:
We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue, and peripheral blood mononuclear cells using single-cell RNA sequencing (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution.
Results:
We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics, and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand–receptor pairs with the potential to mutually influence their gene-expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene-expression data. An increased proportion of TME fibroblasts was associated with the worst prognosis in these patients.
Conclusions:
We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports colorectal cancer growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune-checkpoint–resistant MSS tumors.