bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Role of KEAP1/NFE2L2 Mutations in the Chemotherapeutic Response of Patients with Non–Small Cell Lung Cancer
Authors: Jeong Youngtae , Hellyer Jessica A. , Stehr Henning , Hoang Ngoc T. , Niu Xiaomin , Das Millie , Padda Sukhmani K. , Ramchandran Kavitha , Neal Joel W. , Wakelee Heather , Diehn Maximilian
Published: April 2023

AbstractPurpose:
Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in patients with non–small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored.
Experimental Design:
We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wild-type patients. Time to treatment failure after first-line platinum doublet chemotherapy and overall survival was compared between the two groups.
Results:
Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In patients with NSCLC, median time to treatment failure (TTF) after first-line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared with 8.3 months in the control group (P < 0.0001). Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (P = 0.006).
Conclusions:
Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter TTF and OS after first-line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of patients with NSCLC are therefore needed.
Data from Evaluation of Eribulin Combined with Irinotecan for Treatment of Pediatric Cancer Xenografts
Authors: Robles Andrew J. , Kurmasheva Raushan T. , Bandyopadhyay Abhik , Phelps Doris A. , Erickson Stephen W. , Lai Zhao , Kurmashev Dias , Chen Yidong , Smith Malcom A. , Houghton Peter J.
Published: April 2023

AbstractPurpose:
Vincristine combined with camptothecin derivatives showed synergy in preclinical pediatric cancer models, and the combinations are effective in treatment of childhood solid tumors. We determined whether the synergy between vincristine and irinotecan extends to eribulin, another microtubule inhibitor.
Experimental Design:
Vincristine or eribulin, alone or combined with irinotecan, was studied in 12 xenograft models. Tumor regression and time to event were used to assess antitumor activity. Pharmacodynamic studies and RNA sequencing (RNA-seq) were conducted 24 and 144 hours after single-agent or combination treatment. Effects on vascular development were studied in Matrigel plugs implanted in mice. The interaction between binary combinations was examined in vitro.
Results:
Eribulin combined with irinotecan was more effective than vincristine–irinotecan in 6 of 12 models. Pharmacodynamic markers induced by eribulin (phospho-histone H3) and irinotecan (γ-H2A.X) were abrogated in combination-treated tumors. The predominant RNA-seq signature in combination-treated tumors was activation of the TP53 pathway with increased nuclear TP53. Massive apoptosis was observed 24 hours only after treatment with the eribulin combination. In vitro, neither combination showed interaction using combination index analysis. Eribulin alone and the combination caused alterations in developing vasculature.
Conclusions:
The eribulin combination is very active in these xenograft models, but not synergistic in vitro. The combination reduced pharmacodynamic markers indicative of single-agent mechanisms but in tumors, dramatically activated the TP53 pathway. Although a mechanism for in vivo synergy requires further study, it is possible that eribulin-induced inhibition of microtubule dynamics enhances irinotecan-induced nuclear accumulation of TP53, leading to rapid cell death.
Data from Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites
Authors: Nassar Amin H. , Umeton Renato , Kim Jaegil , Lundgren Kevin , Harshman Lauren , Van Allen Eliezer M. , Preston Mark , Dong Fei , Bellmunt Joaquim , Mouw Kent W. , Choueiri Toni K. , Sonpavde Guru , Kwiatkowski David J.
Published: April 2023

AbstractPurpose:
The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets.
Experimental Design:
Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC.
Results:
FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%–58% vs. 4%; 9%–22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently.
Conclusions:
Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.
Data from Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma
Authors: Vaubel Rachael A. , Tian Shulan , Remonde Dioval , Schroeder Mark A. , Mladek Ann C. , Kitange Gaspar J. , Caron Alissa , Kollmeyer Thomas M. , Grove Rebecca , Peng Sen , Carlson Brett L. , Ma Daniel J. , Sarkar Gobinda , Evers Lisa , Decker Paul A. , Yan Huihuang , Dhruv Harshil D. , Berens Michael E. , Wang Qianghu , Marin Bianca M. , Klee Eric W. , Califano Andrea , LaChance Daniel H. , Eckel-Passow Jeanette E. , Verhaak Roel G. , Sulman Erik P. , Burns Terry C. , Meyer Fredrick B. , O'Neill Brian P. , Tran Nhan L. , Giannini Caterina , Jenkins Robert B. , Parney Ian F. , Sarkaria Jann N.
Published: April 2023

AbstractPurpose:
Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization.
Experimental Design:
PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models.
Results:
PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient–PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection.
Conclusions:
Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.
Data from NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263
Authors: Dastur Anahita , Choi AHyun , Costa Carlotta , Yin Xunqin , Williams August , McClanaghan Joseph , Greenberg Max , Roderick Justine , Patel Neha U. , Boisvert Jessica , McDermott Ultan , Garnett Mathew J. , Almenara Jorge , Grant Steven , Rizzo Kathryn , Engelman Jeffrey A. , Kelliher Michelle , Faber Anthony C. , Benes Cyril H.
Published: April 2023

AbstractPurpose:
Effective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL.
Experimental Design:
We performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both in vitro experiments and in vivo studies on patient-derived xenograft models.
Results:
We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax in vitro and leads to tumor regressions in vivo.
Conclusions:
Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.
Data from Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival
Authors: Tang Wei , Putluri Vasanta , Ambati Chandrashekar R. , Dorsey Tiffany H. , Putluri Nagireddy , Ambs Stefan
Published: April 2023

AbstractPurpose:
Metabolomics is a discovery tool for novel associations of metabolites with disease. Here, we interrogated the metabolome of human breast tumors to describe metabolites whose accumulation affects tumor biology.
Experimental Design:
We applied large-scale metabolomics followed by absolute quantification and machine learning-based feature selection using LASSO to identify metabolites that show a robust association with tumor biology and disease outcome. Key observations were validated with the analysis of an independent dataset and cell culture experiments.
Results:
LASSO-based feature selection revealed an association of tumor glycochenodeoxycholate levels with improved breast cancer survival, which was confirmed using a Cox proportional hazards model. Absolute quantification of four bile acids, including glycochenodeoxycholate and microbiome-derived deoxycholate, corroborated the accumulation of bile acids in breast tumors. Levels of glycochenodeoxycholate and other bile acids showed an inverse association with the proliferation score in tumors and the expression of cell-cycle and G2–M checkpoint genes, which was corroborated with cell culture experiments. Moreover, tumor levels of these bile acids markedly correlated with metabolites in the steroid metabolism pathway and increased expression of key genes in this pathway, suggesting that bile acids may interfere with hormonal pathways in the breast. Finally, a proteome analysis identified the complement and coagulation cascade as being upregulated in glycochenodeoxycholate-high tumors.
Conclusions:
We describe the unexpected accumulation of liver- and microbiome-derived bile acids in breast tumors. Tumors with increased bile acids show decreased proliferation, thus fall into a good prognosis category, and exhibit significant changes in steroid metabolism.
Data from Loss of SMAD4 Promotes Colorectal Cancer Progression by Recruiting Tumor-Associated Neutrophils via the CXCL1/8–CXCR2 Axis
Authors: Ogawa Ryotaro , Yamamoto Takamasa , Hirai Hideyo , Hanada Keita , Kiyasu Yoshiyuki , Nishikawa Gen , Mizuno Rei , Inamoto Susumu , Itatani Yoshiro , Sakai Yoshiharu , Kawada Kenji
Published: April 2023

AbstractPurpose:
SMAD4 is a key transcriptional factor of TGFβ signaling and acts as a tumor suppressor in colorectal cancer. In the present study, we explored the immunologic effect of SMAD4 on the tumor microenvironment.
Experimental Design:
Using 99 clinical specimens and human colorectal cancer cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2, and other proteins with clinical specimens. Finally, we determined the serum levels of CXCL1 and CXCL8 in 125 patients with colorectal cancer.
Results:
SMAD4 knockdown from human colorectal cancer cells upregulated the expression of CXCL1 and CXCL8, which recruited neutrophils to colorectal cancer tumor via CXCR2. In turn, when neutrophils were exposed to the supernatant of SMAD4-negative colorectal cancer cells, they produced a large amount of CXCL1 and CXCL8 by themselves in vitro. In human clinical specimens, we found that neutrophil infiltration into the peritumoral stroma was more marked in SMAD4-negative colorectal cancer compared with that in SMAD4-positive colorectal cancer, and that both CXCL1 and CXCL8 were abundantly expressed in the tumor-infiltrating neutrophils. Neutrophils isolated from primary colorectal cancer expressed significantly higher levels of CXCL1 and CXCL8 than did those isolated from peripheral blood. Furthermore, tumor-infiltrating neutrophils expressed MMP2 and MMP9 in addition to ARG1 and IDO. Serum CXCL8 level was significantly higher in colorectal cancer patients, especially those at stage II/III, and statistical analysis indicated a high CXCL8 level was associated with a shorter overall survival and relapse-free survival.
Conclusions:
Blockade of the CXCL1/8–CXCR2 axis could be a novel therapeutic approach against SMAD4-negative colorectal cancer.
Data from Colony-Stimulating Factor 1 Receptor (CSF1R) Activates AKT/mTOR Signaling and Promotes T-Cell Lymphoma Viability
Authors: Murga-Zamalloa Carlos , Rolland Delphine C.M. , Polk Avery , Wolfe Ashley , Dewar Hiran , Chowdhury Pinki , Onder Ozlem , Dewar Rajan , Brown Noah A. , Bailey Nathanael G. , Inamdar Kedar , Lim Megan S. , Elenitoba-Johnson Kojo S.J. , Wilcox Ryan A.
Published: April 2023

AbstractPurpose:
Peripheral T-cell lymphomas are clinically aggressive and usually fatal, as few complete or durable remissions are achieved with currently available therapies. Recent evidence supports a critical role for lymphoma-associated macrophages during T-cell lymphoma progression, but the specific signals involved in the cross-talk between malignant T cells and their microenvironment are poorly understood. Colony-stimulator factor 1 receptor (CSF1R, CD115) is required for the homeostatic survival of tissue-resident macrophages. Interestingly, its aberrant expression has been reported in a subset of tumors. In this article, we evaluated its expression and oncogenic role in T-cell lymphomas.
Experimental Design:
Loss-of-function studies, including pharmacologic inhibition with a clinically available tyrosine kinase inhibitor, pexidartinib, were performed in multiple in vitro and in vivo models. In addition, proteomic and genomic screenings were performed to discover signaling pathways that are activated downstream of CSF1R signaling.
Results:
We observed that CSF1R is aberrantly expressed in many T-cell lymphomas, including a significant number of peripheral and cutaneous T-cell lymphomas. Colony-stimulating factor 1 (CSF1), in an autocrine or paracrine-dependent manner, leads to CSF1R autophosphorylation and activation in malignant T cells. Furthermore, CSF1R signaling was associated with significant changes in gene expression and in the phosphoproteome, implicating PI3K/AKT/mTOR in CSF1R-mediated T-cell lymphoma growth. We also demonstrated that inhibition of CSF1R in vivo and in vitro models is associated with decreased T-cell lymphoma growth.
Conclusions:
Collectively, these findings implicate CSF1R in T-cell lymphomagenesis and have significant therapeutic implications.
Data from NQO1-dependent, Tumor-selective Radiosensitization of Non–small Cell Lung Cancers
Authors: Motea Edward A. , Huang Xiumei , Singh Naveen , Kilgore Jessica A. , Williams Noelle S. , Xie Xian-Jin , Gerber David E. , Beg Muhammad S. , Bey Erik A. , Boothman David A.
Published: April 2023

AbstractPurpose:
Development of tumor-specific therapies for the treatment of recalcitrant non–small cell lung cancers (NSCLC) is urgently needed. Here, we investigated the ability of β-lapachone (β-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1–3 Gy) in NSCLCs that overexpress NAD(P)H:Quinone Oxidoreductase 1 (NQO1).
Experimental Design:
The mechanism of lethality of low-dose IR in combination with sublethal doses of β-lap was evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograft models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus cotreatments were performed to validate therapeutic efficacy and mechanism of action.
Results:
β-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased double-strand break (DSB) lesions over time in vitro. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 β-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (∼12 units) of any normal tissue. PK/PD responses confirm that IR + β-lap treatments hyperactivate PARP activity, greatly lower NAD+/ATP levels, and dramatically inhibit DSB repair in exposed NQO1+ cancer tissue, whereas low NQO1 levels and high levels of catalase in associated normal tissue were protective.
Conclusions:
Our data suggest that combination of sublethal doses of β-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + β-lap against patients with NQO1+ NSCLCs.
Data from Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression
Authors: Bernard Vincent , Semaan Alexander , Huang Jonathan , San Lucas F. Anthony , Mulu Feven C. , Stephens Bret M. , Guerrero Paola A. , Huang Yanqing , Zhao Jun , Kamyabi Nabiollah , Sen Subrata , Scheet Paul A. , Taniguchi Cullen M. , Kim Michael P. , Tzeng Ching-Wei , Katz Matthew H. , Singhi Aatur D. , Maitra Anirban , Alvarez Hector A.
Published: April 2023

AbstractPurpose:
Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs), represent a bona fide pathway to invasive neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single-cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneities that accompany multistep progression from noninvasive IPMNs to PDAC.
Experimental Design:
Single-cell RNA sequencing was performed through droplet-based sequencing on 5,403 cells from 2 low-grade IPMNs (LGD-IPMNs), 2 high-grade IPMNs (HGD-IPMN), and 2 PDACs (all surgically resected).
Results:
Analysis of single-cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of noninvasive dysplasia to invasive cancer. Although HGD-IPMNs expressed many core signaling pathways described in PDAC, LGD-IPMNs harbored subsets of single cells with a transcriptomic profile that overlapped with invasive cancer. Notably, a proinflammatory immune component was readily seen in low-grade IPMNs, composed of cytotoxic T cells, activated T-helper cells, and dendritic cells, which was progressively depleted during neoplastic progression, accompanied by infiltration of myeloid-derived suppressor cells. Finally, stromal myofibroblast populations were heterogeneous and acquired a previously described tumor-promoting and immune-evading phenotype during invasive carcinogenesis.
Conclusions:
This study demonstrates the ability to perform high-resolution profiling of the transcriptomic changes that occur during multistep progression of cystic PDAC precursors to cancer. Notably, single-cell analysis provides an unparalleled insight into both the epithelial and microenvironmental heterogeneities that accompany early cancer pathogenesis and might be a useful substrate to identify targets for cancer interception.

See related commentary by Hernandez-Barco et al., p. 2027
Data from lncRNA THAP9-AS1 Promotes Pancreatic Ductal Adenocarcinoma Growth and Leads to a Poor Clinical Outcome via Sponging miR-484 and Interacting with YAP
Authors: Li Nan , Yang Guohua , Luo Liyun , Ling Li , Wang Xiaorong , Shi Lejuan , Lan Junsong , Jia Xiaoting , Zhang Qiong , Long Ze , Liu Jinbao , Hu Weimin , He Zhimin , Liu Haiying , Liu Wanqing , Zheng Guopei
Published: April 2023

AbstractPurpose:
Long noncoding RNAs (lncRNA) have been observed in various cancer types. Our bioinformatic analysis of existing databases demonstrated overexpression of lncRNA THAP9-AS1 in pancreatic ductal adenocarcinoma (PDAC). We aimed to investigate the roles and mechanisms of THAP9-AS1 in PDAC.
Experimental Design:
The overexpression of THAP9-AS1 in samples of patients with pancreatic cancer was characterized and was associated with clinical outcomes. The nonprotein coding property of the THAP9-AS1 was verified. Various in vitro and in vivo experiments were performed to investigate the interaction between THAP9-AS1 and YAP signaling.
Results:
We demonstrated that lncRNA THAP9-AS1 is overexpressed in PDAC in multiple patient sample sets, which is significantly associated with poor outcome of patients with PDAC. THAP9-AS1 promotes PDAC cells growth both in vitro and in vivo. THAP9-AS1 exerts its effects via enhancing YAP signaling. Ectopic YAP expression overcame the effects of THAP9-AS1 knockdown. Inversely, YAP knockdown diminished the effects of THAP9-AS1 overexpression. THAP9-AS1 acts as a competing endogenous RNA for miR-484, leading to YAP upregulation. Moreover, THAP9-AS1 binds to YAP protein and inhibits the phosphorylation-mediated inactivation of YAP by LATS1. Reciprocally, YAP/TEAD1 complex promotes THAP9-AS1 transcription to form a feed-forward circuit. Importantly, THAP9-AS1 level positively correlates with YAP expression in PDAC tissues. YAP overexpression also predicts a poor outcome in patients with PDAC.
Conclusions:
Our findings indicate that THAP9-AS1 plays an important role in PDAC growth via enhancing YAP signaling, which in turn also modulates THAP9-AS1 transcription. THAP9-AS1/YAP axis may serve as a potential biomarker and therapeutic target for PDAC treatment.
Data from Near-Infrared Dye-Labeled Anti-Prostate Stem Cell Antigen Minibody Enables Real-Time Fluorescence Imaging and Targeted Surgery in Translational Mouse Models
Authors: Zhang Mo , Kobayashi Naoko , Zettlitz Kirstin A. , Kono Evelyn A. , Yamashiro Joyce M. , Tsai Wen-Ting K. , Jiang Ziyue K. , Tran Chau P. , Wang Chung , Guan Johnny , Wu Anna M. , Reiter Robert E.
Published: April 2023

AbstractPurpose:
The inability to intraoperatively distinguish primary tumor, as well as lymphatic spread, increases the probability of positive surgical margins, tumor recurrence, and surgical toxicity. The goal of this study was to develop a tumor-specific optical probe for real-time fluorescence-guided surgery.
Experimental Design:
A humanized antibody fragment against PSCA (A11 minibody, A11 Mb) was conjugated with a near-infrared fluorophore, IRDye800CW. The integrity and binding of the probe to PSCA were confirmed by gel electrophoresis, size-exclusion chromatography, and flow cytometry, respectively. The ability of the probe to detect tumor-infiltrated lymph nodes and metastatic lesions was evaluated in 2 xenograft models, as well as in transgenic mice expressing human PSCA (hPSCA). An invasive intramuscular model was utilized to evaluate the efficacy of the A11 Mb-IRDye800CW-guided surgery.
Results:
A11 Mb was successfully conjugated with IRDye800CW and retained specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 48 hours. The A11 Mb-IRDye800CW specifically detected PSCA-positive primary tumors, tumor-infiltrated lymph nodes, and distant metastases with high contrast. Fluorescence guidance facilitated more complete tumor resection, reduced tumor recurrence, and improved overall survival, compared with conventional white light surgery. The probe successfully identified primary orthotopic tumors and metastatic lesions in hPSCA transgenic mice.
Conclusions:
Real-time fluorescence image–guided surgery with A11 Mb-IRDye800CW enabled detection of lymph node metastases and positive surgical margins, facilitated more complete tumor removal, and improved survival, compared with white light surgery. These results may be translatable into clinical practice to improve surgical and patient outcomes.
Data from Disease Monitoring Using Post-induction Circulating Tumor DNA Analysis Following First-Line Therapy in Patients with Metastatic Colorectal Cancer
Authors: Max Ma Xiaoju , Bendell Johanna C. , Hurwitz Herbert I. , Ju Christine , Lee John J. , Lovejoy Alex , Mancao Christoph , Nicholas Alan , Price Richard , Sommer Nicolas , Tikoo Nalin , Yao Lijing , Yaung Stephanie J. , Palma John F.
Published: April 2023

AbstractPurpose:
We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy.
Experimental Design:
The Sequencing Triplet With Avastin and Maintenance (STEAM) was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered concurrently or sequentially, versus FOLFOX-BEV in first-line mCRC. Evaluation of biomarkers associated with treatment outcomes was an exploratory endpoint. Patients in the biomarker-evaluable population (BEP) had 1 tissue sample, 1 pre-induction plasma sample, and 1 post-induction plasma sample collected ≤60 days of induction from last drug date.
Results:
Among the 280 patients enrolled in STEAM, 183 had sequenced and evaluable tumor tissue, 118 had matched pre-induction plasma, and 54 (BEP) had ctDNA-evaluable sequencing data for pre- and post-induction plasma. The most common somatic variants in tumor tissue and pre-induction plasma were TP53, APC, and KRAS. Patients with lower-than-median versus higher-than-median post-induction mean allele fraction (mAF) levels had longer median PFS (17.7 vs. 7.5 months, HR, 0.33; 95% confidence interval, 0.17–0.63). Higher levels of post-induction mAF and post-induction mean mutant molecules per milliliter (mMMPM), and changes in ctDNA (stratified by a 10-fold or 100-fold reduction in mAF between pre- and post-induction plasma), were associated with shorter PFS. Post-induction mAF and mMMPM generally correlated with each other (ρ = 0.987, P < 0.0001).
Conclusions:
ctDNA quantification in post-induction plasma may serve as a prognostic biomarker for mCRC post-treatment outcomes.
Data from A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort
Authors: Tien An-Chi , Li Jing , Bao Xun , Derogatis Alanna , Kim Seongho , Mehta Shwetal , Sanai Nader
Published: April 2023

AbstractPurpose:
CDK4/6-dependent cell-cycle regulation is disrupted in most glioblastomas. This study assesses the central nervous system (CNS) pharmacokinetics and tumor pharmacodynamics of ribociclib, a highly selective CDK4/6 inhibitor, in patients with recurrent glioblastoma.
Patients and Methods:
Patients with recurrent glioblastoma with intact retinoblastoma protein (RB) expression and CDKN2A deletion or CDK4/6 amplification were treated with ribociclib daily (900 mg) for 5 days before tumor resection. Blood, tumor, and cerebrospinal fluid (CSF) samples were collected, and total and unbound ribociclib concentrations were determined. Pharmacodynamic effects, assessed by RB and FOXM1 phosphorylation, were compared with matched archival tissue. Patients with positive pharmacokinetic and pharmacodynamic effects were enrolled into the expansion cohort for preliminary assessment of progression-free survival (PFS).
Results:
Twelve patients were enrolled. The mean unbound ribociclib concentrations in CSF, nonenhancing, and enhancing tumor regions were 0.374 μmol/L, 0.560, and 2.152 μmol/kg, respectively, which were more than 5-fold the in vitro IC50 for inhibition of CDK4/6 (0.04 μmol/L). G1-to-S phase suppression was inferred by decreases in phosphorylation of RB (P < 0.01) and cellular proliferation (P < 0.05). Six of 12 patients were enrolled into the pharmacokinetic/pharmacodynamic-guided expansion cohort and demonstrated a median PFS of 9.7 weeks. Examination of recurrent tumors following monotherapy indicated upregulation of the PI3K/mTOR pathway.
Conclusions:
Ribociclib exhibited good CNS penetration, and target modulation was indicated by inhibition of RB phosphorylation and tumor proliferation. Ribociclib monotherapy showed limited clinical efficacy in patients with recurrent glioblastoma. Combination therapy with CDK4/6 and PI3K/mTOR inhibitors may be explored for treating recurrent glioblastoma.
Data from A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma In Situ
Authors: Mittal Karuna , Toss Michael S. , Wei Guanhao , Kaur Jaspreet , Choi Da Hoon , Melton Brian D. , Osan Remus M. , Miligy Islam M. , Green Andrew R. , Janssen Emiel A.M. , Søiland Håvard , Gogineni Keerthi , Manne Upender , Rida Padmashree , Rakha Emad A. , Aneja Ritu
Published: April 2023

AbstractPurpose:
The purpose of this study is to predict risk of local recurrence (LR) in ductal carcinoma in situ (DCIS) with a new visualization and quantification approach using centrosome amplification (CA), a cancer cell–specific trait widely associated with aggressiveness.
Experimental Design:
This first-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS and assigns a quantitative centrosomal amplification score (CAS) to each sample. Analyses were performed in a discovery cohort (DC, n = 133) and a validation cohort (VC, n = 119).
Results:
DCIS cases with LR exhibited significantly higher CAS than recurrence-free cases. Higher CAS was associated with a greater risk of developing LR (HR, 6.3 and 4.8 for DC and VC, respectively; P < 0.001). CAS remained an independent predictor of relapse-free survival (HR, 7.4 and 4.5 for DC and VC, respectively; P < 0.001) even after accounting for potentially confounding factors [grade, age, comedo necrosis, and radiotherapy (RT)]. Patient stratification using CAS (P < 0.0001) was superior to that by Van Nuys Prognostic Index (VNPI; HR for CAS = 6.2 vs. HR for VNPI = 1.1). Among patients treated with breast-conserving surgery alone, CAS identified patients likely to benefit from adjuvant RT.
Conclusions:
CAS predicted 10-year LR risk for patients who underwent surgical management alone and identified patients who may be at low risk of recurrence, and for whom adjuvant RT may not be required. CAS demonstrated the highest concordance among the known prognostic models such as VNPI and clinicopathologic variables such as grade, age, and comedo necrosis.
Data from A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma
Authors: Hall Peter E. , Lewis Rachel , Syed Nelofer , Shaffer Richard , Evanson Jane , Ellis Stephen , Williams Matthew , Feng Xiaoxing , Johnston Amanda , Thomson Jim A. , Harris Fiona P. , Jena Raj , Matys Tomasz , Jefferies Sarah , Smith Kate , Wu Bor-Wen , Bomalaski John S. , Crook Timothy , O'Neill Kevin , Paraskevopoulos Dimitris , Khadeir Ramsay S. , Sheaff Michael , Pacey Simon , Plowman Piers N. , Szlosarek Peter W.
Published: April 2023

AbstractPurpose:
Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed.
Patients and Methods:
We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16–06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy.
Results:
Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti–ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5–20.8) and overall survival was 6.3 months (95% CI, 1.8–9.7).
Conclusions:
In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.
Data from Detection of NRG1 Gene Fusions in Solid Tumors
Authors: Jonna Sushma , Feldman Rebecca A. , Swensen Jeffrey , Gatalica Zoran , Korn Wolfgang M. , Borghaei Hossein , Ma Patrick C. , Nieva Jorge J. , Spira Alexander I. , Vanderwalde Ari M. , Wozniak Antoinette J. , Kim Edward S. , Liu Stephen V.
Published: April 2023

AbstractPurpose:
NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners.
Experimental Design:
Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)–certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner.
Results:
Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non–small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer.
Conclusions:
NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.

See related commentary by Dimou and Camidge, p. 4865
Data from Neutrophil Extracellular Traps Induced by IL8 Promote Diffuse Large B-cell Lymphoma Progression via the TLR9 Signaling
Authors: Nie Man , Yang Linbin , Bi Xiwen , Wang Yu , Sun Peng , Yang Hang , Liu Panpan , Li Zhiming , Xia Yi , Jiang Wenqi
Published: April 2023

AbstractPurpose:
More than 30% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment failure after first-line therapy. Neutrophil extracellular traps (NETs), a pathogen-trapping structure in tumor microenvironment, can promote the transition of autoimmunity to lymphomagenesis. Here, we investigate whether NETs play a novel role in DLBCL progression and its underlying mechanism.

Experimental Design: NETs in DLBCL tumor samples and plasma were detected by immunofluorescence and ELISA, respectively. The correlation between NETs and clinical features were analyzed. The effects of NETs on cellular proliferation and migration and mechanisms were explored, and the mechanism of NET formation was also studied by a series of in vitro and in vivo assays.
Results:
Higher levels of NETs in plasma and tumor tissues were associated with dismal outcome in patients with DLBCL. Furthermore, we identified NETs increased cell proliferation and migration in vitro and tumor growth and lymph node dissemination in vivo. Mechanistically, DLBCL-derived IL8 interacted with its receptor (CXCR2) on neutrophils, resulting in the formation of NETs via Src, p38, and ERK signaling. Newly formed NETs directly upregulated the Toll-like receptor 9 (TLR9) pathways in DLBCL and subsequently activated NFκB, STAT3, and p38 pathways to promote tumor progression. More importantly, disruption of NETs, blocking IL8–CXCR2 axis or inhibiting TLR9 could retard tumor progression in preclinical models.
Conclusions:
Our data reveal a tumor–NETs aggressive interaction in DLBCL and indicate that NETs is a useful prognostic biomarker and targeting this novel cross-talk represents a new therapeutic opportunity in this challenging disease.
Data from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis
Authors: Yan Dongqing , Pomicter Anthony D. , Tantravahi Srinivas , Mason Clinton C. , Senina Anna V. , Ahmann Jonathan M. , Wang Qiang , Than Hein , Patel Ami B. , Heaton William L. , Eiring Anna M. , Clair Phillip M. , Gantz Kevin C. , Redwine Hannah M. , Swierczek Sabina I. , Halverson Brayden J. , Baloglu Erkan , Shacham Sharon , Khorashad Jamshid S. , Kelley Todd W. , Salama Mohamed E. , Miles Rodney R. , Boucher Kenneth M. , Prchal Josef T. , O'Hare Thomas , Deininger Michael W.
Published: April 2023

AbstractPurpose:
Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR, or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis.
Experimental Design:
A short hairpin RNA library screening was performed on JAK2V617F-mutant HEL cells. Nuclear–cytoplasmic transport (NCT) genes including RAN and RANBP2 were among top candidates. JAK2V617F-mutant cell lines, human primary myelofibrosis CD34+ cells, and a retroviral JAK2V617F-driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor).
Results:
JAK2V617F-mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34+ cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2V617F-mutant cells in vivo.
Conclusions:
Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.
Data from First-in-Class, First-in-Human Study Evaluating LV305, a Dendritic-Cell Tropic Lentiviral Vector, in Sarcoma and Other Solid Tumors Expressing NY-ESO-1
Authors: Somaiah Neeta , Block Matthew S. , Kim Joseph W. , Shapiro Geoffrey I. , Do Khanh T. , Hwu Patrick , Eder Joseph P. , Jones Robin L. , Lu Hailing , ter Meulen Jan H. , Bohac Chet , Chen Michael , Hsu Frank J. , Gnjatic Sacha , Pollack Seth M.
Published: April 2023

AbstractPurpose:
LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells in vivo. LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1–expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors.
Patients and Methods:
Adults with previously treated, advanced, NY-ESO-1–positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 108 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 108 vg, 109 vg, 1010 vg x 4 doses).
Results:
Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma (n = 24), ovarian (n = 8), melanoma (n = 6), and lung cancer (n = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting >36 months. Anti–NY-ESO-1-specific CD4+ and/or CD8+ T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti–NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis.
Conclusions:
This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer.
Data from First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity
Authors: Gan Hui K. , Millward Michael , Hua Ye , Qi Chuan , Sai Yang , Su Weiguo , Wang Jian , Zhang Lilin , Frigault Melanie M. , Morgan Shethah , Yang Liu , Lickliter Jason D.
Published: April 2023

AbstractPurpose:
Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib).
Patients and Methods:
This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity.
Results:
Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, Cmax was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks.
Conclusions:
The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
Data from The Number of Screening Cycles Needed to Reduce Prostate Cancer Mortality in the Finnish Section of the European Randomized Study of Prostate Cancer (ERSPC)
Authors: Pakarainen Tomi , Nevalainen Jaakko , Talala Kirsi , Taari Kimmo , Raitanen Jani , Kujala Paula , Stenman Ulf-Håkan , Tammela Teuvo L.J. , Auvinen Anssi
Published: April 2023

AbstractPurpose:
The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer mortality by PSA-based screening. The aim of the study is to evaluate screening effect on prostate cancer incidence and mortality in relation to number of screening rounds attended.

Experimental Design: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance, then remained among the once-screened until the second screen and similarly for the possible third round. The control arm was the reference. Follow-up started at randomization and ended at death, emigration, or end of 2013. Prostate cancer incidence and mortality, as well lung cancer and overall mortality were evaluated.
Results:
Prostate cancer incidence was increased among screened men, but was not directly related to the number of screening rounds. Prostate cancer mortality was decreased in men screened twice or three times, but did not materially differ in those who did not attend the screening, and in men screened once compared with the control arm. The largest mortality reduction was in men screened three times [HR 0.17; 95% confidence interval (CI), 0.09–0.33]. However, a reduction was also seen in lung cancer (HR 0.59; 95% CI, 0.47–0.73) and overall mortality (HR 0.56; 95% CI, 0.52–0.60).
Conclusions:
Assuming a similar relative reduction being due to selection bias and screening in prostate cancer as other causes of death (40% reduction), approximately half of the observed prostate cancer mortality reduction by repeated screening is likely to be noncausal and a real screening effect may account for up to 40% reduction in men screened three times. Prostate cancer mortality reduction can only be achieved by repeated screening cycles.