bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from CKLF1 Enhances Inflammation-Mediated Carcinogenesis and Prevents Doxorubicin-Induced Apoptosis via IL6/STAT3 Signaling in HCC
Authors: Liu Youyi , Liu Lijuan , Zhou Yan , Zhou Ping , Yan Qiujin , Chen Xiaobei , Ding Shuang , Zhu Fan
Published: April 2023

AbstractPurpose:
Hepatocellular carcinoma (HCC), one of the most common and deadliest malignancies worldwide, has a poor prognosis, owing to its high potential for vascular invasion and metastasis and the lack of biomarkers for early diagnosis. Thus, it must be a crucial factor for investigating therapeutic strategies for HCC to identify the functional molecular targets. Here, we reported a novel chemokine, CKLF1, that might act as a pivotal modulator in the invasion and metastasis of HCC and could serve as an attractive target for cancer therapy.
Experimental Design:
Bioinformatics analysis, PCR, Western blotting, and IHC were performed to detect the expression of CKLF1 in HCC. The function of CKLF1 was demonstrated by a series of in vitro and in vivo experiments. Pharmacologic treatment, flow cytometry, and Western blotting were carried out to demonstrate the potential mechanisms of CKLF1.
Results:
We proved that CKLF1 was overexpressed in HCC tissues and was related to tumor stage, vascular invasion, and patient survival. Then, functional assays showed that CKLF1 promoted hepatocellular carcinogenesis and metastatic potential. Finally, the IL6/STAT3 signaling pathway was involved in the mechanistic investigation. The results demonstrated that CKLF1 enhanced the progression of HCC and prevented doxorubicin-induced apoptosis through activating the IL6/STAT3 pathway.
Conclusions:
These data showed that CKLF1 inhibited apoptosis and promoted malignant transformation through the IL6/STAT3 pathway, and ultimately enhanced the development and metastasis of HCC. Thus, our work revealed that CKLF1 was a significant prognostic factor of HCC and might be a potential molecular therapeutic target for HCC.
Data from Effects of Age and Immune Landscape on Outcome in HER2-Positive Breast Cancer in the NCCTG N9831 (Alliance) and NSABP B-31 (NRG) Trials
Authors: Chumsri Saranya , Serie Daniel J. , Li Zhuo , Pogue-Geile Katherine L. , Soyano-Muller Aixa E. , Mashadi-Hossein Afshin , Warren Sarah , Lou Yanyan , Colon-Otero Gerardo , Knutson Keith L. , Perez Edith A. , Moreno-Aspitia Alvaro , Thompson E. Aubrey
Published: April 2023

AbstractPurpose:
Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown.
Experimental Design:
A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated.
Results:
In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28–0.66; P < 0.001; and age > 40; HR, 0.56; 95% CI, 0.45–0.69; P < 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29–0.68; P < 0.001; and age > 40; HR, 0.42; 95% CI, 0.33–0.54; P < 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor–positive subset, but not the hormone receptor–negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years.
Conclusions:
Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.
Data from Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma
Authors: Wu Rui-Yan , Kong Peng-Fei , Xia Liang-Ping , Huang Yun , Li Zhi-Ling , Tang Yun-Yun , Chen Yu-Hong , Li Xuan , Senthilkumar Ravichandran , Zhang Hai-Liang , Sun Ting , Xu Xue-Lian , Yu Yan , Mai Jia , Peng Xiao-Dan , Yang Dong , Zhou Li-Huan , Feng Gong-Kan , Deng Rong , Zhu Xiao-Feng
Published: April 2023

AbstractPurpose:
Immune checkpoint blockade (ICB) therapy induces durable tumor regressions in a minority of patients with cancer. In this study, we aimed to identify kinase inhibitors that were capable of increasing the antimelanoma immunity.
Experimental Design:
Flow cytometry–based screening was performed to identify kinase inhibitors that can block the IFNγ-induced PD-L1 expression in melanoma cells. The pharmacologic activities of regorafenib alone or in combination with immunotherapy in vitro and in vivo were determined. The mechanisms of regorafenib were explored and analyzed in melanoma patients treated with or without anti–PD-1 using The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.
Results:
Through screening of a kinase inhibitor library, we found approximately 20 agents that caused more than half reduction of cell surface PD-L1 level, and regorafenib was one of the most potent agents. Furthermore, our results showed that regorafenib, in vitro and in vivo, strongly promoted the antitumor efficacy when combined with IFNγ or ICB. By targeting the RET–Src axis, regorafenib potently inhibited JAK1/2–STAT1 and MAPK signaling and subsequently attenuated the IFNγ-induced PD-L1 and IDO1 expression without affecting MHC-I expression much. Moreover, RET and Src co-high expression was an independent unfavorable prognosis factor in melanoma patients with or without ICB through inhibiting the antitumor immune response.
Conclusions:
Our data unveiled a new mechanism of alleviating IFNγ-induced PD-L1 and IDO1 expression and provided a rationale to explore a novel combination of ICB with regorafenib clinically, especially in melanoma with RET/Src axis activation.
Data from Chimeric Antigen Receptor T Cells Targeting CD79b Show Efficacy in Lymphoma with or without Cotargeting CD19
Authors: Ormhøj Maria , Scarfò Irene , Cabral Maria L. , Bailey Stefanie R. , Lorrey Selena J. , Bouffard Amanda A. , Castano Ana P. , Larson Rebecca C. , Riley Lauren S. , Schmidts Andrea , Choi Bryan D. , Andersen Rikke S. , Cédile Oriane , Nyvold Charlotte G. , Christensen Jacob H. , Gjerstorff Morten F. , Ditzel Henrik J. , Weinstock David M. , Barington Torben , Frigault Matthew J. , Maus Marcela V.
Published: April 2023

AbstractPurpose:
T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA approved for the treatment of relapsed or refractory large B-cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging.
Experimental Design:
We developed a novel CAR construct directed against CD79b, a critical receptor for successful B-cell development that remains highly expressed in several subtypes of B-cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models.
Results:
We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19+, CD19−, and mixed CD19+/CD19−B-cell lymphoma.
Conclusions:
Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B-cell lymphomas.
Data from Use of Ex Vivo Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for HER2 Mutant Non–Small Cell Lung Cancer
Authors: Ivanova Elena , Kuraguchi Mari , Xu Man , Portell Andrew J. , Taus Luke , Diala Irmina , Lalani Alshad S. , Choi Jihyun , Chambers Emily S. , Li Shuai , Liu Shengwu , Chen Ting , Barbie Thanh U. , Oxnard Geoffrey R. , Haworth Jacob J. , Wong Kwok-Kin , Dahlberg Suzanne E. , Aref Amir A. , Barbie David A. , Bahcall Magda , Paweletz Cloud P. , Jänne Pasi A.
Published: April 2023

AbstractPurpose:
Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non–small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system.
Experimental Design:
We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2YVMA genetically engineered mouse model.
Results:
Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling.
Conclusions:
The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.
Data from Dissecting the Stromal Signaling and Regulation of Myeloid Cells and Memory Effector T Cells in Pancreatic Cancer
Authors: Blair Alex B. , Kim Victoria M. , Muth Stephen T. , Saung May Tun , Lokker Nathalie , Blouw Barbara , Armstrong Todd D. , Jaffee Elizabeth M. , Tsujikawa Takahiro , Coussens Lisa M. , He Jin , Burkhart Richard A. , Wolfgang Christopher L. , Zheng Lei
Published: April 2023

AbstractPurpose:
Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component.
Experimental Design:
A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20.
Results:
Targeting stroma by degrading HA with PEGPH20 in combination with vaccine decreases CXCL12/CXCR4/CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8+ T cells, respectively. This corresponds with increased CCR7− effector memory T-cell infiltration, an increase in tumor-specific IFNγ, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target.
Conclusions:
This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.
Data from NKT Cells Coexpressing a GD2-Specific Chimeric Antigen Receptor and IL15 Show Enhanced In Vivo Persistence and Antitumor Activity against Neuroblastoma
Authors: Xu Xin , Huang Wei , Heczey Andras , Liu Daofeng , Guo Linjie , Wood Michael , Jin Jingling , Courtney Amy N. , Liu Bin , Di Pierro Erica J. , Hicks John , Barragan Gabriel A. , Ngai Ho , Chen Yuhui , Savoldo Barbara , Dotti Gianpietro , Metelitsa Leonid S.
Published: April 2023

AbstractPurpose:
Vα24-invariant natural killer T cells (NKT) are attractive carriers for chimeric antigen receptors (CAR) due to their inherent antitumor properties and preferential localization to tumor sites. However, limited persistence of CAR-NKTs in tumor-bearing mice is associated with tumor recurrence. Here, we evaluated whether coexpression of the NKT homeostatic cytokine IL15 with a CAR enhances the in vivo persistence and therapeutic efficacy of CAR-NKTs.
Experimental Design:
Human primary NKTs were ex vivo expanded and transduced with CAR constructs containing an optimized GD2-specific single-chain variable fragment and either the CD28 or 4-1BB costimulatory endodomain, each with or without IL15 (GD2.CAR or GD2.CAR.15). Constructs that mediated robust CAR-NKT cell expansion were selected for further functional evaluation in vitro and in xenogeneic mouse models of neuroblastoma.
Results:
Coexpression of IL15 with either costimulatory domain increased CAR-NKT absolute numbers. However, constructs containing 4-1BB induced excessive activation-induced cell death and reduced numeric expansion of NKTs compared with respective CD28-based constructs. Further evaluation of CD28-based GD2.CAR and GD2.CAR.15 showed that coexpression of IL15 led to reduced expression levels of exhaustion markers in NKTs and increased multiround in vitro tumor cell killing. Following transfer into mice bearing neuroblastoma xenografts, GD2.CAR.15 NKTs demonstrated enhanced in vivo persistence, increased localization to tumor sites, and improved tumor control compared with GD2.CAR NKTs. Importantly, GD2.CAR.15 NKTs did not produce significant toxicity as determined by histopathologic analysis.
Conclusions:
Our results informed selection of the CD28-based GD2.CAR.15 construct for clinical testing and led to initiation of a first-in-human CAR-NKT cell clinical trial (NCT03294954).
Data from Noncanonical TGFβ Pathway Relieves the Blockade of IL1β/TGFβ-Mediated Crosstalk between Tumor and Stroma: TGFBR1 and TAK1 Inhibition in Colorectal Cancer
Authors: Guillén Díaz-Maroto Natalia , Sanz-Pamplona Rebeca , Berdiel-Acer Mireia , Cimas Francisco J. , García Elena , Gonçalves-Ribeiro Samuel , Albert Nerea , Garcia-Vicién Gemma , Capella Gabriel , Moreno Victor , Salazar Ramon , Villanueva Alberto , Molleví David G.
Published: April 2023

AbstractPurpose:
The aim of the study is blocking the recruitment of a protective stroma by altering the crosstalk between normal stromal cells and tumor cells for stripping tumors of the protection conferred by the microenvironment.
Experimental Design:
A transcriptomic analysis of cocultured normal colonic fibroblasts and colorectal tumor cells was performed. We focused on the study of molecules that mediate the communication between both compartments and that entail fibroblasts’ activation and the alteration of the sensitivity to chemotherapy. We identified targets for the blocking of the tumor–stroma interaction. Finally, we tested, in vivo, the blockade of the tumor–stroma interaction in orthotopic models derived from patients and in models of acquired resistance to oxaliplatin.
Results:
IL1β/TGFβ1 are the triggers for fibroblasts’ recruitment and conversion into carcinoma-associated fibroblasts (CAF) in colorectal cancer. CAFs then secrete proinflammatory factors that alter sensitivity in tumor cells, activating JAK/STAT and PI3KCA/AKT pathways. Blocking such crosstalk with a neutralizing IL1β antibody and a TGFBR1 inhibitor is relieved by the TAK1-mediated activation of the noncanonical TGFβ pathway, which induces a change in the cytokine/chemokine repertoire that maintains a sustained activation of AKT in tumor cells. TAK1 plus TGFBR1 inhibition blocks IL1β/TGFβ1-mediated fibroblast activation, decreasing the secretion of proinflammatory cytokines. In turn, tumor cells became more sensitive to chemotherapy. In vivo, the combination of a TAK1 inhibitor plus TGFBR1 inhibitor reduced the metastatic capacity of tumor cells and the recruitment of fibroblasts.
Conclusions:
Our findings provide a translational rationale for the inhibition of TAK1 and TGFBR1 to remove the chemoprotection conferred by CAFs.
Data from Genetic Aberrations in the CDK4 Pathway Are Associated with Innate Resistance to PD-1 Blockade in Chinese Patients with Non-Cutaneous Melanoma
Authors: Yu Jiayi , Yan Junya , Guo Qian , Chi Zhihong , Tang Bixia , Zheng Bin , Yu Jinyu , Yin Ting , Cheng Zhiyuan , Wu Xiaowen , Yu Huan , Dai Jie , Sheng Xinan , Si Lu , Cui Chuanliang , Bai Xue , Mao Lili , Lian Bin , Wang Xuan , Yan Xieqia , Li Siming , Zhou Li , Flaherty Keith T. , Guo Jun , Kong Yan
Published: April 2023

AbstractPurpose:
PD-1 checkpoint blockade immunotherapy induces long and durable response in patients with advanced melanoma. However, only a subset of patients with melanoma benefit from this approach. The mechanism triggering the innate resistance of anti–PD-1 therapy remains unclear.

Experimental Design: Whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) analyses were performed in a training cohort (n = 31) using baseline tumor biopsies of patients with advanced melanoma treated with the anti–PD-1 antibody. Copy-number variations (CNVs) for the genes CDK4, CCND1, and CDKN2A were assayed using a TaqMan copy-number assay in a validation cohort (n = 85). The effect of CDK4/6 inhibitors combined with anti–PD-1 antibody monotherapy was evaluated in PD-1–humanized mouse (C57BL/6-hPD-1) and humanized immune system (HIS) patient-derived xenograft (PDX) models.
Results:
WES revealed several significant gene copy-number gains in the patients of no clinical benefit cohort, such as 12q14.1 loci, which harbor CDK4. The association between CDK4 gain and innate resistance to anti–PD-1 therapy was validated in 85 patients with melanoma (P < 0.05). RNA-Seq analysis of CDK4-normal cell lines and CDK4-normal tumors showed altered transcriptional output in TNFα signaling via NF-κB, inflammatory response, and IFNγ response gene set. In addition, CDK4/6 inhibitor (palbociclib) treatment increased PD-L1 protein levels and enhanced efficacy (P < 0.05) in the C57BL/6-hPD-1 melanoma cell and the HIS PDX model.
Conclusions:
In summary, we discovered that genetic aberrations in the CDK4 pathway are associated with innate resistance to anti–PD-1 therapy in patients with advanced melanoma. Moreover, our study provides a strong rationale for combining CDK4/6 inhibitors with anti–PD-1 antibody for the treatment of advanced melanomas.
Data from Clinical Efficacy and Tumor Microenvironment Influence in a Dose-Escalation Study of Anti-CD19 Chimeric Antigen Receptor T Cells in Refractory B-Cell Non-Hodgkin's Lymphoma
Authors: Yan Zi-Xun , Li Li , Wang Wen , OuYang Bin-Shen , Cheng Shu , Wang Li , Wu Wen , Xu Peng-Peng , Muftuoglu Muharrem , Hao Ming , Yang Su , Zhang Mu-Chen , Zheng Zhong , Li James , Zhao Wei-Li
Published: April 2023

AbstractPurpose:
Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains of great interest.
Patients and Methods:
A phase I, first-in-human, dose-escalation study of anti-CD19 JWCAR029 was conducted in refractory B-NHL (NCT03355859) and 10 patients received CAR T cells at an escalating dose of 2.5 × 107(n = 3), 5 × 107(n = 4), and 1 × 108(n = 3) cells. Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphoma patients on Day −6 (1 day before lymphodepletion) and on Day 11 after CAR T-cell infusion when adequate CAR T-cell expansion was detected.
Results:
The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieving complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 cytokine release syndrome occurred in all patients and grade 3 neurotoxicity in 1 patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in 3 different dose levels, but CAR T cells were significantly higher in patients achieved complete remission on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients. Increased tumor-associated macrophage infiltration was negatively associated with remission status.
Conclusions:
JWCAR029 was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact in CAR T therapy response.
Data from Purinostat Mesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for the Treatment of BCR-ABL–Induced B-Cell Acute Lymphoblastic Leukemia
Authors: Yang Linyu , Qiu Qiang , Tang Minghai , Wang Fang , Yi Yuyao , Yi Dongni , Yang Zhuang , Zhu Zejiang , Zheng Shoujun , Yang Jianhong , Pei Heying , Zheng Li , Chen Yong , Gou Liping , Luo Liya , Deng Xing , Ye Haoyu , Hu Yiguo , Niu Ting , Chen Lijuan
Published: April 2023

AbstractPurpose:
This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph+ B-cell acute lymphoblastic leukemia (B-ALL).
Experimental Design:
Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph+ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph+ B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties in vivo. BCR-ABL(T315I)–induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph+ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph+ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate.
Results:
Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph+ leukemia cell lines and primary Ph+ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph+ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph+ B-ALL, BCR-ABL(T315I)–induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph+ B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.
Conclusions:
Purinostat mesylate provides a new therapeutic strategy for patients with Ph+ B-ALL, including those who relapse after TKI treatment.
Data from FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia
Authors: Krauss Aviva C. , Gao Xin , Li Liang , Manning Michael L. , Patel Paresma , Fu Wentao , Janoria Kumar G. , Gieser Gerlie , Bateman David A. , Przepiorka Donna , Shen Yuan Li , Shord Stacy S. , Sheth Christopher M. , Banerjee Anamitro , Liu Jiang , Goldberg Kirsten B. , Farrell Ann T. , Blumenthal Gideon M. , Pazdur Richard
Published: April 2023

Abstract
On August 3, 2017, the FDA granted regular approval to Vyxeos (also known as CPX-351; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos with a standard combination of daunorubicin and cytarabine (“7+3”) in 309 patients 60–75 years of age with newly diagnosed t-AML or AML-MRC. Because of elemental copper concerns with the Vyxeos formulation, patients with Wilson disease were excluded from the study. Vyxeos demonstrated an improvement in overall survival (HR 0.69; 95% confidence interval, 0.52–0.90; P = 0.005) with an estimated median overall survival of 9.6 months compared with 5.9 months for the “7+3” control arm. The toxicity profile of Vyxeos was similar to that seen with standard “7+3” with the exception of more prolonged neutropenia and thrombocytopenia on the Vyxeos arm. Because the pharmacology of Vyxeos differs from that of other formulations of daunorubicin and cytarabine, labeling includes a warning against interchanging formulations during treatment. This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC.
Data from Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett's Esophagus: A Prospective Validation Study
Authors: Wang Zhixiong , Kambhampati Thiruvengadam Swetha , Cheng Yulan , Ma Ke , Simsek Cem , Tieu Alan H. , Abraham John M. , Liu Xi , Prasath Vishnu , Duncan Mark , Stark Alejandro , Trick Alexander , Tsai Hua-Ling , Wang Hao , He Yulong , Khashab Mouen A. , Ngamruengphong Saowanee , Shin Eun J. , Wang Tza-Huei , Meltzer Stephen J.
Published: April 2023

AbstractPurpose:
Barrett's esophagus is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for Barrett's esophagus diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a Barrett's esophagus detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB).
Experimental Design:
We conducted a prospective cohort study on 80 patients (52 in the training set; 28 in the test set). We used MOB to extract and bisulfite-convert DNA, followed by quantitative methylation-specific PCR to assess methylation levels of 8 previously selected candidate markers. Lasso regression was applied to establish a prediction model in the training set, which was then tested on the independent test set.
Results:
In the training set, five of eight candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in Barrett's esophagus patients than in controls. We built a four-biomarker-plus-age lasso regression model for Barrett's esophagus diagnosis. The AUC was 0.894, with sensitivity 94.4% [95% confidence interval (CI), 71%–99%] and specificity 62.2% (95% CI, 44.6%–77.3%) in the training set. This model also performed with high accuracy for Barrett's esophagus diagnosis in an independent test set: AUC = 0.929 (P < 0.001; 95% CI, 0.810%–1%), with sensitivity=78.6% (95% CI, 48.8%–94.3%) and specificity = 92.8% (95% CI, 64.1%–99.6%).
Conclusions:
EsophaCap, in combination with an epigenetic biomarker panel and the MOB method, is a promising, well-tolerated, low-cost esophageal sampling strategy for Barrett's esophagus diagnosis. This approach merits further prospective studies in larger populations.
Data from Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer
Authors: Saleh Anthony D. , Cheng Hui , Martin Scott E. , Si Han , Ormanoglu Pinar , Carlson Sophie , Clavijo Paul E. , Yang Xinping , Das Rita , Cornelius Shaleeka , Couper Jamie , Chepeha Douglas , Danilova Ludmila , Harris Thomas M. , Prystowsky Michael B. , Childs Geoffrey J. , Smith Richard V. , Robertson A. Gordon , Jones Steven J. M. , Cherniack Andrew D. , Kim Sang S. , Rait Antonina , Pirollo Kathleen F. , Chang Esther H. , Chen Zhong , Van Waes Carter
Published: April 2023

AbstractPurpose:
To identify deregulated and inhibitory miRNAs and generate novel mimics for replacement nanomedicine for head and neck squamous cell carcinomas (HNSCC).
Experimental Design:
We integrated miRNA and mRNA expression, copy number variation, and DNA methylation results from The Cancer Genome Atlas (TCGA), with a functional genome-wide screen.
Results:
We reveal that the miR-30 family is commonly repressed, and all 5 members sharing these seed sequence similarly inhibit HNSCC proliferation in vitro. We uncover a previously unrecognized inverse relationship with overexpression of a network of important predicted target mRNAs deregulated in HNSCC, that includes key molecules involved in proliferation (EGFR, MET, IGF1R, IRS1, E2F7), differentiation (WNT7B, FZD2), adhesion, and invasion (ITGA6, SERPINE1). Reexpression of the most differentially repressed family member, miR-30a-5p, suppressed this mRNA program, selected signaling proteins and pathways, and inhibited cell proliferation, migration, and invasion in vitro. Furthermore, a novel miR-30a-5p mimic formulated into a targeted nanomedicine significantly inhibited HNSCC xenograft tumor growth and target growth receptors EGFR and MET in vivo. Significantly decreased miR-30a/e family expression was related to DNA promoter hypermethylation and/or copy loss in TCGA data, and clinically with decreased disease-specific survival in a validation dataset. Strikingly, decreased miR-30e-5p distinguished oropharyngeal HNSCC with poor prognosis in TCGA (P = 0.002) and validation (P = 0.007) datasets, identifying a novel candidate biomarker and target for this HNSCC subset.
Conclusions:
We identify the miR-30 family as an important regulator of signal networks and tumor suppressor in a subset of HNSCC patients, which may benefit from miRNA replacement nanomedicine therapy.
Data from The Proteomic Landscape of Pancreatic Ductal Adenocarcinoma Liver Metastases Identifies Molecular Subtypes and Associations with Clinical Response
Authors: Law Henry C.-H. , Lagundžin Dragana , Clement Emalie J. , Qiao Fangfang , Wagner Zachary S. , Krieger Kimiko L. , Costanzo-Garvey Diane , Caffrey Thomas C. , Grem Jean L. , DiMaio Dominick J. , Grandgenett Paul M. , Cook Leah M. , Fisher Kurt W. , Yu Fang , Hollingsworth Michael A. , Woods Nicholas T.
Published: April 2023

AbstractPurpose:
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease that can be separated into distinct subtypes based on molecular signatures. Identifying PDAC subtype-specific therapeutic vulnerabilities is necessary to develop precision medicine approaches to treat PDAC.
Experimental Design:
A total of 56 PDAC liver metastases were obtained from the UNMC Rapid Autopsy Program and analyzed with quantitative proteomics. PDAC subtypes were identified by principal component analysis based on protein expression profiling. Proteomic subtypes were further characterized by the associated clinical information, including but not limited to survival analysis, drug treatment response, and smoking and drinking status.
Results:
Over 3,960 proteins were identified and used to delineate four distinct PDAC microenvironment subtypes: (i) metabolic; (ii) progenitor-like; (iii) proliferative; and (iv) inflammatory. PDAC risk factors of alcohol and tobacco consumption correlate with subtype classifications. Enhanced survival is observed in FOLFIRINOX treated metabolic and progenitor-like subtypes compared with the proliferative and inflammatory subtypes. In addition, TYMP, PDCD6IP, ERAP1, and STMN showed significant association with patient survival in a subtype-specific manner. Gemcitabine-induced alterations in the proteome identify proteins, such as serine hydroxymethyltransferase 1, associated with drug resistance.
Conclusions:
These data demonstrate that proteomic analysis of clinical PDAC liver metastases can identify molecular signatures unique to disease subtypes and point to opportunities for therapeutic development to improve the treatment of PDAC.
Data from Primary Preclinical and Clinical Evaluation of 68Ga-DOTA-TMVP1 as a Novel VEGFR-3 PET Imaging Radiotracer in Gynecological Cancer
Authors: Li Fei , Zhang Zhenzhong , Cai Jiong , Chen Xi , Zhou Ying , Ma Xiangyi , Dong Qingjian , Li Fang , Xi Ling
Published: April 2023

AbstractPurpose:
Tumor periphery and lymph nodes of tumor-induced lymphangiogenesis often abundantly express VEGFR-3. In our previous study, we identified a 5-amino acid peptide named TMVP1, which binds specifically to VEGFR-3. The objective of this study was to develop a novel 68Ga-labeled TMVP1 for VEGFR-3 PET imaging and to investigate its safety, biodistribution, and tumor-localizing efficacy in xenograft tumor models and a small cohort of patients with recurrent ovarian and cervical cancer.
Experimental Design:
The DOTA-conjugated TMVP1 peptide was labeled with radionuclide 68Ga. SPR and saturation binding assays were used for the receptor-binding studies. Gynecologic xenograft tumors were employed for small-animal PET imaging and biodistribution of 68Ga-DOTA-TMVP1 in vivo. In the clinical study, 5 healthy volunteers and 8 patients with gynecologic cancer underwent whole-body PET/CT after being injected with 68Ga-DOTA-TMVP1.
Results:
DOTA-TMVP1 was successfully labeled with 68Ga. LECs showed higher binding capacity with 68Ga-DOTA-TMVP1 than LEC(shVEGFR-3) and human umbilical vein endothelial cells. In mice with subcutaneous C33-A and SKOV-3 xenografts, the tracer was rapidly eliminated through the kidney to the bladder, and the small-animal PET/CT helped to clearly visualize the tumors. In patients with recurrent ovarian cancer and cervical cancer, tracer accumulation well above the background level was demonstrated in most identified sites of disease; especially with recurrent endodermal sinus tumors, the diagnostic value of 68Ga-DOTA-TMVP1 was comparable with that of 18F-FDG PET/CT.
Conclusions:
68Ga-DOTA-TMVP1 is a potential PET tracer for imaging VEGFR-3 with favorable pharmacokinetics.
Data from ERK Regulates HIF1α-Mediated Platinum Resistance by Directly Targeting PHD2 in Ovarian Cancer
Authors: Li Zhuqing , Zhou Wei , Zhang Yi , Sun Wei , Yung Mingo M.H. , Sun Jing , Li Jing , Chen Chi-Wei , Li Zongzhu , Meng Yunxiao , Chai Jie , Zhou Yuan , Liu Stephanie S. , Cheung Annie N.Y. , Ngan Hextan Y.S. , Chan David W. , Zheng Wei , Zhu Wenge
Published: April 2023

AbstractPurpose:
Up to 80% of patients with ovarian cancer develop platinum resistance over time to platinum-based chemotherapy. Increased HIF1α level is an important mechanism governing platinum resistance in platinum-resistant ovarian cancer (PROC). However, the mechanism regulating HIF1α stability in PROC remains largely unknown. Here, we elucidate the mechanism of HIF1α stability regulation in PROC and explore therapeutic approaches to overcome cisplatin resistance in ovarian cancer.
Experimental Design:
We first used a quantitative high-throughput combinational screen (qHTCS) to identify novel drugs that could resensitize PROC cells to cisplatin. Next, we evaluated the combination efficacy of inhibitors of HIF1α (YC-1), ERK (selumetinib), and TGFβ1 (SB431542) with platinum drugs by in vitro and in vivo experiments. Moreover, a novel TGFβ1/ERK/PHD2-mediated pathway regulating HIF1α stability in PROC was discovered.
Results:
YC-1 and selumetinib resensitized PROC cells to cisplatin. Next, the prolyl hydroxylase domain-containing protein 2 (PHD2) was shown to be a direct substrate of ERK. Phosphorylation of PHD2 by ERK prevents its binding to HIF1α, thus inhibiting HIF1α hydroxylation and degradation—increasing HIF1α stability. Significantly, ERK/PHD2 signaling in PROC cells is dependent on TGFβ1, promoting platinum resistance by stabilizing HIF1α. Inhibition of TGFβ1 by SB431542, ERK by selumetinib, or HIF1α by YC-1 efficiently overcame platinum resistance both in vitro and in vivo. The results from clinical samples confirm activation of the ERK/PHD2/HIF1α axis in patients with PROC, correlating highly with poor prognoses for patients.
Conclusions:
HIF1α stabilization is regulated by TGFβ1/ERK/PHD2 axis in PROC. Hence, inhibiting TGFβ1, ERK, or HIF1α is potential strategy for treating patients with PROC.
Data from A Phase II and Biomarker Study of Sorafenib Combined with Modified FOLFOX in Patients with Advanced Hepatocellular Carcinoma
Authors: Goyal Lipika , Zheng Hui , Abrams Thomas A. , Miksad Rebecca , Bullock Andrea J. , Allen Jill N. , Yurgelun Matthew B. , Clark Jeffrey W. , Kambadakone Avinash , Muzikansky Alona , Knowles Michelle , Galway Aralee , Afflitto Anthony J. , Dinicola Caroline F. , Regan Eileen , Hato Tai , Mamessier Emilie , Shigeta Kohei , Jain Rakesh K. , Duda Dan G. , Zhu Andrew X.
Published: April 2023

AbstractPurpose:
Sorafenib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC). The phase III SHARP trial showed a median time-to-progression (mTTP) of 5.5 months, overall response rate (ORR) of 2%, and median overall survival (mOS) of 10.7 months with sorafenib. FOLFOX4 has shown modest activity in advanced HCC. We evaluated the combination of sorafenib and modified (m)FOLFOX in a single-arm, multicenter phase II study.
Patients and Methods:
The study included Child–Pugh A patients with advanced HCC and no prior systemic therapies. Patients received sorafenib 400 mg twice a day for 2 weeks, followed by concurrent mFOLFOX [5-fluorouracil (5-FU) 1,200 mg/m2/day for 46 hours, leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2 biweekly]. The primary endpoint was mTTP with an alternative hypothesis of 7 months, and secondary endpoints included ORR, mOS, and circulating biomarkers.
Results:
The study enrolled 40 patients: HCV/EtOH/HBV, 43%/28%/13%; Child–Pugh A5, 70%. Notable grade 3/4 adverse events (AE) included AST/ALT elevation (28%/15%), diarrhea (13%), hyperbilirubinemia (10%), hand–foot syndrome (8%), and bleeding (8%). mTTP was 7.7 months [95% confidence interval (CI): 4.4–8.9], ORR 18%, and mOS 15.1 months (7.9–16.9). Sorafenib + mFOLFOX increased plasma PlGF, VEGF-D, sVEGFR1, IL12p70, and CAIX and CD4+ and CD8+ effector T lymphocytes and decreased plasma sVEGFR2 and s-c-KIT and regulatory T cells (Tregs). Shorter TTP was associated with high baseline sVEGFR1. Shorter TTP and OS were associated with increases in Tregs and CD56Dim natural killer (NK) cells after sorafenib alone and plasma sMET after combination treatment (all P < 0.05).
Conclusions:
Sorafenib + mFOLFOX met the prespecified endpoint with encouraging efficacy but moderate hepatotoxicity. Thus, this regimen may be effective in select patients with adequate liver reserve. Biomarker evaluations suggested a correlation between time-to-progression (TTP) and angiogenic biomarkers and circulating Tregs.
Data from MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion
Authors: Chalishazar Milind D. , Wait Sarah J. , Huang Fang , Ireland Abbie S. , Mukhopadhyay Anandaroop , Lee Younjee , Schuman Sophia S. , Guthrie Matthew R. , Berrett Kristofer C. , Vahrenkamp Jeffery M. , Hu Zeping , Kudla Marek , Modzelewska Katarzyna , Wang Guoying , Ingolia Nicholas T. , Gertz Jason , Lum David H. , Cosulich Sabina C. , Bomalaski John S. , DeBerardinis Ralph J. , Oliver Trudy G.
Published: April 2023

AbstractPurpose:
Small-cell lung cancer (SCLC) has been treated clinically as a homogeneous disease, but recent discoveries suggest that SCLC is heterogeneous. Whether metabolic differences exist among SCLC subtypes is largely unexplored. In this study, we aimed to determine whether metabolic vulnerabilities exist between SCLC subtypes that can be therapeutically exploited.
Experimental Design:
We performed steady state metabolomics on tumors isolated from distinct genetically engineered mouse models (GEMM) representing the MYC- and MYCL-driven subtypes of SCLC. Using genetic and pharmacologic approaches, we validated our findings in chemo-naïve and -resistant human SCLC cell lines, multiple GEMMs, four human cell line xenografts, and four newly derived PDX models.
Results:
We discover that SCLC subtypes driven by different MYC family members have distinct metabolic profiles. MYC-driven SCLC preferentially depends on arginine-regulated pathways including polyamine biosynthesis and mTOR pathway activation. Chemo-resistant SCLC cells exhibit increased MYC expression and similar metabolic liabilities as chemo-naïve MYC-driven cells. Arginine depletion with pegylated arginine deiminase (ADI-PEG 20) dramatically suppresses tumor growth and promotes survival of mice specifically with MYC-driven tumors, including in GEMMs, human cell line xenografts, and a patient-derived xenograft from a relapsed patient. Finally, ADI-PEG 20 is significantly more effective than the standard-of-care chemotherapy.
Conclusions:
These data identify metabolic heterogeneity within SCLC and suggest arginine deprivation as a subtype-specific therapeutic vulnerability for MYC-driven SCLC.
Data from D-2-Hydroxyglutarate Is an Intercellular Mediator in IDH-Mutant Gliomas Inhibiting Complement and T Cells
Authors: Zhang Lingjun , Sorensen Mia D. , Kristensen Bjarne W. , Reifenberger Guido , McIntyre Thomas M. , Lin Feng
Published: April 2023

Abstract
Purpose: Somatic mutations in the isocitrate dehydrogenase (IDH)-1 and -2 genes are remarkably penetrant in diffuse gliomas. These highly effective gain-of-function mutations enable mutant IDH to efficiently metabolize isocitrate to D-2-hydroxyglutarate (D 2-HG) that accumulates to high concentrations within the tumor microenvironment. D 2-HG is an intracellular effector that promotes tumor growth through widespread epigenetic changes in IDH-mutant tumor cells, but its potential role as an intercellular immune regulator remains understudied.

Experimental Design: Complement activation and CD4+, CD8+, or FOXP3+ T-cell infiltration into primary tumor tissue were determined by immunohistochemistry using sections from 72 gliomas of World Health Organization (WHO) grade III and IV with or without IDH mutations. Ex vivo experiments with D 2-HG identified immune inhibitory mechanisms.

Results: IDH mutation associated with significantly reduced complement activation and decreased numbers of tumor-infiltrating CD4+ and CD8+ T cells with comparable FOXP3+/CD4+ ratios. D 2-HG potently inhibited activation of complement by the classical and alternative pathways, attenuated complement-mediated glioma cell damage, decreased cellular C3b(iC3b) opsonization, and impaired complement-mediated phagocytosis. Although D 2-HG did not affect dendritic cell differentiation or function, it significantly inhibited activated T-cell migration, proliferation, and cytokine secretion.

Conclusions: D 2-HG suppresses the host immune system, potentially promoting immune escape of IDH-mutant tumors. Clin Cancer Res; 24(21); 5381–91. ©2018 AACR.
Data from An FDA Review of Drug Development in Nonmetastatic Castration-resistant Prostate Cancer
Authors: Brave Michael , Weinstock Chana , Brewer Jamie R. , Chi Dow-Chung , Suzman Daniel L. , Cheng Joyce , Zhang Lijun , Sridhara Rajeshwari , Ibrahim Amna , Kluetz Paul G. , Pazdur Richard , Beaver Julia A.
Published: April 2023

Abstract
The FDA has approved three androgen receptor inhibitors—enzalutamide, apalutamide, and darolutamide—for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.
Data from Identifying Recurrent Malignant Glioma after Treatment Using Amide Proton Transfer-Weighted MR Imaging: A Validation Study with Image-Guided Stereotactic Biopsy
Authors: Jiang Shanshan , Eberhart Charles G. , Lim Michael , Heo Hye-Young , Zhang Yi , Blair Lindsay , Wen Zhibo , Holdhoff Matthias , Lin Doris , Huang Peng , Qin Huamin , Quinones-Hinojosa Alfredo , Weingart Jon D. , Barker Peter B. , Pomper Martin G. , Laterra John , van Zijl Peter C.M. , Blakeley Jaishri O. , Zhou Jinyuan
Published: April 2023

AbstractPurpose:
To quantify the accuracy of amide proton transfer-weighted (APTw) MRI for identifying active glioma after treatment via radiographically guided stereotactic tissue validation.

Experimental Design: Twenty-one patients who were referred for surgery for MRI features concerning for tumor progression versus treatment effect underwent preoperative APTw imaging. Stereotactic biopsy samples were taken from regions of interest with varying APTw signal intensities. The relationship between final clinical pathology and the histopathology of each of the 64 specimens was analyzed relative to APTw results. Analysis of confirmed recurrent tumor or treatment effect tissue was used to perform ROC analysis.
Results:
Eighteen of 21 patients had recurrent tumor, and 3 had treatment effect on clinical pathology. In 12 patients, there were multiple histopathologic assignments confirmed within the same tumor. Of the 64 total specimens, 20 specimens were active glioma, 27 mixed active and quiescent glioma, and 17 quiescent/no identifiable tumor. APTw signal intensity and histopathologic assignment, cellularity, and proliferation index had significant positive correlations (R = 0.651, 0.580, and 0.458, respectively; all P < 0.001). ROC analysis with a 1.79% APTw intensity cutoff differentiated active from nonactive tumor (AUC of 0.881) with 85.1% sensitivity and 94.1% specificity. Analysis of clinical pathology showed the mean APTw intensity for each patient had 94.4% sensitivity and 100% positive predictive value for identifying recurrent glioma at this cutoff.
Conclusions:
APTw imaging hyperintensity may be a marker of active malignant glioma. It is able to distinguish between regions of heterogeneous abnormality on anatomic brain MRI with high sensitivity and specificity.