bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from CTLA-4 Limits Anti-CD20–Mediated Tumor Regression
Authors: Ren Zhenhua , Guo Jingya , Liao Jing , Luan Yan , Liu Zhida , Sun Zhichen , Liu Xiaojuan , Liang Yong , Peng Hua , Fu Yang-Xin
Published: April 2023

Abstract
Purpose: The inhibition of tumor growth by anti-CD20 antibody (Ab) treatment is mediated by Ab- and complement-dependent cytotoxicity in xenograft tumor models. In addition, anti-CD20 therapy for B-cell lymphoma can result in intrinsic and extrinsic tumor resistance to further Ab treatment. However, adaptive immune response–related resistance has not been well studied in anti-CD20–mediated tumor control, and adaptive immunity has long been underestimated. The purpose of this study was to explore whether T cells are involved in mediating the effects of anti-CD20 therapy and what factors contribute to adaptive immune response–related resistance.

Experimental Design: Using a syngeneic mouse B-cell lymphoma model, we investigated the role of CD8+ T cells in anti-CD20–mediated tumor regression. Furthermore, we revealed how the tumor-specific T-cell response was initiated by anti-CD20. Finally, we studied adaptive immune response–related resistance in advanced B-cell lymphoma.

Results: CD8+ T cells played an essential role in anti-CD20–mediated tumor regression. Mechanistically, anti-CD20 therapy promoted dendritic cell (DC)-mediated cross-presentation. Importantly, macrophages were also necessary for the increase in the tumor-specific CTL response after anti-CD20 treatment, via the production of type I IFN to activate DC function. Furthermore, adaptive resistance is gradually developed through the CTLA-4 pathway in Treg cells in larger lymphomas. Further blockade of CTLA-4 can synergize with anti-CD20 treatment in antitumor activities.

Conclusions: The therapeutic function of anti-CD20 depends on tumor-specific CD8+ T-cell responses initiated by anti-CD20 through macrophages and DCs. CTLA-4 blockade can synergize with anti-CD20 to overcome adaptive immune response–related resistance in advanced B-cell lymphoma. Clin Cancer Res; 23(1); 193–203. ©2016 AACR.
Data from Targeting Androgen Receptor Activation Function-1 with EPI to Overcome Resistance Mechanisms in Castration-Resistant Prostate Cancer
Authors: Yang Yu Chi , Banuelos Carmen Adriana , Mawji Nasrin R. , Wang Jun , Kato Minoru , Haile Simon , McEwan Iain J. , Plymate Stephen , Sadar Marianne D.
Published: April 2023

Abstract
Purpose: Persistent androgen receptor (AR) transcriptional activity is clinically evident in castration-resistant prostate cancer (CRPC). Therefore, AR remains as a viable therapeutic target for CRPC. All current hormonal therapies target the C-terminus ligand-binding domain (LBD) of AR. By using EPI to target AR activation function-1 (AF-1), in the N-terminal domain that is essential for AR transactivation, we evaluate the ability of EPI to overcome several clinically relevant AR-related mechanisms of resistance.

Experimental Design: To study the effect of EPI on AR transcriptional activity against overexpressed coactivators, such as SRC1-3 and p300, luciferase reporter assays were performed using LNCaP cells. AR-negative COS-1 cells were employed for reporter assays to examine whether the length of polyglutamine tract affects inhibition by EPI. The effect of EPI on constitutively active AR splice variants was studied in LNCaP95 cells, which express AR-V7 variant. To evaluate the effect of EPI on the proliferation of LNCaP95 cells, we performed in vitro BrdUrd incorporation assay and in vivo studies using xenografts in mice.

Results: EPI effectively overcame several molecular alterations underlying aberrant AR activity, including overexpressed coactivators, AR gain-of-function mutations, and constitutively active AR-V7. EPI inhibited AR transcriptional activity regardless of the length of polyglutamine tract. Importantly, EPI significantly inhibited the in vitro and in vivo proliferation of LNCaP95 prostate cancer cells, which are androgen independent and enzalutamide resistant.

Conclusions: These findings support EPI as a promising therapeutic agent to treat CRPC, particularly against tumors driven by constitutively active AR splice variants that are resistant to LBD-targeting drugs. Clin Cancer Res; 22(17); 4466–77. ©2016 AACR.

See related commentary by Sharp et al., p. 4280
Data from Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors
Authors: Infante Jeffrey R. , Hollebecque Antoine , Postel-Vinay Sophie , Bauer Todd M. , Blackwood Elizabeth M. , Evangelista Marie , Mahrus Sami , Peale Franklin V. , Lu Xuyang , Sahasranaman Srikumar , Zhu Rui , Chen Yuan , Ding Xiao , Murray Elaine R. , Schutzman Jennifer L. , Lauchle Jennifer O. , Soria Jean-Charles , LoRusso Patricia M.
Published: April 2023

Abstract
Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors.

Experimental Design: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased to 1,000 mg/m2 (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. TP53 mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses.

Results: Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m2. Dose-limiting toxicities included thrombocytopenia (n = 5), neutropenia (n = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin.

Conclusions: Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. Clin Cancer Res; 23(10); 2423–32. ©2016 AACR.
Data from In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3–Mediated Apoptosis
Authors: Fornari Francesca , Pollutri Daniela , Patrizi Clarissa , La Bella Tiziana , Marinelli Sara , Casadei Gardini Andrea , Marisi Giorgia , Baron Toaldo Marco , Baglioni Michele , Salvatore Veronica , Callegari Elisa , Baldassarre Maurizio , Galassi Marzia , Giovannini Catia , Cescon Matteo , Ravaioli Matteo , Negrini Massimo , Bolondi Luigi , Gramantieri Laura
Published: April 2023

Abstract
Purpose: The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved in vivo efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC.

Experimental Design: A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC.

Results: MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients.

Conclusions: MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. Clin Cancer Res; 23(14); 3953–65. ©2017 AACR.
Data from Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth
Authors: Li Ming , Radvanyi Laszlo , Yin Bingnan , Rycaj Kiera , Li Jia , Chivukula Raghavender , Lin Kevin , Lu Yue , Shen JianJun , Chang David Z. , Li Donghui , Johanning Gary L. , Wang-Johanning Feng
Published: April 2023

Abstract
Purpose: We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer.

Experimental Design: shRNA was employed to knockdown (KD) the expression of HERV-K in pancreatic cancer cells.

Results: HERV-K env expression was detected in seven pancreatic cancer cell lines and in 80% of pancreatic cancer patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several pancreatic cancer cell lines. Reverse transcriptase activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in pancreatic cancer patient sera (N = 106) than in normal donor sera (N = 40). Importantly, the in vitro and in vivo growth rates of three pancreatic cancer cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-Seq results revealed changes in gene expression after HERV-K env KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several pancreatic cancer cells or tumors.

Conclusions: These results demonstrate that HERV-K influences signal transduction via the RAS–ERK–RSK pathway in pancreatic cancer. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of pancreatic cancer, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis, and immunotherapy of pancreatic cancer. Clin Cancer Res; 23(19); 5892–911. ©2017 AACR.
Data from Validation of the 12-gene Predictive Signature for Adjuvant Chemotherapy Response in Lung Cancer
Authors: Xie Yang , Lu Wei , Wang Shidan , Tang Ximing , Tang Hao , Zhou Yunyun , Moran Cesar , Behrens Carmen , Roth Jack A. , Zhou Qinghua , Johnson David H. , Swisher Stephen G. , Heymach John V. , Papadimitrakopoulou Vassiliki A. , Xiao Guanghua , Minna John D. , Wistuba Ignacio I.
Published: April 2023

AbstractPurpose:
Response to adjuvant chemotherapy after tumor resection varies widely among patients with non–small cell lung cancer (NSCLC); therefore, it is of clinical importance to prospectively predict who will benefit from adjuvant chemotherapy before starting the treatment. The goal of this study is to validate a 12-gene adjuvant chemotherapy predictive signature developed from a previous study using a clinical-grade assay.
Experimental Design:
We developed a clinical-grade assay for formalin-fixed, paraffin-embedded (FFPE) samples using the NanoString nCounter platform to measure the mRNA expression of the previously published 12-gene set. The predictive performance was validated in a cohort of 207 patients with early-stage resected NSCLC with matched propensity score of adjuvant chemotherapy.
Results:
The effects of adjuvant chemotherapy were significantly different in patients from the predicted adjuvant chemotherapy benefit group and those in the predicted adjuvant chemotherapy nonbenefit group (P = 0.0056 for interaction between predicted risk group and adjuvant chemotherapy). Specifically, in the predicted adjuvant chemotherapy benefit group, the patients receiving adjuvant chemotherapy had significant recurrence-free survival (RFS) benefit (HR = 0.34; P = 0.016; adjuvant chemotherapy vs. nonadjuvant chemotherapy), while in the predicted adjuvant chemotherapy nonbenefit group, the patients receiving adjuvant chemotherapy actually had worse RFS (HR = 1.86; P = 0.14; adjuvant chemotherapy vs. nonadjuvant chemotherapy) than those who did not receive adjuvant chemotherapy.
Conclusions:
This study validated that the 12-gene signature and the FFPE-based clinical assay predict that patients whose resected lung adenocarcinomas exhibit an adjuvant chemotherapy benefit gene expression pattern and who then receive adjuvant chemotherapy have significant survival advantage compared with patients whose tumors exhibit the benefit pattern but do not receive adjuvant chemotherapy.
Data from Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL
Authors: Jones Luke , Richmond Jennifer , Evans Kathryn , Carol Hernan , Jing Duohui , Kurmasheva Raushan T. , Billups Catherine A. , Houghton Peter J. , Smith Malcolm A. , Lock Richard B.
Published: April 2023

Abstract
Purpose: Robust preclinical models of pediatric acute lymphoblastic leukemia (ALL) are essential in prioritizing promising therapies for clinical assessment in high-risk patients. Patient-derived xenograft (PDX) models of ALL provide a clinically relevant platform for assessing novel drugs, with efficacy generally assessed by enumerating circulating human lymphoblasts in mouse peripheral blood (PB) as an indicator of disease burden. While allowing indirect measurement of disease burden in real time, this technique cannot assess treatment effects on internal reservoirs of disease. We explore benefits of bioluminescence imaging (BLI) to evaluate drug responses in ALL PDXs, compared with PB monitoring. BLI-based thresholds of drug response are also explored.

Experimental Design: ALL PDXs were lentivirally transduced to stably express luciferase and green fluorescent protein. In vivo PDX responses to an induction-type regimen of vincristine, dexamethasone, and L-asparaginase were assessed by BLI and PB. Residual disease at day 28 after treatment initiation was assessed by flow cytometric analysis of major organs. BLI and PB were subsequently used to evaluate efficacy of the Bcl-2 inhibitor venetoclax.

Results: BLI considerably accelerated and enhanced detection of leukemia burden compared with PB and identified sites of residual disease during treatment in a quantitative manner, highlighting limitations in current PB-based scoring criteria. Using BLI alongside enumeration of human lymphoblasts in PB and bone marrow, we were able to redefine response criteria analogous to the clinical setting.

Conclusions: BLI substantially improves the stringency of preclinical drug testing in pediatric ALL PDXs, which will likely be important in prioritizing effective agents for clinical assessment. Clin Cancer Res; 23(14); 3744–55. ©2017 AACR.
Data from Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies
Authors: Kelly Kevin , Mejia Alex , Suhasini Avvaru N. , Lin An-Ping , Kuhn John , Karnad Anand B. , Weitman Steven , Aguiar Ricardo C.T.
Published: April 2023

Abstract
Purpose: In this study, we aimed to validate our extensive preclinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics, and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential antitumor activity of the PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B-cell malignancies.

Experimental Design: Single-center, exploratory phase Ib open-label, nonrandomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8 to 14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease.

Results: Ten patients, median age 65 years with an average of three prior therapies, were enrolled. The median number of cycles administered was 4 (range, 1–13). Treatment was well tolerated; the most common ≥grade 2 treatment-related adverse events were fatigue, anorexia (≥25%), and transient ≥ grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49–315) versus 91 days (28–139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days (range, 28–315).

Conclusions: Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active. Clin Cancer Res; 23(5); 1186–92. ©2016 AACR.
Data from The Prediction of Clinical Outcome in Hepatocellular Carcinoma Based on a Six-Gene Metastasis Signature
Authors: Yuan Shengxian , Wang Jie , Yang Yuan , Zhang Jin , Liu Hui , Xiao Juanjuan , Xu Qingguo , Huang Xinhui , Xiang Bangde , Zhu Shaoliang , Li Lequn , Liu Jingfeng , Liu Lei , Zhou Weiping
Published: April 2023

Abstract
Purpose: The dismal outcome of hepatocellular carcinoma (HCC) is largely attributed to its early recurrence and venous metastases. We aimed to develop a metastasis-related model to predict hepatocellular carcinoma prognosis.

Experimental Design: Using microarrays, sequencing, and RT-PCR, we measured the expression of mRNAs and lncRNAs in a training set of 94 well-defined low-risk (LRM) and high-risk metastatic (HRM) HCC patients from a Shanghai cohort. We refined a metastasis signature and established a corresponding model using logistic regression analysis. The validation set consisted of 567 HCC patients from four-center cohorts. Survival analysis was performed according to the metastasis model.

Results: Using relative expression of tumor to para-tumor tissues, we refined the metastasis signature of five mRNAs and one lncRNA. A generalized linear model was further established to predict the probability of metastasis (MP). Using MP cutoff of 0.7 to separate LRM and HRM in Shanghai cohort, the specificity and sensitivity of the model were 96% [95% confidence interval (CI), 85%–99%] and 74% (95% CI, 58%–86%), respectively. Furthermore, HRM patients showed a significantly shorter overall and recurrence-free survival in validation cohorts (P < 0.05 for each cohort). Early HCC patients also have a poorer outcome for multicenter HRM patients. Finally, Cox regression analysis indicated that continuous MP was an independent risk factor and associated with the recurrence and survival of HCC patients after resection (HR 2.98–16.6, P < 0.05).

Conclusions: We developed an applicable six-gene metastasis signature, which is robust and reproducible in multicenter cohorts for HCC prognosis. Clin Cancer Res; 23(1); 289–97. ©2016 AACR.
Data from Fecal Bacteria Act as Novel Biomarkers for Noninvasive Diagnosis of Colorectal Cancer
Authors: Liang Qiaoyi , Chiu Jonathan , Chen Yingxuan , Huang Yanqin , Higashimori Akira , Fang Jingyuan , Brim Hassan , Ashktorab Hassan , Ng Siew Chien , Ng Simon Siu Man , Zheng Shu , Chan Francis Ka Leung , Sung Joseph Jao Yiu , Yu Jun
Published: April 2023

Abstract
Purpose: Gut microbiota have been implicated in the development of colorectal cancer. We evaluated the utility of fecal bacterial marker candidates identified by our metagenome sequencing analysis for colorectal cancer diagnosis.

Experimental Design: Subjects (total 439; 203 colorectal cancer and 236 healthy subjects) from two independent Asian cohorts were included. Probe-based duplex quantitative PCR (qPCR) assays were established for the quantification of bacterial marker candidates.

Results: Candidates identified by metagenome sequencing, including Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Roseburia intestinalis (Ri), Clostridium hathewayi (Ch), and one undefined species (labeled as m7), were examined in fecal samples of 203 colorectal cancer patients and 236 healthy controls by duplex-qPCR. Strong positive correlations were demonstrated between the quantification of each candidate by our qPCR assays and metagenomics approach (r = 0.801–0.934, all P < 0.0001). Fn was significantly more abundant in colorectal cancer than controls (P < 0.0001), with AUROC of 0.868 (P < 0.0001). At the best cut-off value maximizing sum of sensitivity and specificity, Fn discriminated colorectal cancer from controls with a sensitivity of 77.7%, and specificity of 79.5% in cohort I. A simple linear combination of four bacteria (Fn + Ch + m7-Bc) showed an improved diagnostic ability compared with Fn alone (AUROC = 0.886, P < 0.0001) in cohort I. These findings were further confirmed in an independent cohort II. In particular, improved diagnostic performances of Fn alone (sensitivity 92.8%, specificity 79.8%) and four bacteria (sensitivity 92.8%, specificity 81.5%) were achieved in combination with fecal immunochemical testing for the detection of colorectal cancer.

Conclusions: Stool-based colorectal cancer–associated bacteria can serve as novel noninvasive diagnostic biomarkers for colorectal cancer. Clin Cancer Res; 23(8); 2061–70. ©2016 AACR.
Data from Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial
Authors: Xu Ran , Shimizu Fumiko , Hovinga Koos , Beal Kathryn , Karimi Sasan , Droms Leif , Peck Kyung K. , Gutin Philip , Iorgulescu J. Bryan , Kaley Thomas , DeAngelis Lisa , Pentsova Elena , Nolan Craig , Grommes Christian , Chan Timothy , Bobrow Dylan , Hormigo Adilia , Cross Justin R. , Wu Nian , Takebe Naoko , Panageas Katherine , Ivy Percy , Supko Jeffrey G. , Tabar Viviane , Omuro Antonio
Published: April 2023

Abstract
Purpose: High-grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO4929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed antiangiogenic role.

Experimental Design: In this phase 0/I trial, 21 patients with newly diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the MTD, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuroimaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood–brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment.

Results: Treatment was well tolerated and no dose-limiting toxicities were observed. IHC of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133+ CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes, and an increase in VEGF-dependent angiogenic factors.

Conclusions: The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has a variable blood–brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. Clin Cancer Res; 22(19); 4786–96. ©2016 AACR.
Data from A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma
Authors: Rodriguez-Blanco Jezabel , Li Bin , Long Jun , Shen Chen , Yang Fan , Orton Darren , Collins Sara , Kasahara Noriyuki , Ayad Nagi G. , McCrea Heather J. , Roussel Martine F. , Weiss William A. , Capobianco Anthony J. , Robbins David J.
Published: April 2023

Abstract
Purpose: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1α (CK1α) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a second-generation CK1α activator against TRP53-mutant, MYCN-amplified medulloblastoma.

Experimental Design: The ability of this CK1α activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1α activators was demonstrated using a TRP53-mutant, MYCN-amplified patient-derived xenograft.

Results: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival.

Conclusions: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitor–resistant medulloblastoma, including those harboring mutations in TRP53.
Data from Radiomics Features of Multiparametric MRI as Novel Prognostic Factors in Advanced Nasopharyngeal Carcinoma
Authors: Zhang Bin , Tian Jie , Dong Di , Gu Dongsheng , Dong Yuhao , Zhang Lu , Lian Zhouyang , Liu Jing , Luo Xiaoning , Pei Shufang , Mo Xiaokai , Huang Wenhui , Ouyang Fusheng , Guo Baoliang , Liang Long , Chen Wenbo , Liang Changhong , Zhang Shuixing
Published: April 2023

Abstract
Purpose: To identify MRI-based radiomics as prognostic factors in patients with advanced nasopharyngeal carcinoma (NPC).

Experimental Design: One-hundred and eighteen patients (training cohort: n = 88; validation cohort: n = 30) with advanced NPC were enrolled. A total of 970 radiomics features were extracted from T2-weighted (T2-w) and contrast-enhanced T1-weighted (CET1-w) MRI. Least absolute shrinkage and selection operator (LASSO) regression was applied to select features for progression-free survival (PFS) nomograms. Nomogram discrimination and calibration were evaluated. Associations between radiomics features and clinical data were investigated using heatmaps.

Results: The radiomics signatures were significantly associated with PFS. A radiomics signature derived from joint CET1-w and T2-w images showed better prognostic performance than signatures derived from CET1-w or T2-w images alone. One radiomics nomogram combined a radiomics signature from joint CET1-w and T2-w images with the TNM staging system. This nomogram showed a significant improvement over the TNM staging system in terms of evaluating PFS in the training cohort (C-index, 0.761 vs. 0.514; P < 2.68 × 10−9). Another radiomics nomogram integrated the radiomics signature with all clinical data, and thereby outperformed a nomogram based on clinical data alone (C-index, 0.776 vs. 0.649; P < 1.60 × 10−7). Calibration curves showed good agreement. Findings were confirmed in the validation cohort. Heatmaps revealed associations between radiomics features and tumor stages.

Conclusions: Multiparametric MRI-based radiomics nomograms provided improved prognostic ability in advanced NPC. These results provide an illustrative example of precision medicine and may affect treatment strategies. Clin Cancer Res; 23(15); 4259–69. ©2017 AACR.
Data from Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer
Authors: Shelar Sandeep , Shim Eun-Hee , Brinkley Garrett J. , Kundu Anirban , Carobbio Francesca , Poston Tyler , Tan Jubilee , Parekh Vishwas , Benson Daniel , Crossman David K. , Buckhaults Phillip J. , Rakheja Dinesh , Kirkman Richard , Sato Yusuke , Ogawa Seishi , Dutta Shilpa , Velu Sadanandan E. , Emberley Ethan , Pan Alison , Chen Jason , Huang Tony , Absher Devin , Becker Anja , Kunick Conrad , Sudarshan Sunil
Published: April 2023

AbstractPurpose:
Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated.
Experimental Design:
Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on in vitro and in vivo phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression.
Results:
L2HGDH suppresses both in vitro cell migration and in vivo tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in an L-2-HG–dependent manner. Moreover, in vivo growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC.
Conclusions:
Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG–driven kidney cancers.
Data from Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial
Authors: Kyi Chrisann , Roudko Vladimir , Sabado Rachel , Saenger Yvonne , Loging William , Mandeli John , Thin Tin Htwe , Lehrer Deborah , Donovan Michael , Posner Marshall , Misiukiewicz Krzysztof , Greenbaum Benjamin , Salazar Andres , Friedlander Philip , Bhardwaj Nina
Published: April 2023

Abstract
Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells.

Patients and Methods: In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood.

Results: Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (

Conclusions: Poly-ICLC was well tolerated in patients with solid cancer and generated local and systemic immune responses, as evident in the patient achieving clinical benefit. These results warrant further investigation and are currently being explored in a multicenter phase II clinical trial (NCT02423863). Clin Cancer Res; 24(20); 4937–48. ©2018 AACR.
Data from The Effectiveness of Checkpoint Inhibitor Combinations and Administration Timing Can Be Measured by Granzyme B PET Imaging
Authors: Larimer Benjamin M. , Bloch Emily , Nesti Sarah , Austin Emily E. , Wehrenberg-Klee Eric , Boland Genevieve , Mahmood Umar
Published: April 2023

AbstractPurpose:
The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combinations, and that GZP uptake could be compared between therapeutic regimens and dosing schedules as an early biomarker of relative efficacy.
Experimental Design:
Two models, MC38 and CT26, were treated with a series of checkpoint inhibitors. GZP PET imaging was performed to assess tumoral GZP uptake, and tumor volume changes were subsequently monitored to determine response. The average GZP PET uptake and response of each treatment group were correlated to evaluate the utility of GZP PET for comparing therapeutic efficacy.
Results:
In both tumor models, GZP PET imaging was highly accurate for predicting response, with 93% sensitivity and 94% negative predictive value. Mean tumoral GZP signal intensity of treatment groups linearly correlated with percent response across all therapies and schedules. Moreover, GZP PET correctly predicted that sequential dose scheduling of PD-1 and CTLA-4 targeted therapies demonstrates comparative efficacy to concurrent administration.
Conclusions:
Granzyme B quantification is a highly sensitive and specific early measure of therapeutic efficacy for checkpoint inhibitor regimens. This work provides evidence that GZP PET imaging may be useful for rapid assessment of therapeutic efficacy in the context of clinical trials for both novel drugs as well as dosing regimens.
Data from Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14–mutant Non–small Cell Lung Cancer
Authors: Suzawa Ken , Offin Michael , Lu Daniel , Kurzatkowski Christopher , Vojnic Morana , Smith Roger S. , Sabari Joshua K. , Tai Huichun , Mattar Marissa , Khodos Inna , de Stanchina Elisa , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Lockwood William W. , Drilon Alexander , Ladanyi Marc , Somwar Romel
Published: April 2023

AbstractPurpose:
MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear.
Experimental Design:
We examined clinical and genomic data from 113 patients with lung cancer with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models.
Results:
Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models.
Conclusions:
KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.
Data from Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
Authors: Engstrom Lars D. , Aranda Ruth , Lee Matthew , Tovar Elizabeth A. , Essenburg Curt J. , Madaj Zachary , Chiang Harrah , Briere David , Hallin Jill , Lopez-Casas Pedro P. , Baños Natalia , Menendez Camino , Hidalgo Manuel , Tassell Vanessa , Chao Richard , Chudova Darya I. , Lanman Richard B. , Olson Peter , Bazhenova Lyudmilla , Patel Sandip Pravin , Graveel Carrie , Nishino Mizuki , Shapiro Geoffrey I. , Peled Nir , Awad Mark M. , Jänne Pasi A. , Christensen James G.
Published: April 2023

Abstract
Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non–small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del–positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.

Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.

Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.

Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661–72. ©2017 AACR.
Data from SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer
Authors: Tao Zhen , McCall Neal S. , Wiedemann Norbert , Vuagniaux Grégoire , Yuan Zhiyong , Lu Bo
Published: April 2023

AbstractPurpose:
Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrial-derived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity.
Experimental Design:
To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8+ T cells and TNFα, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFα, or anti-IFNγ antibodies. Tumor-infiltrating OVA-specific CD8+ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFα, IFNγ, and IL1β and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA.
Results:
ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8+ cells, TNFα, and IFNγ with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs.
Conclusions:
Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFα, IFNγ, and CD8+ T-cell–dependent manner. This provides a novel strategy to enhance the immunogenicity of ART.
Data from Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models
Authors: Suominen Mari I. , Fagerlund Katja M. , Rissanen Jukka P. , Konkol Yvonne M. , Morko Jukka P. , Peng ZhiQi , Alhoniemi Esa J. , Laine Salla K. , Corey Eva , Mumberg Dominik , Ziegelbauer Karl , Käkönen Sanna-Maria , Halleen Jussi M. , Vessella Robert L. , Scholz Arne
Published: April 2023

Abstract
Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.

Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12–17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.

Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.

Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335–46. ©2017 AACR.
Data from Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma
Authors: Audenet François , Isharwal Sumit , Cha Eugene K. , Donoghue Mark T.A. , Drill Esther N. , Ostrovnaya Irina , Pietzak Eugene J. , Sfakianos John P. , Bagrodia Aditya , Murugan Paari , Dalbagni Guido , Donahue Timothy F. , Rosenberg Jonathan E. , Bajorin Dean F. , Arcila Maria E. , Hechtman Jaclyn F. , Berger Michael F. , Taylor Barry S. , Al-Ahmadie Hikmat , Iyer Gopa , Bochner Bernard H. , Coleman Jonathan A. , Solit David B.
Published: April 2023

AbstractPurpose:
To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors.
Experimental Design:
We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.
Results:
With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.
Conclusions:
UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.
Data from Neurotensin Receptor 1 Antagonist SR48692 Improves Response to Carboplatin by Enhancing Apoptosis and Inhibiting Drug Efflux in Ovarian Cancer
Authors: Liu Jin , Agopiantz Mikaël , Poupon Joël , Wu Zherui , Just Pierre-Alexandre , Borghese Bruno , Ségal-Bendirdjian Evelyne , Gauchotte Guillaume , Gompel Anne , Forgez Patricia
Published: April 2023

Abstract
Purpose: The high affinity receptor 1 (NTSR1) and its agonist, neurotensin (NTS), are correlated with tumor cell aggressiveness in most solid tumors. As chemoresistance and tumor aggressiveness are often related, we decided to study the role of the NTSR1 complex within platinum-based chemotherapy responses. In an ovarian model, we studied carboplatin because it is the main standard of care for ovarian cancer.

Experimental Design: Experimental tumors and in vitro studies were performed using SKOV3 and A2780 cells treated with carboplatin, with or without a very specific NTSR1 antagonist, SR48692. We measured the effects of these treatments on cell apoptosis and apoptosis-related proteins, platinum accumulation in the cell and nucleus, and the expression and localization of platinum transporters. NTS and NTSR1 labeling was measured in patients with ovarian cancer.

Results: SR48692 enhanced the response to carboplatin in ovarian cancer cells and experimental tumors. When SR48692 is combined with carboplatin, we noted a major improvement of platinum-induced DNA damage and cell death, as well as a decrease in tumor growth. The relationship of these results to clinical studies was made by the detection of NTS and NTSR1 in 72% and 74% of ovarian cancer, respectively. Furthermore, in a large series of high-grade ovarian cancer, NTSR1 mRNA was shown to correlate with higher stages and platinum resistance.

Conclusions: This study strongly suggests that the addition of NTSR1 inhibitor in combination with platinum salt–based therapy will improve the response to the drug. Clin Cancer Res; 23(21); 6516–28. ©2017 AACR.