bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer
Authors: Li Shuai , Liu Shengwu , Deng Jiehui , Akbay Esra A. , Hai Josephine , Ambrogio Chiara , Zhang Long , Zhou Fangyu , Jenkins Russell W. , Adeegbe Dennis O. , Gao Peng , Wang Xiaoen , Paweletz Cloud P. , Herter-Sprie Grit S. , Chen Ting , Gutiérrez-Quiceno Laura , Zhang Yanxi , Merlino Ashley A. , Quinn Max M. , Zeng Yu , Yu Xiaoting , Liu Yuting , Fan Lichao , Aguirre Andrew J. , Barbie David A. , Yi Xianghua , Wong Kwok-Kin
Published: April 2023

Abstract
Purpose: Despite the challenge to directly target mutant KRAS due to its high GTP affinity, some agents are under development against downstream signaling pathways, such as MEK inhibitors. However, it remains controversial whether MEK inhibitors can boost current chemotherapy in KRAS-mutant lung tumors in clinic. Considering the genomic heterogeneity among patients with lung cancer, it is valuable to test potential therapeutics in KRAS mutation–driven mouse models.

Experimental Design: We first compared the pERK1/2 level in lung cancer samples with different KRAS substitutions and generated a new genetically engineered mouse model whose tumor was driven by KRASG12C, the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRASG12C tumors compared with KRASG12D tumors. Moreover, we generated KRASG12C/p53R270H model to explore the role of a dominant negative p53 mutation detected in patients in responsiveness to MEK inhibition.

Results: We determined higher pERK1/2 in KRASG12C lung tumors compared with KRASG12D. Using mouse models, we further identified that KRASG12C tumors are significantly more sensitive to selumetinib compared with KrasG12D tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRASG12C mice. Interestingly, p53 co-mutation rendered KRASG12C lung tumors less sensitive to combination treatment with selumetinib and chemotherapy.

Conclusions: Our data demonstrate that unique KRAS mutations and concurrent mutations in tumor-suppressor genes are important factors for lung tumor responses to MEK inhibitor. Our preclinical study supports further clinical evaluation of combined MEK inhibition and chemotherapy for lung cancer patients harboring KRASG12C and wild-type p53 status. Clin Cancer Res; 24(19); 4854–64. ©2018 AACR.
Data from ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism
Authors: Liu Mingyang , Yang Jingxuan , Zhang Yuqing , Zhou Zhijun , Cui Xiaobo , Zhang Liyang , Fung Kar-Ming , Zheng Wei , Allard Felicia D. , Yee Eric U. , Ding Kai , Wu Huanwen , Liang Zhiyong , Zheng Lei , Fernandez-Zapico Martin E. , Li Yi-Ping , Bronze Michael S. , Morris Katherine T. , Postier Russell G. , Houchen Courtney W. , Yang Jing , Li Min
Published: April 2023

Abstract
Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis.

Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts.

Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1.

Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. Clin Cancer Res; 24(13); 3186–96. ©2018 AACR.
Data from Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
Authors: Welti Jonathan , Sharp Adam , Yuan Wei , Dolling David , Nava Rodrigues Daniel , Figueiredo Ines , Gil Veronica , Neeb Antje , Clarke Matthew , Seed George , Crespo Mateus , Sumanasuriya Semini , Ning Jian , Knight Eleanor , Francis Jeffrey C. , Hughes Ashley , Halsey Wendy S. , Paschalis Alec , Mani Ram S. , Raj Ganesh V. , Plymate Stephen R. , Carreira Suzanne , Boysen Gunther , Chinnaiyan Arul M. , Swain Amanda , de Bono Johann S.
Published: April 2023

Abstract
Purpose: Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC.

Experimental Design: We determined associations between BET expression, AR-driven transcription, and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer models.

Results: Nuclear BRD4 protein expression increases significantly (P ≤ 0.01) with castration resistance in same patient treatment-naïve (median H-score; interquartile range: 100; 100–170) and CRPC (150; 110–200) biopsies, with higher expression at diagnosis associating with worse outcome (HR, 3.25; 95% CI, 1.50–7.01; P ≤ 0.001). BRD2, BRD3, and BRD4 RNA expression in CRPC biopsies correlates with AR-driven transcription (all P ≤ 0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of prostate cancer cells and patient-derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (P ≤ 0.001) of a patient-derived xenograft model of CRPC with AR amplification and AR-V7 expression.

Conclusions: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies. Clin Cancer Res; 24(13); 3149–62. ©2018 AACR.
Data from Long Noncoding RNA MPRL Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via Disruption of Pre-miRNA Processing
Authors: Tian Tian , Lv Xiaobin , Pan Guokai , Lu Yingjuan , Chen Weixiong , He Wang , Lei Xinyuan , Zhang Hanqing , Liu Mo , Sun Sheng , Ou Zhanpeng , Lin Xinyu , Cai Lei , He Lile , Tu Zhiming , Wang Xinhui , Tannous Bakhos A. , Ferrone Soldano , Li Jinsong , Fan Song
Published: April 2023

AbstractPurpose:
The overall biological roles and clinical significance of most long noncoding RNAs (lncRNA) in chemosensitivity are not fully understood. We investigated the biological function, mechanism, and clinical significance of lncRNA NR_034085, which we termed miRNA processing–related lncRNA (MPRL), in tongue squamous cell carcinoma (TSCC).
Experimental Design:
LncRNA expression in TSCC cell lines with cisplatin treatment was measured by lncRNA microarray and confirmed in TSCC tissues. The functional roles of MPRL were demonstrated by a series of in vitro and in vivo experiments. The miRNA profiles, RNA pull-down, RNA immunoprecipitation, serial deletion analysis, and luciferase analyses were used to investigate the potential mechanisms of MPRL.
Results:
We found that MPRL expression was significantly upregulated in TSCC cell lines treated with cisplatin and transactivated by E2F1. MPRL controlled mitochondrial fission and cisplatin sensitivity through miR–483-5p. In exploring the underlying interaction between MPRL and miR–483-5p, we identified that cytoplasmic MPRL directly binds to pre–miR–483 within the loop region and blocks pre–miR–483 recognition and cleavage by TRBP–DICER-complex, thereby inhibiting miR–483-5p generation and upregulating miR–483-5p downstream target-FIS1 expression. Furthermore, overexpression or knockdown MPRL altered tumor apoptosis and growth in mouse xenografts. Importantly, we found that high expression of MPRL and pre–miR–483, and low expression of miR–483-5p were significantly associated with neoadjuvant chemosensitivity and better TSCC patients’ prognosis.
Conclusions:
We propose a model in which lncRNAs impair microprocessor recognition and are efficient of pre-miRNA cropping. In addition, our study reveals a novel regulatory network for mitochondrial fission and chemosensitivity and new biomarkers for prediction of neoadjuvant chemosensitivity in TSCC.

These findings uncover a novel mechanism by which lncRNA determines mitochondrial fission and cisplatin chemosensitivity by inhibition of pre-miRNA processing and provide for the first time the rationale for lncRNA and miRNA biogenesis for predicting chemosensitivity and patient clinical prognosis.
Data from An Effective Epigenetic-PARP Inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA Mutations
Authors: Pulliam Nicholas , Fang Fang , Ozes Ali R. , Tang Jessica , Adewuyi Adeoluwa , Keer Harold , Lyons John , Baylin Stephen B. , Matei Daniela , Nakshatri Harikrishna , Rassool Feyruz V. , Miller Kathy D. , Nephew Kenneth P.
Published: April 2023

Abstract
Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status.

Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed.

Results: Combination of guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP “trapping” by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models.

Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type– or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers. Clin Cancer Res; 24(13); 3163–75. ©2018 AACR.
Data from Cyclin E Overexpression Sensitizes Triple-Negative Breast Cancer to Wee1 Kinase Inhibition
Authors: Chen Xian , Low Kwang-Huei , Alexander Angela , Jiang Yufeng , Karakas Cansu , Hess Kenneth R. , Carey Jason P.W. , Bui Tuyen N. , Vijayaraghavan Smruthi , Evans Kurt W. , Yi Min , Ellis D. Christian , Cheung Kwok-Leung , Ellis Ian O. , Fu Siqing , Meric-Bernstam Funda , Hunt Kelly K. , Keyomarsi Khandan
Published: April 2023

AbstractPurpose:
Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775.
Experimental Design:
Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E–mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cell lines.
Results:
Cyclin E overexpression (i) is enriched in TNBCs with high recurrence rates, (ii) sensitizes TNBC cell lines and PDX models to AZD1775, (iii) leads to CDK2-dependent activation of DNA replication stress pathways, and (iv) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E–low tumors) and result in DNA replicative stress. Such drug-mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy.

Conclusions:Cyclin E is a potential biomarker of response (i) for AZD1775 as monotherapy in cyclin E–high TNBC tumors and (ii) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E–low TNBC tumors.
Data from IFNγ-induced Chemokines Are Required for CXCR3-mediated T-Cell Recruitment and Antitumor Efficacy of Anti-HER2/CD3 Bispecific Antibody
Authors: Li Ji , Ybarra Ryan , Mak Judy , Herault Aurelie , De Almeida Patricia , Arrazate Alfonso , Ziai James , Totpal Klara , Junttila Melissa R. , Walsh Kevin B. , Junttila Teemu T.
Published: April 2023

AbstractPurpose:
The response to cancer immune therapy is dependent on endogenous tumor-reactive T cells. To bypass this requirement, CD3-bispecific antibodies have been developed to induce a polyclonal T-cell response against the tumor. Anti-HER2/CD3 T-cell–dependent bispecific (TDB) antibody is highly efficacious in the treatment of HER2-overexpressing tumors in mice. Efficacy and immunologic effects of anti-HER2/CD3 TDB were investigated in mammary tumor model with very few T cells prior treatment. We further describe the mechanism for TDB-induced T-cell recruitment to tumors.
Experimental Design:
The immunologic effects and the mechanism of CD3-bispecific antibody-induced T-cell recruitment into spontaneous HER2-overexpressing mammary tumors was studied using human HER2 transgenic, immunocompetent mouse models.
Results:
Anti-HER2/CD3 TDB treatment induced an inflammatory response in tumors converting them from poorly infiltrated to an inflamed, T-cell abundant, phenotype. Multiple mechanisms accounted for the TDB-induced increase in T cells within tumors. TDB treatment induced CD8+ T-cell proliferation. T cells were also actively recruited post-TDB treatment by IFNγ-dependent T-cell chemokines mediated via CXCR3. This active T-cell recruitment by TDB-induced chemokine signaling was the dominant mechanism and necessary for the therapeutic activity of anti-HER2/CD3 TDB.
Conclusions:
In summary, we demonstrate that the activity of anti-HER2/CD3 TDB was not dependent on high-level baseline T-cell infiltration. Our results suggest that anti-HER2/CD3 TDB may be efficacious in patients and indications that respond poorly to checkpoint inhibitors. An active T-cell recruitment mediated by TDB-induced chemokine signaling was the major mechanism for T-cell recruitment.
Data from FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia
Authors: Jen Emily Y. , Ko Chia-Wen , Lee Jee Eun , Del Valle Pedro L. , Aydanian Antonina , Jewell Charles , Norsworthy Kelly J. , Przepiorka Donna , Nie Lei , Liu Jiang , Sheth Christopher M. , Shapiro Marjorie , Farrell Ann T. , Pazdur Richard
Published: April 2023

Abstract
On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody–drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51–0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53–0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242–6. ©2018 AACR.
Data from SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy
Authors: Wang Feng , Xia Xiaojun , Yang Chunying , Shen Jianliang , Mai Junhua , Kim Han-Cheon , Kirui Dickson , Kang Ya'an , Fleming Jason B. , Koay Eugene J. , Mitra Sankar , Ferrari Mauro , Shen Haifa
Published: April 2023

Abstract
Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy.

Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells.

Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples.

Conclusions: Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Clin Cancer Res; 24(13); 3176–85. ©2018 AACR.
Data from A Survey on Data Reproducibility and the Effect of Publication Process on the Ethical Reporting of Laboratory Research
Authors: Boulbes Delphine R. , Costello Tracy , Baggerly Keith , Fan Fan , Wang Rui , Bhattacharya Rajat , Ye Xiangcang , Ellis Lee M.
Published: April 2023

Abstract
Purpose: The successful translation of laboratory research into effective therapies is dependent upon the validity of peer-reviewed publications. However, several publications in recent years suggested that published scientific findings could be reproduced only 11% to 45% of the time. Multiple surveys attempted to elucidate the fundamental causes of data irreproducibility and underscored potential solutions, more robust experimental designs, better statistics, and better mentorship. However, no prior survey has addressed the role of the review and publication process on honest reporting.

Experimental Design: We developed an anonymous online survey intended for trainees involved in bench research. The survey included questions related to mentoring/career development, research practice, integrity, and transparency, and how the pressure to publish and the publication process itself influence their reporting practices.

Results: Responses to questions related to mentoring and training practices were largely positive, although an average of approximately 25% did not seem to receive optimal mentoring. A total of 39.2% revealed having been pressured by a principle investigator or collaborator to produce “positive” data. About 62.8% admitted that the pressure to publish influences the way they report data. The majority of respondents did not believe that extensive revisions significantly improved the manuscript while adding to the cost and time invested.

Conclusions: This survey indicates that trainees believe that the pressure to publish affects honest reporting, mostly emanating from our system of rewards and advancement. The publication process itself affects faculty and trainees and appears to influence a shift in their ethics from honest reporting (“negative data”) to selective reporting, data falsification, or even fabrication. Clin Cancer Res; 24(14); 3447–55. ©2018 AACR.
Data from Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE)
Authors: Wang Zhaoming , Liu Qi , Wilson Carmen L. , Easton John , Mulder Heather , Chang Ti-Cheng , Rusch Michael C. , Edmonson Michael N. , Rice Stephen V. , Ehrhardt Matthew J. , Howell Rebecca M. , Kesserwan Chimene A. , Wu Gang , Nichols Kim E. , Downing James R. , Hudson Melissa M. , Zhang Jinghui , Yasui Yutaka , Robison Leslie L.
Published: April 2023

AbstractPurpose:
The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinants implicated in breast cancer susceptibility in the general population.
Experimental Design:
Whole-genome sequencing (30×) was performed on survivors in the St Jude Lifetime Cohort, and germline mutations in breast cancer predisposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants. Relative rate (RR) and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression.
Results:
The analysis included 1,133 female survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4–67.4), of whom 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5–53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest versus lowest quintiles were 2.7 (95% CI, 1.0–7.3), 3.0 (95% CI, 1.1–8.1), and 2.4 (95% CI, 0.1–81.1) for all survivors and survivors with and without chest irradiation, respectively. Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI, 1.2–8.3).
Conclusions:
Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors.
Data from Immunogenomic Analyses of Advanced Serous Ovarian Cancer Reveal Immune Score is a Strong Prognostic Factor and an Indicator of Chemosensitivity
Authors: Hao Dapeng , Liu Jie , Chen Meng , Li JingJing , Wang Li , Li Xiaobo , Zhao Qi , Di Li-jun
Published: April 2023

Abstract
Purpose: Ovarian cancer is one of the first human cancers for which in situ immune response was reported to be important for the clinical outcome. To elucidate the mechanistic relationship between immune repertoire and cancer genotype in ovarian cancer, the development of a well-defined immune score for ovarian cancer is required.

Experimental Design: From a collection of 2,203 patient samples of advanced ovarian cancer from public available resources, we evaluated the prognostic values for a compendium of immune marker genes and proposed an immune score. The relationships between immune score, tumor-infiltrating immune cells, cancer genotypes, and their impact on patient outcome were characterized.

Results: Loss of chemokine and IFNγ pathway genes is frequent in ovarian cancer and is significantly associated with low immune score and poor outcome. Chemotherapy can increase the immune score of tumors by inducing the expression of IFNγ inducible chemokines. High immune score is significantly associated with BRCA1/2 mutation status and the response to chemotherapy. Multivariate analysis revealed that immune score is a strong predictor of patient survival and the response to immunotherapy.

Conclusions: Our results reveal the drivers of the immune repertoire of advanced ovarian cancer and demonstrate the importance of immune score as an independent prognostic signature and a potent indicator of intratumoral immune status. Clin Cancer Res; 24(15); 3560–71. ©2018 AACR.
Data from Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End Joining
Authors: Liu Qi , Ma Lin , Jones Trevor , Palomero Luis , Pujana Miquel Angel , Martinez-Ruiz Haydeliz , Ha Patrick K. , Murnane John , Cuartas Isabel , Seoane Joan , Baumann Michael , Linge Annett , Barcellos-Hoff Mary Helen
Published: April 2023

AbstractPurpose:
Following cytotoxic therapy, 70% of patients with human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (HNSCC) are alive at 5 years compared with 30% of those with similar HPV-negative cancer. Loss of TGFβ signaling is a poorly studied consequence of HPV that could contribute to patient outcome by compromising DNA repair.
Experimental Design:
Human HNSCC cell lines (n = 9), patient-derived xenografts (n = 9), tissue microarray (n = 194), TCGA expression data (n = 279), and primary tumor specimens (n = 10) were used to define the relationship between TGFβ competency, response to DNA damage, and type of DNA repair.
Results:
Analysis of HNSCC specimens in situ and in vitro showed that HPV associated with loss of TGFβ signaling that increased response to radiation or cisplatin. TGFβ suppressed miR-182, which inhibited both BRCA1, necessary for homologous recombination repair (HRR), and FOXO3, required for ATM kinase activity. TGFβ signaling blockade by either HPV or inhibitors released miR182 control, compromised HRR and increased response to PARP inhibition. Antagonizing miR-182 rescued the HRR deficit in HPV-positive cells. Loss of TGFβ signaling unexpectedly increased repair by error prone, alternative end-joining (alt-EJ).
Conclusions:
HPV-positive HNSCC cells are unresponsive to TGFβ. Abrogated TGFβ signaling compromises repair by HRR and increases reliance on alt-EJ, which provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGFβ’s role in DNA repair proficiency and further raises the translational potential of TGFβ inhibitors in cancer therapy.
Data from Prognostic Value of Deep Learning PET/CT-Based Radiomics: Potential Role for Future Individual Induction Chemotherapy in Advanced Nasopharyngeal Carcinoma
Authors: Peng Hao , Dong Di , Fang Meng-Jie , Li Lu , Tang Ling-Long , Chen Lei , Li Wen-Fei , Mao Yan-Ping , Fan Wei , Liu Li-Zhi , Tian Li , Lin Ai-Hua , Sun Ying , Tian Jie , Ma Jun
Published: April 2023

AbstractPurpose:
We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)–based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal carcinoma (NPC).
Experimental Design:
We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (n = 470), and then validated it on a test set (n = 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein–Barr virus (EBV) DNA.
Results:
A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (P < 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 [95% confidence interval (95% CI), 0.709–0.800] in the training set and 0.722 (95% CI, 0.652–0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (P < 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC.
Conclusions:
Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.
Data from Development and Validation of a Novel Signature to Predict Overall Survival in “Driver Gene–negative” Lung Adenocarcinoma (LUAD): Results of a Multicenter Study
Authors: Cui Yongmei , Fang Wenfeng , Li Chaofeng , Tang Kejing , Zhang Jian , Lei Yiyan , He Weiling , Peng Sui , Kuang Ming , Zhang Hui , Chen Lili , Xu Di , Tang Cuilan , Zhang Wenhui , Zhu Yuxin , Jiang Wenting , Jiang Neng , Sun Yu , Chen Yangshan , Wang Han , Lai Yingrong , Li Shuhua , He Qiong , Zhou Jianwen , Zhang Yang , Lin Millicent , Chen Honglei , Zhou Chenzhi , Wang Chunlin , Wang Jianhong , Zou Xuenong , Wang Liantang , Ke Zunfu
Published: April 2023

AbstractPurpose:
Examining the role of developmental signaling pathways in “driver gene–negative” lung adenocarcinoma (patients with lung adenocarcinoma negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as “driver gene–negative”) may shed light on the clinical research and treatment for this lung adenocarcinoma subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of “driver gene–negative” lung adenocarcinoma.
Experimental Design:
In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired lung adenocarcinoma and adjacent normal tissues. In the training phase, tissue microarrays and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature.
Results:
Kyoto Encyclopedia of Genes and Genomes pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “driver gene–negative” lung adenocarcinoma. Furthermore, the Wnt/β-catenin pathway–based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/β-catenin pathway–based CSDW signature comprising 4 genes (CTNNB1 or β-catenin, SOX9, DVL3, and Wnt2b) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival [HR, 10.42; 6.46–16.79; P < 0.001) than patients with low-risk scores.
Conclusions:
The CSDW signature is a reliable prognostic tool and may represent genes that are potential drug targets for “driver gene–negative” lung adenocarcinoma.
Data from Identification and Characterization of Synthetic Viability with ERCC1 Deficiency in Response to Interstrand Crosslinks in Lung Cancer
Authors: Heyza Joshua R. , Lei Wen , Watza Donovan , Zhang Hao , Chen Wei , Back Jessica B. , Schwartz Ann G. , Bepler Gerold , Patrick Steve M.
Published: April 2023

AbstractPurpose:
ERCC1/XPF is a DNA endonuclease with variable expression in primary tumor specimens, and has been investigated as a predictive biomarker for efficacy of platinum-based chemotherapy. The failure of clinical trials utilizing ERCC1 expression to predict response to platinum-based chemotherapy suggests additional mechanisms underlying the basic biology of ERCC1 in the response to interstrand crosslinks (ICLs) remain unknown. We aimed to characterize a panel of ERCC1 knockout (Δ) cell lines, where we identified a synthetic viable phenotype in response to ICLs with ERCC1 deficiency.
Experimental Design:
We utilized the CRISPR-Cas9 system to create a panel of ERCC1Δ lung cancer cell lines which we characterized.
Results:
We observe that loss of ERCC1 hypersensitizes cells to cisplatin when wild-type (WT) p53 is retained, whereas there is only modest sensitivity in cell lines that are p53mutant/null. In addition, when p53 is disrupted by CRISPR-Cas9 (p53*) in ERCC1Δ/p53WT cells, there is reduced apoptosis and increased viability after platinum treatment. These results were recapitulated in 2 patient data sets utilizing p53 mutation analysis and ERCC1 expression to assess overall survival. We also show that kinetics of ICL-repair (ICL-R) differ between ERCC1Δ/p53WT and ERCC1Δ/p53* cells. Finally, we provide evidence that cisplatin tolerance in the context of ERCC1 deficiency relies on DNA-PKcs and BRCA1 function.
Conclusions:
Our findings implicate p53 as a potential confounding variable in clinical assessments of ERCC1 as a platinum biomarker via promoting an environment in which error-prone mechanisms of ICL-R may be able to partially compensate for loss of ERCC1.

See related commentary by Friboulet et al., p. 2369
Data from Plasma 25-Hydroxyvitamin D Levels and Survival in Patients with Advanced or Metastatic Colorectal Cancer: Findings from CALGB/SWOG 80405 (Alliance)
Authors: Yuan Chen , Sato Kaori , Hollis Bruce W. , Zhang Sui , Niedzwiecki Donna , Ou Fang-Shu , Chang I-Wen , O'Neil Bert H. , Innocenti Federico , Lenz Heinz-Josef , Blanke Charles D. , Goldberg Richard M. , Venook Alan P. , Mayer Robert J. , Fuchs Charles S. , Meyerhardt Jeffrey A. , Ng Kimmie
Published: April 2023

AbstractPurpose:
Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer.
Experimental Design:
We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders.
Results:
At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20–<30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (Ptrend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53–0.83) for OS and 0.81 (95% CI, 0.66–1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics.
Conclusions:
In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.
Data from Oxygen-enhanced MRI Is Feasible, Repeatable, and Detects Radiotherapy-induced Change in Hypoxia in Xenograft Models and in Patients with Non–small Cell Lung Cancer
Authors: Salem Ahmed , Little Ross A. , Latif Ayşe , Featherstone Adam K. , Babur Muhammad , Peset Isabel , Cheung Susan , Watson Yvonne , Tessyman Victoria , Mistry Hitesh , Ashton Garry , Behan Caron , Matthews Julian C. , Asselin Marie-Claude , Bristow Robert G. , Jackson Alan , Parker Geoff J.M. , Faivre-Finn Corinne , Williams Kaye J. , O'Connor James P.B.
Published: April 2023

AbstractPurpose:
Hypoxia is associated with poor prognosis and is predictive of poor response to cancer treatments, including radiotherapy. Developing noninvasive biomarkers that both detect hypoxia prior to treatment and track change in tumor hypoxia following treatment is required urgently.
Experimental Design:
We evaluated the ability of oxygen-enhanced MRI (OE-MRI) to map and quantify therapy-induced changes in tumor hypoxia by measuring oxygen-refractory signals in perfused tissue (perfused Oxy-R). Clinical first-in-human study in patients with non–small cell lung cancer (NSCLC) was performed alongside preclinical experiments in two xenograft tumors (Calu6 NSCLC model and U87 glioma model).
Results:
MRI perfused Oxy-R tumor fraction measurement of hypoxia was validated with ex vivo tissue pathology in both xenograft models. Calu6 and U87 experiments showed that MRI perfused Oxy-R tumor volume was reduced relative to control following single fraction 10-Gy radiation and fractionated chemoradiotherapy (P < 0.001) due to both improved perfusion and reduced oxygen consumption rate. Next, evaluation of 23 patients with NSCLC showed that OE-MRI was clinically feasible and that tumor perfused Oxy-R volume is repeatable [interclass correlation coefficient: 0.961 (95% CI, 0.858–0.990); coefficient of variation: 25.880%]. Group-wise perfused Oxy-R volume was reduced at 14 days following start of radiotherapy (P = 0.015). OE-MRI detected between-subject variation in hypoxia modification in both xenograft and patient tumors.
Conclusions:
These findings support applying OE-MRI biomarkers to monitor hypoxia modification, to stratify patients in clinical trials of hypoxia-modifying therapies, to identify patients with hypoxic tumors that may fail treatment with immunotherapy, and to guide adaptive radiotherapy by mapping regional hypoxia.
Data from Clinical and Antitumor Immune Responses in Relapsed/Refractory Follicular Lymphoma Patients after Intranodal Injections of IFNα-Dendritic Cells and Rituximab: a Phase I Clinical Trial
Authors: Cox M. Christina , Castiello Luciano , Mattei Mauro , Santodonato Laura , D'Agostino Giuseppina , Muraro Elena , Martorelli Debora , Lapenta Caterina , Di Napoli Arianna , Di Landro Francesca , Cangemi Michela , Pavan Antonio , Castaldo Paolo , Hohaus Stefan , Donati Simona , Montefiore Enrica , Berdini Cinzia , Carlei Davide , Monque Domenica M. , Ruco Luigi , Prosperi Daniela , Tafuri Agostino , Spadaro Francesca , Sestili Paola , Spada Massimo , Dolcetti Riccardo , Santini Stefano M. , Rozera Carmela , Aricò Eleonora , Capone Imerio , Belardelli Filippo
Published: April 2023

AbstractPurpose:
This study was aimed at evaluating the feasibility, safety, immunologic and clinical responses in patients with follicular lymphoma treated with monocyte-derived dendritic cells generated in the presence of IFNα and GM-CSF (IFN-DC) in combination with low doses of rituximab.
Patients and Methods:
Firstly, we analyzed in vitro and in vivo the immunologic properties of IFN-DC against follicular lymphoma. Thus, we performed a phase I trial in 8 patients with refractory and relapsed follicular lymphoma based on sequential intranodal injections of low-dose of rituximab and unloaded IFN-DC and report the safety, clinical, and immunologic results of the enrolled patients.
Results:
Preclinical studies indicated that IFN-DC can synergize with rituximab leading to increased cytotoxicity and T-cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37%, and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11–47). Notably, following the combined therapy all patients showed induction/enhancement of T-cell responses by CD107 degranulation or IFNγ ELISPOT assay against patient-specific tumor IGHV sequences.
Conclusions:
These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor-specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in patients with cancer.
Data from LRP6 Ectodomain Prevents SDF-1/CXCR4-Induced Breast Cancer Metastasis to Lung
Authors: Zhang Jiankang , Chen Jinxiao , Wo Da , Yan Hongwei , Liu Peng , Ma En , Li Limei , Zheng Liang , Chen Daxin , Yu Zuoren , Liang Chunli , Peng Jun , Ren Dan-ni , Zhu Weidong
Published: April 2023

AbstractPurpose:
Lung metastasis is an important cause of breast cancer–related deaths, in which SDF-1/CXCR4 signaling pathway plays a critical role. Single transmembrane protein LRP6 is viewed as an oncogene via activating the Wnt/β-catenin signaling pathway. Our work aims to investigate the relationship between SDF-1/CXCR4 and LRP6 in breast cancer lung metastasis.
Experimental Design:
We examined the expressions and functions of SDF-1/CXCR4 and LRP6 as well as their relationship in breast cancer in vitro and in vivo.
Results:
LRP6 ectodomain (LRP6N) directly bound to CXCR4 and competitively prevented SDF-1 binding to CXCR4. LRP6N prevented SDF-1/CXCR4-induced metastasis to lung and prolonged survival in mice bearing breast tumors, whereas LRP6 knockdown activated SDF-1/CXCR4 signal transduction and promoted lung metastasis and tumor death. Furthermore, patients with breast cancer with high CXCR4 expression had poor prognosis, which was exacerbated by low LRP6 expression but improved by high LRP6 expression. Interestingly, a secreted LRP6N was found in the serum of mice and humans, which was downregulated by the onset of cancer metastasis in both mice bearing breast cancer as well as in patients with breast cancer.
Conclusions:
LRP6N might be a promising diagnostic marker for the early detection of breast cancer metastasis as well as an inhibitor of SDF-1/CXCR4-induced breast cancer metastasis. LRP6N also provides an interesting link between Wnt signaling and SDF-1/CXCR4 signaling, the two key pathways involved in cancer development.
Data from Comprehensive Next-Generation Sequencing Unambiguously Distinguishes Separate Primary Lung Carcinomas From Intrapulmonary Metastases: Comparison with Standard Histopathologic Approach
Authors: Chang Jason C. , Alex Deepu , Bott Matthew , Tan Kay See , Seshan Venkatraman , Golden Andrew , Sauter Jennifer L. , Buonocore Darren J. , Vanderbilt Chad M. , Gupta Sounak , Desmeules Patrice , Bodd Francis M. , Riely Gregory J. , Rusch Valerie W. , Jones David R. , Arcila Maria E. , Travis William D. , Ladanyi Marc , Rekhtman Natasha
Published: April 2023

AbstractPurpose:
In patients with >1 non–small cell lung carcinoma (NSCLC), the distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is a common diagnostic dilemma with critical staging implications. Here, we compared the performance of comprehensive next-generation sequencing (NGS) with standard histopathologic approaches for distinguishing NSCLC clonal relationships in clinical practice.
Experimental Design:
We queried 4,119 NSCLCs analyzed by 341–468 gene MSK-IMPACT NGS assay for patients with >1 surgically resected tumor profiled by NGS. Tumor relatedness predicted by prospective histopathologic assessment was contrasted with comparative genomic profiling by subsequent NGS.
Results:
Sixty patients with NGS performed on >1 NSCLCs were identified, yielding 76 tumor pairs. NGS classified tumor pairs into 51 definite SPLCs (median, 14; up to 72 unique somatic mutations per pair), and 25 IPMs (24 definite, one high probability; median, 5; up to 16 shared somatic mutations per pair). Prospective histologic prediction was discordant with NGS in 17 cases (22%), particularly in the prediction of IPMs (44% discordant). Retrospective review highlighted several histologic challenges, including morphologic progression in some IPMs. We subsampled MSK-IMPACT data to model the performance of less comprehensive assays, and identified several clinicopathologic differences between NGS-defined tumor pairs, including increased risk of subsequent recurrence for IPMs.
Conclusions:
Comprehensive NGS allows unambiguous delineation of clonal relationship among NSCLCs. In comparison, standard histopathologic approach is adequate in most cases, but has notable limitations in the recognition of IPMs. Our results support the adoption of broad panel NGS to supplement histology for robust discrimination of NSCLC clonal relationships in clinical practice.