bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors
Authors: Koutros Stella , Rao Nina , Moore Lee E. , Nickerson Michael L. , Lee Donghyuk , Zhu Bin , Pardo Larissa A. , Baris Dalsu , Schwenn Molly , Johnson Alison , Jones Kristine , Garcia-Closas Montserrat , Prokunina-Olsson Ludmila , Silverman Debra T. , Rothman Nathaniel , Dean Michael 
Published: April 2021

Abstract

Purpose:
Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non–muscle-invasive bladder cancer with detailed risk factor information.

Experimental Design:
We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case–control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors.

Results:
Non-silent KDM6A mutations were more common in females than males (OR = 1.83; 95% CI, 1.05–3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater ERCC2-Signature mutations compared with former (P = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09–1.80; P = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations (P = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17–2.01; P = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with ERCC2-Signature mutations and APOBEC-Signature13 mutations among current (Ptrend = 0.005) and former smokers (P = 0.0004), respectively.

Conclusions:
These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.
Can Biomarkers Guide Oncolytic Virus Immunotherapy?
Authors: Kaufman Howard L. 
Published: April 2021

Abstract
Defects in tumor cell IFNγ signaling is associated with resistance to immune checkpoint inhibitors. Recently, these defects were found to confer increased sensitivity to oncolytic virus infection. Differential expression of innate sensing elements in tumor cells may serve as predictive biomarkers of oncolytic virus immunotherapy in patients with cancer.
See related article by Nguyen et al., p. 3432
High-Throughput Screening Identifies Idasanutlin as a Resensitizing Drug for Venetoclax-Resistant Neuroblastoma Cells
Authors: Vernooij Lindy , Bate-Eya Laurel T. , Alles Lindy K. , Lee Jasmine Y. , Koopmans Bianca , Jonus Hunter C. , Schubert Nil A. , Schild Linda , Lelieveld Daphne , Egan David A. , Kerstjens Mark , Stam Ronald W. , Koster Jan , Goldsmith Kelly C. , Molenaar Jan J. , Dolman M. Emmy M. 
Published: April 2021

AbstractNeuroblastoma tumors frequently overexpress the anti-apoptotic protein B-cell lymphoma/leukemia 2 (BCL-2). We previously showed that treating BCL-2–dependent neuroblastoma cells with the BCL-2 inhibitor venetoclax results in apoptosis, but unfortunately partial therapy resistance is observed. The current study describes the identification of drugs capable of resensitizing venetoclax-resistant neuroblastoma cells to venetoclax. To examine these effects, venetoclax resistance was induced in BCL-2–dependent neuroblastoma cell lines KCNR and SJNB12 by continuous exposure to high venetoclax concentrations. Non-resistant and venetoclax-resistant neuroblastoma cell lines were exposed to a 209-compound library in the absence and presence of venetoclax to identify compounds that were more effective in the venetoclax-resistant cell lines under venetoclax pressure. Top hits were further validated in combination with venetoclax using BCL-2–dependent neuroblastoma model systems. Overall, high-throughput drug screening identified the MDM2 inhibitor idasanutlin as a promising resensitizing agent for venetoclax-resistant neuroblastoma cell lines. Idasanutlin treatment induced BAX-mediated apoptosis in venetoclax-resistant neuroblastoma cells in the presence of venetoclax, whereas it caused p21-mediated growth arrest in control cells. In vivo combination treatment showed tumor regression and superior efficacy over single-agent therapies in a BCL-2–dependent neuroblastoma cell line xenograft and a patient-derived xenograft. However, xenografts less dependent on BCL-2 were not sensitive to venetoclax–idasanutlin combination therapy. This study demonstrates that idasanutlin can overcome resistance to the BCL-2 inhibitor venetoclax in preclinical neuroblastoma model systems, which supports clinical development of a treatment strategy combining the two therapies.
Novel TGFβ Inhibitors Ameliorate Oral Squamous Cell Carcinoma Progression and Improve the Antitumor Immune Response of Anti–PD-L1 Immunotherapy
Authors: Ludwig Nils , Wieteska Łukasz , Hinck Cynthia S. , Yerneni Saigopalakrishna S. , Azambuja Juliana H. , Bauer Richard J. , Reichert Torsten E. , Hinck Andrew P. , Whiteside Theresa L. 
Published: April 2021

Abstract
TGFβ is a key regulator of oral squamous cell carcinoma (OSCC) progression, and its potential role as a therapeutic target has been investigated with a limited success. This study evaluates two novel TGFβ inhibitors as mono or combinatorial therapy with anti–PD-L1 antibodies (α-PD-L1 Ab) in a murine OSCC model. Immunocompetent C57BL/6 mice bearing malignant oral lesions induced by 4-nitroquinoline 1-oxide (4-NQO) were treated for 4 weeks with TGFβ inhibitors mRER (i.p., 50 μg/d) or mmTGFβ2-7m (10 μg/d delivered by osmotic pumps) alone or in combination with α-PD-L1 Abs (7× i.p. of 100 μg/72 h). Tumor progression and body weight were monitored. Levels of bioactive TGFβ in serum were quantified using a TGFβ bioassay. Tissues were analyzed by immunohistology and flow cytometry. Therapy with mRER or mmTGFβ2-7m reduced tumor burden (P &lt; 0.05) and decreased body weight loss compared with controls. In inhibitor-treated mice, levels of TGFβ in tumor tissue and serum were reduced (P &lt; 0.05), whereas they increased with tumor progression in controls. Both inhibitors enhanced CD8+ T-cell infiltration into tumors and mRER reduced levels of myeloid-derived suppressor cells (P &lt; 0.001). In combination with α-PD-L1 Abs, tumor burden was not further reduced; however, mmTGFβ2-7m further reduced weight loss (P &lt; 0.05). The collagen-rich stroma was reduced by using combinatorial TGFβ/PD-L1 therapies (P &lt; 0.05), enabling an accelerated lymphocyte infiltration into tumor tissues. The blockade of TGFβ signaling by mRER or mmTGFβ2-7m ameliorated in vivo progression of established murine OSCC. The inhibitors promoted antitumor immune responses, alone and in combination with α-PD-L1 Abs.
Abstract IA-005: Base excision repair and cancer
Authors: Sweasy Joann B. 
Published: April 2021

Abstract
The Base Excision Repair (BER) machinery has evolved to process DNA bases damaged by reactive oxygen and nitrogen species as well as base lesions induced by alkylating agents. Deficient repair of damaged bases results in mutagenesis and genomic instability, whereas efficient repair of alkylating agents used to treat tumors leads to drug resistance. Human genome sequencing studies show that there are hundreds of germline variants in BER genes that are likely to encode proteins with altered function. This presentation will focus on the mechanistic insights gained from our characterization of some of these germline BER variants. We have discovered that variants in DNA glycosylase and DNA polymerase genes induce genomic instability and cellular transformation when expressed in non-transformed cells. These phenotypes result from defective or aberrant enzymatic function. Our results suggest that germline variants of BER genes likely increase risk for cancer and other diseases.
Citation Format: Joann B. Sweasy. Base excision repair and cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-005.
Abstract IA-007: Exploiting DNA repair defects in head and neck squamous cell carcinoma
Authors: Vens Conchita 
Published: April 2021

Abstract
DNA damage repair pathways govern genomic integrity and determine cellular sensitivities to radiation and chemotherapeutic agents. Recent genetic studies highlight the identification of an increasing number of DNA repair gene defects in many different cancer types. DNA damage response and repair inhibitors on the other hand provide opportunities to exploit such defects inherent to cancer cells. Combined with radiotherapy they are highly effective radiosensitizers that show some tumor specificity in that they cause greater radiation dose enhancement in cells with repair defects. To optimize such potent combinations, robust and sensitive biomarkers are needed to 1) assess effectivity and guide clinical trial designs and 2) to identify repair defects in individual patients. Radiotherapy is a mainstay in the treatment of advanced HPV-negative head and neck squamous cell carcinoma (HNSCC). There is a need for improved treatment options in this patient population. Indicating particular crosslink repair sensitivity and frequent cancer cell repair defects, cumulative cisplatin dose is an important factor in determining patient outcomes after chemoradiotherapy. Indeed, preclinical and genetic data highlight the frequent manifestation of DNA crosslink repair defects in HNSCC. Genetic biomarkers have therefore been generated and tested to support the identification of patients in need for novel treatment options and of crosslink repair defects in HNSCC for combination with PARP inhibitors.
Citation Format: Conchita Vens. Exploiting DNA repair defects in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-007.
Abstract IA-009: TGFβ regulation of DNA repair across cancer types predicts response to genotoxic therapies
Authors: Barcellos-Hoff Mary Helen 
Published: April 2021

Abstract
Transforming growth factor β (TGFβ) has a long-standing but poorly understood role in DNA repair and genomic stability. We recently showed that inhibition or loss of TGFβ signaling decreases homologous recombination and increases use of alternative end-joining (alt-EJ), an error-prone DNA repair process (Liu et al. Clin. Ca. Res. 2018). New experimental studies show that TGFβ actively suppresses genes involved in alt-EJ. Because many cancers have compromised TGFβ signaling, we determined the mechanistic implications of the relationship between TGFβ and alt-EJ using gene expression signatures by analyzing their association with outcomes in the Cancer Genome Atlas (TCGA). These studies show that the anti-correlation of TGFβ and alt-EJ regardless of tumor type is significantly associated with survival in patients treated with radiotherapy or chemoradiation. Prospective identification of patients in which TGFβ opposes effective genotoxic therapy will expand the potential therapeutic scope of TGFβ inhibitors.
Citation Format: Mary Helen Barcellos-Hoff. TGFβ regulation of DNA repair across cancer types predicts response to genotoxic therapies [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-009.
Abstract IA-011: Translation to clinical trials: Are we shooting the right arrows at the target?
Authors: Sharma Ricky A. 
Published: April 2021

Abstract
Dependent on the stage of the cancer, 25-40% of patients require curative or palliative radiotherapy as part of their primary care treatment. The DNA Damage response (DDR) pathways have been a major area of interest for drug development as tumors often harbor mutations in the DDR pathways. The development of new DDR inhibitors offers wide-ranging opportunities to combine DDR inhibition with radiation therapy. Emerging evidence also supports the use of DDR inhibitors to promote immune stimulatory effects of radiation therapy by further activating the DNA sensing cGAS-STING pathway. DDR inhibitors in combination with RT have been shown to alter PDL-1 expression and have also been linked to modulating cytokine expression to alter the tumor microenvironment. This should be considered in the context of over 300 clinical trials ongoing which are combining immunotherapy with radiotherapy and important clinical studies of this combination therapy which have been published in patients with lung cancer. Significant progress is being made in understanding new drug-radiotherapy combinations and advancing them towards the clinic.
Citation Format: Ricky A. Sharma. Translation to clinical trials: Are we shooting the right arrows at the target? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-011.
Abstract IA-016: Metabolic deregulation drives a redox vulnerability in pancreatic cancer
Authors: Koritzinsky Marianne , Jain Pallavi , Dvorkin-Gheva Anna , Malbeteau Lucie , Dhavarasa Piriththiv , Brown Kevin R. , Jang Gun Ho , Vora Parth , Notta Faiyaz , Moffat Jason , Boutros Paul C. 
Published: April 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an almost universally fatal malignancy and there is an urgent need for new therapeutic targets. PDAC cells harbor genetic alterations and display metabolic changes that render them vulnerable to perturbations in redox homeostasis. Peroxiredoxin 4 (PRDX4) supports redox homeostasis by metabolizing H2O2 in the endoplasmic reticulum (ER). Based on functional genomics, we found that PDAC cell lines are dependent on PRDX4 for their growth and survival. We validated this dependency in established and primary PDAC cells, as well as in 3D models and orthotopic xenografts. PRDX4 depletion led to increased levels of reactive oxygen species (ROS). Tumor cells are exposed to fluctuating oxygen levels, which are known to augment ROS production. In line with this, PRDX4 addiction was also exacerbated in cells exposed to hypoxia and reoxygenation. Cell death induced by PRDX4 depletion was accompanied by DNA damage and a DNA-PKcs-governed DNA damage response. As such, PRDX4 depletion also sensitized cells and tumors to ionizing radiation. The source of ROS that created a dependency on PRDX4 was attributed to NADPH oxidase 4 (NOX4), which localizes to the ER membrane. The functional requirement for PRDX4 was correlated with cellular NADPH levels across different models of PDAC and could be rescued by depletion of NOX4 or NADPH. As such, this study has identified NOX4 as a link between metabolic deregulation and ER-specific redox vulnerability in PDAC. Since PRDX4 is not an essential gene in normal tissues, our work also suggests that PRDX4 represents a novel therapeutic target for pancreatic cancer that may be particularly potent in combination with radiotherapy.
Citation Format: Marianne Koritzinsky, Pallavi Jain, Anna Dvorkin-Gheva, Lucie Malbeteau, Piriththiv Dhavarasa, Kevin R. Brown, Gun Ho Jang, Parth Vora, Faiyaz Notta, Jason Moffat, Paul C. Boutros. Metabolic deregulation drives a redox vulnerability in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-016.
Abstract IA-022: Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter
Authors: Gius David 
Published: April 2021

Abstract
Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSODK68Q is accompanied with a change of MnSOD’s stoichiometry from a known homotetramer complex to a monomeric form. Biochemical experiments using the MnSOD-K68Q Ac-mimic, or physically K68-Ac (MnSOD-K68-Ac), suggest that these monomers function as a peroxidase, distinct from the established MnSOD superoxide dismutase activity. MnSODK68Q expressing cells exhibit resistance to tamoxifen (Tam) and cells selected for Tam resistance exhibited increased K68-Ac and monomeric MnSOD. These results suggest a MnSOD-K68-Ac metabolic pathway for Tam resistance, carcinogenesis and tumor progression.
Citation Format: David Gius. Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-022.
Abstract PO-004: A phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma
Authors: Lawrence Yaacov , Porper Keren , Shpatz Yael , Amit Uri , Symon Zvi , Zach Leor 
Published: April 2021

Abstract
Background Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that metabolic stress (moderate hypoglycemia) would enhance the anti-tumor efficacy of concurrent DNA damage. We further hypothesized that concurrent metformin would decrease insulin resistance and consequently elevate ketone blood level. We performed a formal prospective phase I dose-escalation trial to assess the tolerability and feasibility of this approach. Methods A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin (850mg twice-daily) combined with dietary intervention and 3) high-dose metformin (850mg three-times daily) combined with dietary intervention. Statistics: The prediction of blood ketones levels was performed using a mixed-model univariate analysis methodology. Clinicaltrials.gov NCT02149459. Results A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4/5 adverse events. Median levels of β-hydroxybutyrate increased from 0.09 mmol/l at baseline to 0.59 mmol/l during the trial (p=0.006). Ketone levels were associated with dietary factors (ketogenic ratio, p &lt; 0.001), use of metformin (p = 0.02) and low insulin levels (p = 0.002). Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease. Conclusions The intervention was fairly well tolerated. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a KD combined with 850mg metformin twice daily. The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795, and the Rosetrees Trust. The MCT oil was provided by Nutricia, Netherlands.
Citation Format: Yaacov Lawrence, Keren Porper, Yael Shpatz, Uri Amit, Zvi Symon, Leor Zach. A phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-004.
Abstract PO-008: Mechanistic and therapeutic links between purine biosynthesis and DNA damage in glioblastoma
Authors: Scott Andrew J. , Zhou Weihua , Wilder-Romans Kari , Andren Anthony C. , Zhang Li , Umemura Yoshie , Qi Nathan , Lawrence Theodore S. , Lyssiotis Costas A. , Wahl Daniel R 
Published: April 2021

Abstract
Glioblastoma (GBM) is the most common and aggressive adult brain cancer. Radiation therapy (RT) is a critical treatment modality, and development of RT resistance is the predominant cause of recurrence and mortality in GBM patients. Using cell line models as well as patient-derived xenografts and neurospheres in orthotopic brain tumor models, we have identified increased rates and dependence upon de novo purine biosynthesis as a hallmark of GBM RT resistance. More recently, we have discovered that radiation treatment acutely stimulates flux through de novo purine synthesis in cell line and neurosphere models of GBM. This RT-induced increase in de novo purine synthesis is dependent on signaling through the DNA damage response and thus appears to be an adaptive mechanism to supply purines to repair radiation-induced DNA damage. To determine whether this regulatory mechanism also exists in vivo, we have used advanced metabolomic and metabolic tracing techniques with 13C-labeled glucose and 15N-labeled glutamine in mice bearing RT-resistant GBM patient-derived orthotopic brain tumors. We found that that orthotopic GBM PDXs had elevated activity of de novo purine synthesis that increased further after RT, while normal cortex had little activity even after RT. These observations have therapeutic relevance, as targeting this metabolic pathway with the FDA-approved purine biosynthesis inhibitor mycophenolate mofetil (MMF) overcomes GBM radiation resistance in mouse models in vivo. The lack of de novo purine synthesis in normal cortex suggests that targeting this pathway may be tumor specific. Collectively our data suggest that de novo synthesis of purines mediates RT resistance in GBM and that treatment of brain tumors with MMF in combination with RT may be a promising therapeutic strategy in patients.
Citation Format: Andrew J. Scott, Weihua Zhou, Kari Wilder-Romans, Anthony C. Andren, Li Zhang, Yoshie Umemura, Nathan Qi, Theodore S. Lawrence, Costas A. Lyssiotis, Daniel R Wahl. Mechanistic and therapeutic links between purine biosynthesis and DNA damage in glioblastoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-008.