bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 684: Effects of preventive interventions on radiotherapy-induced skin toxicity in women with breast cancer: A systematic review and meta-analysis of randomized controlled trials
Authors: Figueroa Claudia R. , Gelin Rose N. , Khourshid Sereen J. , Lee Eunkyung
Published: July 2021

Radiation therapy (RT)-induced skin toxicity occurs in 95% of patients undergoing RT for breast cancer. Severe cases can interrupt the original treatment regimen and affect many individuals' overall treatment efficacy and quality of life. Many interventions have been tested for the prevention of RT-induced skin toxicity; however, there are no standard recommendations yet determined. This meta-analysis aimed to evaluate the effect of different preventive interventions for RT-induced skin toxicity among breast cancer patients. We searched PubMed, Web of Science, CINAHL, and PsycINFO databases for randomized controlled trials (RCTs) meeting the inclusion criteria and published until December 2019 following the PRISMA reporting guidelines and the PICO statements. The intervention's effect on the incidence of grade ≥2 acute skin toxicity, moist desquamation, and severity score was estimated using the random-effects meta-analyses. Among 6885 publications identified, 38 studies were included in analyses. A total of 3,380 women age 42-88 years diagnosed with stage 0-III who were undergoing RT for breast cancer from all over the world were included. Identified preventive interventions included non-steroid topical agents, topical steroid agents, oral supplements, laser therapy, and films. The meta-analyses showed that interventions significantly reduced the mean severity score by 0.64 (standardized mean difference=-0.64, 95% CI=-0.85, -0.43; I2=57.6%), the incidence of grade ≥2 skin toxicity by 18% (Risk ratio [RR]=0.82, 95% CI=0.74, 0.90; I2=68.4%), and moist desquamation by 55% (RR=0.45, 95% CI=0.27-0.77, I2=48.2%). Subgroup analyses showed that oral supplements were most promising in preventing grade ≥2 skin toxicity (RR=0.32, 95% CI=0.07-1.34, I2=83.1%), suggesting further replications are needed before definitive conclusions are made. This analysis provided evidence of the effectiveness of interventions on the prevention of RT-induced skin toxicity. The effect was greater in reducing the incidence of more severe cases of moist desquamation. More replicative studies are needed to establish the standard preventive care of RT-induced skin toxicity for women with breast cancer, which can help patients comply with RT regimens and improve patients' quality of life.

Citation Format: Claudia R. Figueroa, Rose N. Gelin, Sereen J. Khourshid, Eunkyung Lee. Effects of preventive interventions on radiotherapy-induced skin toxicity in women with breast cancer: A systematic review and meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 684.
Abstract 688: Anti-CNTN4 antibody, GENA-104A07 suppresses tumor growth in murine syngeneic tumor models by regulating T cell function
Authors: Cha Mi Young , Houh Youn Kyung , Kim Yun Yeon , Kim Hyunuk , Chung Joo-Yeon , Park Kyung Mi , Park Hansoo
Published: July 2021

Vast improvements in tumor treatment have been achieved with immune checkpoint inhibitors. They have been approved for use in monotherapy or combinations for patients with different types of cancer. However, the treatments often yield limited benefits and strong responses are observed only in a minority of treated patients. For this reason, enormous efforts have been made to explore primary or acquired resistance mechanisms to improve the available current therapies. CNTN4 (contactin 4, alias BIG-2) is a neuronal cell adhesion molecule, which is mainly expressed in the human brain and functions in axonal growth and guidance. Some genetic evidence has indicated that CNTN4 may be associated with non-neurological disorders such as cancer and cardiovascular conditions as well as neurodevelopmental disorders. Recently we identified CNTN4 as a novel immunomodulatory protein, which is expressed on tumors. In this study, we investigate the potential of CNTN4 as a cancer immunotherapeutic target, using GENA-104A07 to target it. GENA-104A07 is a humanized IgG4 monoclonal antibody that specifically binds to human and mouse CNTN4 with sub-nanomolar binding affinity by ELISA assay, not to any other related proteins having similar sequences. This molecule competitively interferes with the binding of CNTN4 and its receptor protein. The in vitro functional effect showed that the treatment of GENA-104A07 alleviates the immune suppressive effect induced by CNTN4 on T cells. Consequently, the administration of GENA-104A07 induces significant suppression of the tumor growth as monotherapy in syngeneic mouse models with a high expression level of CNTN4. GENA-104A07 treatment increases the expression of activation markers and pro-inflammatory cytokines on T cells. Taken together with in vitro and in vivo studies, the efficacy of GENA-104A07 demonstrated that CNTN4 blockage with monoclonal antibody may provide an immunotherapeutic strategy for human cancer. Currently, the preliminary safety study is ongoing in mice, and IND enabling studies will be initiated early next year with the optimized antibody.

Citation Format: Mi Young Cha, Youn Kyung Houh, Yun Yeon Kim, Hyunuk Kim, Joo-Yeon Chung, Kyung Mi Park, Hansoo Park. Anti-CNTN4 antibody, GENA-104A07 suppresses tumor growth in murine syngeneic tumor models by regulating T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 688.
Abstract 711: Repurposing 2nd generation androgen receptor antagonist Proxalutamide to treat COVID-19
Authors: Ma Liandong , Tong Youzhi , Guo Qiang , Zhou Yifeng , Zhou Qianxiang , Yan Honghua
Published: July 2021

To date, as of 17 November 2020, there have been 55 million confirmed cases of COVID-19, including 1,4 million deaths globally, as reported to WHO. It is, therefore, very critical to discovery and development of the available treatment options for COVID-19. We here discuss the repurposing 2nd generation androgen receptor antagonist Proxalutaminde to treat COVID19. We analyzed the gender disparity of disease severity and progression in 1339 patients with COVID-19 and investigated the mechanism of gender disparity in male vs female patients with COVID 19. As androgen-androgen receptor pathway may contribute to the difference in severity and disease progression in male and female patients with COVID-19, we used cell lines derived from lung, prostate cancer and normal lung epithelial cells to determine the effect of androgen and androgen receptor antagonist Proxalutamide on the expression of two key proteins for SARS-CoV-2 to infect and enter the host cells. Angiotensin converting enzyme 2 (ACE2), a host transmembrane protein provides the binding sites for SARS-CoV-2 on the host cell surface, transmembrane protease serine 2 (TMPRSS2), a cellular serine protease, prims the S protein of SARS-Cov-2 to facilitate the viral entry into the host cells. As cytokine store plays a major role in the disease progression of COVID-19, we examined the effect of GT0918 on inducible nitric oxide synthase (iNOS) and Tumor necrosis factor-alpha (TNF-α), the macrophage polarization/activation markers, in mouse macrophage cells. In this study, we demonstrated higher rates of disease progression and mortality of male COVID-19 patients than female patients. Furthermore, we revealed that androgen-AR activation induced the expression of ACE2 and TMPRSS2 under the androgen-dependent condition in cells derived from prostate and lung cancer, which was inhibited by the blockage of AR signaling with Proxalutamide. Importantly, Proxalutamide also inhibited the expression of iNOS and TNF-α, the biomarkers for macrophage polarization/activation. These results support the role of androgen-AR signaling in the disease progression and mortality in male patients with COVID-19. We are currently conducting clinical study in COVID-19 patients with Proxalutamide in Brazil (NCT04446429).

Citation Format: Liandong Ma, Youzhi Tong, Qiang Guo, Yifeng Zhou, Qianxiang Zhou, Honghua Yan. Repurposing 2nd generation androgen receptor antagonist Proxalutamide to treat COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 711.
Abstract 760: Analysis of ERG and SPOP subtypes in prostate cancer in the Colombian population and their possible implications on prognosis
Authors: Ovalle Wendy Montero , Moreno Yenifer Segura , Sanabria-Salas María Carolina , de Mesa Jorge Mesa López , Ramírez Rodolfo Varela , Boada Vilma Medina , López Martha Lucía Serrano
Published: July 2021

Prostate cancer (PCa) is the type of cancer with the highest incidence and mortality in our country. Current disease prognostic factors do not differentiate aggressive from indolent cases with sufficient certainty and for this reason, it has worked on a characterization of molecular subtypes that allows for a better classification. In localized PCa, fusions between the gene regulated by androgens TMPRSS2 and ERG, or mutations in SPOP (speckle type POZ, the gene that codes for an adapter protein of the Cullin-3-RING-Box1 complex) have been detected in different populations, which has been related to prognosis; however, we do not know the relevance of these molecular alterations in affected Colombians. These two alterations are described within the 7 subtypes reported by the TCGA and are considered mutually exclusive.

Objective: Evaluate the presence of ERG and SPOP subtypes in prostate cancer in the Colombian population and correlate these findings with clinicopathological parameters.

Methodology: For this study, FFPE radical prostatectomy samples from 112 patients with PCa were used, where the TMPRSS2-ERG fusions were studied by FISH, and in negative cases for fusion, mutations in exons 6 and 7 of SPOP were evaluated by sanger sequencing.

Results: Fusion was detected in 71 patients (63.4%), this frequency of the ERG subtype was similar to that observed in the Caucasian population (40-60%). No statistically significant differences were found between the fusion state and the clinicopathological variables analyzed such as age, initial PSA, Gleason score, Gleason grade group, clinical and pathological tumor stage, lymph node involvement, biochemical recurrence-free survival, and overall survival. In the 41 (36.6%) cases negative for fusion, only one mutation (F133L) was detected in exon 7, which has previously been reported in 34 cases.

Conclusions: The frequency of fusion of the ERG subtype detected in our population was 63.4%, no associations were found between the fusion state and the prognosis of the disease. Until now, 1 case has been detected a mutation of exon 7 of SPOP (2.4%). The low frequency of this subtype in Colombians could be explained by the reported variability in the frequency of these mutations according to the population (5% -20%).

Citation Format: Wendy Montero Ovalle, Yenifer Segura Moreno, María Carolina Sanabria-Salas, Jorge Mesa López de Mesa, Rodolfo Varela Ramírez, Vilma Medina Boada, Martha Lucía Serrano López. Analysis of ERG and SPOP subtypes in prostate cancer in the Colombian population and their possible implications on prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 760.
Abstract 772: A novel recurrence-associated metabolic prognostic model for risk stratification and therapeutic responses prediction in patients with stage I lung adenocarcinoma
Authors: Liu Chengming , Sun Nan , He Jie
Published: July 2021

Background: The proportion of patients with stage I lung adenocarcinoma (LUAD) has dramatically increased with the prevalence of low-dose computed tomography use for screening. Up to 30% of patients with stage I LUAD experience recurrence within 5 years after curative surgery. A robust risk stratification tool is urgently needed to predict the patients who might benefit from adjuvant treatment.

Methods: In this first investigation of the relationship between metabolic reprogramming and recurrence in stage I LUAD, we developed a recurrence-associated metabolic signature (RAMS). This RAMS was based on metabolism-associated genes to predict cancer relapse and overall prognosis of patients with stage I LUAD. The clinical significance and immune landscapes of the signature were comprehensively analyzed.

Results: Based on a gene expression profile from the GSE31210 database, functional enrichment analysis revealed a significant difference in metabolic reprogramming that distinguished patients with stage I LUAD with relapse from those without relapse. We then identified a metabolic signature (i.e., RAMS) represented by two genes (ACADM and RPS8) significantly related to recurrence-free survival and overall survival times of patients with stage I LUAD using transcriptome data analysis of a training set. The training set was well-validated in a test set. The discriminatory power of the two-gene metabolic signature was further validated using protein values in an additional independent cohort. The results indicated a clear association between a high-risk score and a very poor patient prognosis. Stratification analysis and multivariate Cox regression analysis revealed that the RAMS was an independent prognostic factor. We also found that risk score was positively correlated with inflammatory response, the antigen-presenting process, and the expression levels of many immunosuppressive checkpoint molecules (e.g., PD-L1, PD-L2, B7-H3, galectin-9, and FGL-1). These results suggested that high-risk patients had immune response suppression. Further analysis revealed that anti-PD-1/PD-L1 immunotherapy did not have significant benefits for high-risk patients. However, they could respond better to chemotherapy.

Conclusion: This study was the first to highlight the relationship between metabolic reprogramming and recurrence in stage I LUAD and develop a clinically feasible signature. This signature may be a powerful prognostic tool and help further optimize the cancer therapy paradigm.

Citation Format: Chengming Liu, Nan Sun, Jie He. A novel recurrence-associated metabolic prognostic model for risk stratification and therapeutic responses prediction in patients with stage I lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 772.
Abstract 788: Differences in somatic TP53 mutation type in breast tumors by race and receptor status
Authors: Pollock Nijole , Ramroop Johnny , McElroy Joseph , Toland Amanda E.
Published: July 2021

Somatic driver mutations in TP53 are associated with triple negative breast cancer (TNBC) and poorer outcomes. African American women with breast cancer are more likely to have TNBC and TP53 driver mutations. Missense driver mutations in TP53 can be loss-of function (LOF) or gain-of-function (GOF). Additionally, some variants show dominant negative (DNE) activity. There are a number of hot-spot TP53 mutations, many occurring at CpG sites. Given the differences in TNBC status and TP53 driver mutation frequency by race, we wanted to determine if there are differences in TP53 mutation type by race. From multiple databases and a literature review, we identified 98 studies with patient race and TP53 mutation details. We compiled TP53 mutations from 2964 breast tumors from these 98 studies. The cohort included 715 (24.1%) Asian, 258 (8.7%) African (AA), and 1931 (65.1%) European (EA) ancestry individuals. Additionally, 60 patients (2%) had Hispanic or Latina ethnicity. Of the somatic TP53 mutations, 939 (31.7%) were GOF, 1739 (58.7%) were LOF, while the remaining 286 (9.6%) were not able to be classified by existing literature. With respect to DNE activity, 1246 (42%) showed DNE, 1190 (40.1%) showed no DNE, and 528 (17.8%) were unknown DNE status. CpG hotspots accounted for 613 (20.6%) mutations. Using Fisher's Exact test, we did not identify significant associations between any of the functional categories and overall race. However, 35.8% of tumors from EA individuals had GOF mutations compared to 29% in AA individuals (p=0.04). Mutations with DNE activity were positively associated with TNBC (OR=1.37, p=0.03) and negative estrogen receptor (ER) status (OR=1.38; p=0.005). Patients with hotspot mutations were slightly younger (mean age 53.61) compared to those with non-hotspot mutations (mean age 55.04), and this association neared significance (p=0.065). Larger cohorts are needed, in particular the AA cohort, to further elucidate some of these borderline findings. In summary, ER negative and TNBC breast tumors are more likely to have DNE TP53 mutations which could reflect biological processes.

Citation Format: Nijole Pollock, Johnny Ramroop, Joseph McElroy, Amanda E. Toland. Differences in somatic TP53 mutation type in breast tumors by race and receptor status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 788.
Abstract 797: Cancers of unknown primary: A descriptive study in the U.S. military health system
Authors: Bytnar Julie A. , Lin Jie , Moncur Joel T. , Shriver Craig D. , Zhu Kangmin
Published: July 2021

Background: Cancers of unknown primary (CUP) are defined as histologically confirmed metastatic cancers that do not have an identified primary site of origin despite an appropriate diagnostic work-up. It is known that accessibility to and quality of medical care are associated with cancer diagnosis. This study aimed to describe the demographic, histologic, and temporal trend characteristics of CUP patients in the Military Health System (MHS), which provides universal healthcare access.

Methods: The data were obtained from the Department of Defense (DoD)'s Automated Tumor Registry (ACTUR) which collects cancer data from beneficiaries who were diagnosed or received treatment in the (MHS). We described the demographic and histologic distributions in CUP patients aged 18 or older diagnosed from 1987-2013. We calculated the proportion of CUP patients among all metastatic cancers and the most common histologic categories of those tumors. We then evaluated whether the proportion of histologic types changed over time.

Results: CUP comprised 15.1% of all metastatic cancers in ACTUR during the study period. The majority of CUP within ACTUR was well and moderately differentiated adenocarcinoma (51.3%) and poorly differentiated carcinomas (23.2%) followed by squamous cell carcinomas (12.5%). The percentages of CUP among metastasized cancers of the same histologic category ranged 12-15% for well and moderately differentiated adenocarcinomas, squamous cell, and poorly differentiated carcinomas, and 41-46% for malignant neuroendocrine carcinomas and undifferentiated neoplasms. However, the percentages varied by sex, race, and age for certain pathologies. The proportion of CUP patients among all metastatic cancer patients has steadily declined from 22.4% to 8.3% from 1987 to 2013.

Conclusion: The proportion and trends of CUP in the MHS were generally consistent with other descriptive CUP studies. This study provides a description of CUP in a healthcare system with universal access and provides a foundation for future studies on CUP.

Citation Format: Julie A. Bytnar, Jie Lin, Joel T. Moncur, Craig D. Shriver, Kangmin Zhu. Cancers of unknown primary: A descriptive study in the U.S. military health system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 797.
Abstract 813: Clinical significance of pathogenic variants in germline BRCA1/2 wild type patients at risk for hereditary breast cancer
Authors: Kuang Xiaying , Shao Nan , Lin Ying
Published: July 2021

Objectives: Approximately, 5-10% of breast cancer (BC) are related to inherited germline mutations. Homologous recombination repair (HRR) of DNA is the most important theory in hereditary cancer, in which BRCA1/2 are the most recognized and tested genes. Genetic testing for hereditary BC has changed significantly. Increasing evidence suggests parallel multigene testing of HRR gene.

Methods: NGS-based germline multigene-panel testing of 105 HRR gene was performed on 159 high risk BC patients with at least one of the following risk factors: triple negative BC, early onset (≤45y), family history of BC and bilateral BC. Capture-base targeted sequencing was performed on white blood cells using a panel consisting of 105 genes related to homologous recombination repair of DNA.

Results: Among the 159 patients of median age 40, All the patients had early stage infiltrating ductal carcinoma. 12 patients (7.55%) had pathogenic BRCA1/2 mutation. We investigated the prevalence of 21 pathogenic germline pathogenic mutations beyond BRCA1/2 from 21 patients spanning 13 HRR genes, resulting in a prevalence rate of 13.21% for pathogenic germline mutations in high risk germline BRCA1/2 WT BC patients. PALB2 is the most common gene with pathogenic mutation (n=5). In these 21 patients, 18 (85.71%) were diagnosed with BC before the age of 45, within 7 patients (33.33%) even younger than 35 years old. 7 of them (33.33%) had bilateral BC; one had triple negative BC (4.76%) and 5 patient (23.81%) had a family history of BC. Nearly half of the patients (n=9) presented at least 2 of the risk factors.

Conclusions: Our study confirms the clinical significance of testing non-BRCA genes, and suggests multigene panel testing for patients at risk for hereditary BC as a routine in patients with those risk factors, especially young and bilateral BC patients even without family history of BC.

Citation Format: Xiaying Kuang, Nan Shao, Ying Lin. Clinical significance of pathogenic variants in germline BRCA1/2 wild type patients at risk for hereditary breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 813.
Abstract 840: Gallstones and risk of cancers of the liver, biliary tract, and pancreas: A prospective study within two U.S. cohorts
Authors: Luo Xiao , yang wanshui , Joshi Amit , Wu Kana , Simon Tracey , Yuan Chen , Jin Lina , Long Lu , Kim Mi Na , Lo Chun-Han , Liu Xing , Abrams Thomas A. , Wolpin Brian M. , Chan Andrew T. , Giovannucci Edward L. , Zhang Xuehong
Published: July 2021

Background: As one of the most common gastrointestinal diseases, gallstones may result in inflammation,altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. Previous studiesfor gallstones and cancers of the liver, biliary tract, and pancreas from the different data sources, inadequateconfounding adjustment, and whether the association varied by potential risk factors is unclear.

Objective: We examined the association of gallstones and cholecystectomy with the risk of cancers of theliver, biliary tract, and pancreas in the United States.

Methods: We followed 115 036 women from the Nurses' Health Study (1982-2012) and 49 729 men fromthe Health Professionals Follow-up Study (1986-2012). History of gallstones, including with or withoutperformed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Coxproportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95%confidence intervals (95%CIs).

Results: During up to 30-year follow-up, we identified 204 incident liver cancer, 225 biliary tract cancer, and1 147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs forindividuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95%CI: 1.14-2.26),4.79 for biliary tract cancer (95%CI: 3.02-7.58), and 1.13 for pancreatic cancer (95%CI: 0.96-1.32). Themultivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95%CI: 0.90-1.95) and1.15 for pancreatic cancer (95%CI: 0.98-1.36).

Conclusions: Gallstones were associated with a higher risk of cancers of the liver, biliary tract, and possiblypancreas. Cholecystectomy was associated with a suggestive increased risk of liver and pancreatic cancer.Our findings provide further evidence for a positive association of gallstones with the risk of cancers in thehepato-pancreato-biliary area.

Citation Format: Xiao Luo, wanshui yang, Amit Joshi, Kana Wu, Tracey Simon, Chen Yuan, Lina Jin, Lu Long, Mi Na Kim, Chun-Han Lo, Xing Liu, Thomas A. Abrams, Brian M. Wolpin, Andrew T. Chan, Edward L. Giovannucci, Xuehong Zhang. Gallstones and risk of cancers of the liver, biliary tract, and pancreas: A prospective study within two U.S. cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 840.
Abstract 843: Coffee consumption and risk of renal cell carcinoma: A meta-analysis of cohort evidence
Authors: Rhee Jongeun , Lim Rachel , Purdue Mark P.
Published: July 2021

Background: Coffee consumption has been associated with a reduced risk of some cancers, although for renal cell carcinoma (RCC) the evidence is inconclusive. Several cohort analyses investigating coffee intake and RCC have been conducted, although most have been limited by small case numbers. To summarize the cohort evidence of this relationship, we conducted a meta-analysis.

Methods: A literature search was performed in PubMed, Embase and The Cochrane Library for all studies published up to May 2020 using the key words “cancer”, “tumor”, “carcinoma”, “malignant neoplasm”, “renal cell carcinoma”, “kidney cancer”, “renal cancer” “coffee”, “caffeine” and “beverages”. Additionally, the reference lists of all retrieved articles and previous meta-analysis studies were checked to identify additional studies. From our collection of full-text articles (n=7219) we excluded irrelevant topic articles (n=7125), non-English articles (n=2), systematic reviews or editorial letter (n=46), relevant articles not reporting measure of association (n=9), case-control studies (n=27). Following these exclusions, 10 cohort studies remained. Meta-analyses using a random effects model were conducted for relative risks (RRs) contrasting the highest vs lowest level of coffee intake per day. In addition, meta-analyses were conducted for reported sex-specific findings as well as findings restricted to non-smokers. Between-study heterogeneity was assessed using Cochran Q-statistic and quantified by Higgins I2 statistic.

Results: In a meta-analysis of the 10 identified studies, we found a summary RR of 0.88 (95% CI 0.78-0.99) relating the highest study category of coffee intake (vs. the lowest category or non-drinkers) and renal cancer risk, with no significant between-study heterogeneity observed (I2=35%, p = 0.13). The summary RR was comparable for men and women (0.89 and 0.85 respectively). A slightly stronger inverse association was observed among non-smokers (RR 0.78, 95% CI 0.59-1.03), although with moderate evidence of study heterogeneity (I2=62%, p = 0.07).

Conclusions: In this meta-analysis of cohort evidence, we observed overall evidence suggestive of a weak inverse association between higher coffee consumption and lower renal cancer risk.

Citation Format: Jongeun Rhee, Rachel Lim, Mark P. Purdue. Coffee consumption and risk of renal cell carcinoma: A meta-analysis of cohort evidence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 843.
Abstract 85: Metastasizing melanoma cells exhibit increased dependence on the pentose phosphate pathway to manage oxidative stress
Authors: Aurora Arin B. , Khivansara VIshal , Leach Ashley , Martin-Sandoval Misty , Mathews Thomas , Morrison Sean J.
Published: July 2021

To study distant metastasis we developed a patient-derived xenograft (PDX) assay in which melanoma cells from patients spontaneously metastasize in NOD/SCID IL2Rγnull (NSG) mice in a manner that correlates with metastatic behavior in patients (Sci Transl Med 4:159). Using this assay, we discovered that distant melanoma metastasis is limited by oxidative stress (Nature 527:186). Reactive Oxygen Species (ROS) increase dramatically in melanoma cells as they metastasize through the blood. The rare cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We found that metastatic melanomas had significant increases in metabolites from the pentose phosphate pathway as compared to primary cutaneous melanomas. Metabolites in the oxidative branch of the pentose phosphate pathway, downstream of the NADPH-regenerating enzyme Glucose-6-Phosphate Dehydrogenase (G6PD), were the most dramatically increased in metastatic nodules. We hypothesized that metastasizing melanoma cells increase their dependence on the pentose phosphate pathway in order to manage oxidative stress. We used CRISPR gene editing to create loss-of-function mutations in G6PD in patient-derived melanomas. When transplanted into NSG mice, the tumors formed by G6PD mutant melanomas showed significantly reduced oxidative pentose phosphate pathway activity, increased ROS levels, decreased NADPH/NADP ratios, and reduced metastatic potential as compared to parental control melanomas. Our results demonstrate that metastasizing melanoma cells exhibit increased dependence upon the pentose phosphate pathway as compared to primary cutaneous tumors. Untargeted metabolomics revealed that G6PD mutant melanomas exhibit increased glutamine utilization, perhaps to compensate for increased oxidative stress.

Citation Format: Arin B. Aurora, VIshal Khivansara, Ashley Leach, Misty Martin-Sandoval, Thomas Mathews, Sean J. Morrison. Metastasizing melanoma cells exhibit increased dependence on the pentose phosphate pathway to manage oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 85.
Abstract 93: Single cell transcriptome analysis maps dynamic epithelial mesenchymal transition and immunological remodeling in thyroid cancer progression
Authors: Chen Xi , Wang Jennifer Rui , Henderson Ying , Yan Yuanqing , Bai Shanshan , Kieser Rachel , Hu Min , Wang Jiping , Navin Nicholas , Lai Stephen , Gao Ruli
Published: July 2021

Anaplastic thyroid cancer (ATC) is arguably the most lethal human malignancy, with a median survival of ~12 weeks. About half of ATC tumors arise from within differentiated forms of thyroid cancer types, most commonly papillary thyroid cancer (PTC), suggesting an evolutionary continuum from PTC to ATC. In contrast to the extreme lethality of ATC, PTC are typically indolent with long life-histories. The molecular mechanisms driving ATC progression from PTC have been challenging to resolve, mostly due to the heterogenous cellular populations that are undergoing dynamic changes during ATC progression. In this study, we applied high throughput 3'-scRNAseq in an unbiased analysis of cell populations in thyroid tumors. We analyzed 90,990 single cell transcriptomes from 8 ATC tumors, 8 PTC tumors and 5 normal thyroids. To make the precise inference of tumor cell lineages, we stratified the epithelial cells into 5 categories by calculating genotypes from scRNAseq data that include: (1) normal epithelial cells in normal thyroids, (2) PTC epithelial cells in PTC tumors, (3) PTC tumor cells in PTC tumors, (4) ATC epithelial cells in ATC tumors, (5) ATC tumor cells in ATC tumors. We then constructed the full epithelial cell development trajectories from normal epithelial to PTC and ATC tumor cells. Our results show that co-existing epithelial and mesenchymal phenotypes is a major characteristic of ATC tumor cells and epithelial-mesenchymal transition (EMT) drives ATC developmental trajectory. We further analyzed the transcriptional programs of immune cell types and their interactions with tumor cells. Our data suggested a unique sub-population of helper T cell and a distinct B cell subtype arise in the tumor microenvironment in response to ATC progression. Collectively, our results identify EMT as the major driving force of thyroid cancer aggressiveness and provide novel insights regarding the immunological remodeling in response to ATC progression.

Citation Format: Xi Chen, Jennifer Rui Wang, Ying Henderson, Yuanqing Yan, Shanshan Bai, Rachel Kieser, Min Hu, Jiping Wang, Nicholas Navin, Stephen Lai, Ruli Gao. Single cell transcriptome analysis maps dynamic epithelial mesenchymal transition and immunological remodeling in thyroid cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 93.
Abstract 934: Identification of a GPC3 specific RNA aptamer and its use in cell specific targeted killing of GPC3 expressing tumors
Authors: Thompson Kristin M. , McGuire Christina , Yuan Jin , Ball Aaron , Sonberg Justin , Wang Yuxun , Zhu Shuhao
Published: July 2021

Aptamers are short oligonucleotides that recognize specific molecular targets due to their folded three-dimensional structures. Aptamers are generated against a target molecule using a process called SELEX. This method allows the in vitro evolution of nucleic acid molecules with highly specific binding to target molecules. Here we describe a nuclease stable, fully modified 2'OMethyl aptamer that recognizes Glypican-3 (GPC3) with high affinity and specificity. GPC3 is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of liver cancers, but not in healthy adult tissues. A conjugate comprising a GPC3 aptamer and Drug Maytansinoid (DM1), a membrane-permeable inhibitor of tubulin which can prevent cell division, is used to specifically target GPC3 expressing cells in vitro and in vivo. The aptamer-drug conjugate (GRX54) is capable of selectively killing a variety of GPC3 expressing liver cells in vitro and has significantly less toxicity in cells not expressing GPC3. The anti-tumor effect of GRX54 was tested in several tumor xenograft mouse models: Hep3B xenograft, Balb/c nude mice and NCI-H446 xenograft, Balb/c nude mice. GRX54 was administered at different doses via intraperitoneal injection (IP). For each group, mice were administered with vehicle or GRX54 once a day (QD) for 3, 5 or 7 days. Tumor weight and growth were measured. An anti-cancer drug Sorafenib Tosylate (30mg/kg, oral administration, once a day - Hep3B xenograft mouse model) or irinotecan (40mg/kg, i.p. twice a day for 4 days - NCI-H446 xenograft mouse model) were used as positive controls. GRX54 decreases Hep3B tumor volume in a Balb/c nude mouse xenograft model by ~30-45% depending on treatment schedule and NCI-H446 tumor volume by ~45-90% depending on treatment schedule. Together, our data show that GRX54 is a novel GPC3-targeting molecule capable of reducing tumor size with IP injection.

Citation Format: Kristin M. Thompson, Christina McGuire, Jin Yuan, Aaron Ball, Justin Sonberg, Yuxun Wang, Shuhao Zhu. Identification of a GPC3 specific RNA aptamer and its use in cell specific targeted killing of GPC3 expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 934.
Abstract 942: ErbB3 overexpression unleashed by miR-205 epigenetic silencing is a therapeutic target in glioblastoma
Authors: De Bacco Francesca , Orzan Francesca , Erriquez Jessica , Casanova Elena , Barault Ludovic , Albano Raffaella , D'Ambrosio Antonio , Bigatto Viola , Reato Gigliola , Patané Monica , Pollo Bianca , Kuesters Geoffrey , Dell'Aglio Carmine , Casorzo Laura , Pellegatta Serena , Finocchiaro Gaetano , Comoglio Paolo M. , Boccaccio Carla
Published: July 2021

In glioblastoma (GBM), the most frequent and lethal brain tumor, targeted therapies suppressing commonly altered signaling pathways has remained so far disappointing. However, in selected patient subsets, specific genetic alterations can confer sensitivity to targeted agents. In this study, by generating an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, we identified a human GBM subset (around 9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. This was driven by inheritable epigenetic or post-transcriptional silencing of the oncosuppressor miR-205 and sustained the malignant phenotype. Unexpectedly, ERBB3, known to be devoid of autonomous signaling properties, was overexpressed in the absence of the other members of the EGFR family, but behaved as a specific signaling platform for FGFRs. ERBB3/FGFR dimerization led to hyperactivation of the PI3K/AKT/mTOR pathway and consequent upregulation of glycolysis, oxidative metabolism and de novo fatty acid biosynthesis. Treatment with a specific antibody (MM121) preventing ERBB3 association with FGFR caused metabolic shutdown and consequent proliferative arrest and apoptosis induction in vitro. Moreover, experimental tumors regenerated through ERBB3 overexpressing stem-like cell transplantation reproduced the features of the original GBMs and, upon treatment with the anti-ERBB3 antibody, significantly regressed. These findings identify a subset of GBM patients where exploitation of an ERBB3-targeted therapy could be effective.

Citation Format: Francesca De Bacco, Francesca Orzan, Jessica Erriquez, Elena Casanova, Ludovic Barault, Raffaella Albano, Antonio D'Ambrosio, Viola Bigatto, Gigliola Reato, Monica Patané, Bianca Pollo, Geoffrey Kuesters, Carmine Dell'Aglio, Laura Casorzo, Serena Pellegatta, Gaetano Finocchiaro, Paolo M. Comoglio, Carla Boccaccio. ErbB3 overexpression unleashed by miR-205 epigenetic silencing is a therapeutic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 942.
Abstract 947: Effects of methadone on ovarian cancer cell-lines and patient-derived tumor-spheroids
Authors: Fiegl Heidelinde , Hagenbuchner Judith , Ausserlechner Michael J. , Kyvelidou Christiana , Seeber Beata , Sopper Sieghart , Tsibulak Irina , Wieser Verena , Roessler Julia , Reiser Elisabeth , Huhtinen Kaisa , Carpén Olli , Parson Walther , Marth Christian , Zeimet Alain G.
Published: July 2021

Background: D,L-Methadone exerts analgesic effects via the mu opioid receptor, encoded by OPRM1 and therefore plays a role in chronic pain management. Although the use of this opioid-receptor agonist as an anti-cancer drug is deemed controversial, this drug is gaining popularity in Europe as an “off-label” therapy despite insufficient research to support its benefits. In preclinical glioblastoma and leukaemia cell culture models D,L-methadone showed apoptotic and chemo-sensitizing effects. Its effects in ovarian cancer (OC) are completely unexplored.

Methods: We analysed the OPRM mRNA expression in six cisplatin-sensitive, two cisplatin-resistant OC cell-lines, 192 OC samples and 12 non-neoplastic control tissues. Pro-angiogenetic, cytotoxic and apoptotic effects of D,L-methadone were evaluated in OC cell-lines and four patient-derived tumor-spheroid models.

Results: OPRM1 was transcriptionally expressed in 69% of OC-tissues and in five of eight OC cell-lines. D,L-methadone exposure significantly reduced cell-viability in five OC cell-lines irrespective of OPRM1 expression. D,L-methadone, applied alone or combined with cisplatin, showed no significant effects on apoptosis or VEGF secretion in cell-lines. Notably, in two of the four spheroid models, treatment with D,L-methadone resulted in significantly enhanced cell growth (by up to 121%), especially after long-term exposure. This is consistent with the observed attenuation of the inhibitory effects of cisplatin in three spheroid models when adding D,L-methadone. The effect of methadone treatment on VEGF secretion in tumor-spheroids was inconclusive.

Conclusions: Our study demonstrates that certain OC samples express OPRM1, which, however, is not a prerequisite for D,L-methadone function. As such, D,L-methadone may exert detrimental effects by stimulating the growth of certain OC-cells and abrogating cisplatin's therapeutic effect.

Citation Format: Heidelinde Fiegl, Judith Hagenbuchner, Michael J. Ausserlechner, Christiana Kyvelidou, Beata Seeber, Sieghart Sopper, Irina Tsibulak, Verena Wieser, Julia Roessler, Elisabeth Reiser, Kaisa Huhtinen, Olli Carpén, Walther Parson, Christian Marth, Alain G. Zeimet. Effects of methadone on ovarian cancer cell-lines and patient-derived tumor-spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 947.
Abstract 954: AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma
Authors: Capoccia Benjamin J. , Donio Michael J. , Richards John O. , Hiebsch Ronald R. , Puro Robyn J. , Kashyap Arun K. , Pereira Daniel S.
Published: July 2021

Overexpression of CD47 by tumor cells exploits an immune checkpoint that prevents tumor recognition and destruction by innate immune cells. Binding of tumor CD47 to SIRPα on macrophages and dendritic cells triggers a “don't eat me” signal that inhibits phagocytosis enabling escape from innate immune surveillance. Blockade of the CD47/SIRPα axis enables immune recognition and phagocytic clearance of tumor cells. We have developed a clinical stage CD47 targeting antibody AO-176, that is highly differentiated among agents in this class. AO-176 not only blocks the CD47/SIRPα interaction to induce tumor cell phagocytosis, but also: a) directly induces solid and hematologic tumor cell cytotoxicity and damage-associated molecular patterns (DAMPs); b) preferentially binds tumor versus normal cells, which is correlated with β1-integrin expression and localization; c) negligibly binds RBC; and d) exhibits improved binding at acidic pH as found in tumor microenvironments.Previously we have shown that AO-176 is efficacious in a variety of solid tumor xenograft models as well as in models of multiple myeloma and AML. Here, we show the therapeutic potential of AO-176 in pre-clinical models of lymphoma where CD47 is upregulated and associated with poor prognosis. Using a variety of cell based and in vivo models we show that AO-176 demonstrates increased binding to lymphoma cells at an acidic versus physiologic pH and that this binding and blocking of the do not eat me signal leads to enhanced phagocytosis of lymphoma cells either alone or in combination with rituximab. In addition, we show that AO-176 induces annexin V positivity in lymphoma cells as well as inducing a variety of DAMPs that ultimately may aid in inducing immunogenic cell death of the lymphoma cells. We also demonstrate that AO-176 is a potent tumor growth inhibitor in lymphoma xenograft models and appears to induce immune infiltrates as well as inflammatory cytokines.Taken together, these data show that AO-176 has strong therapeutic potential in lymphoma. AO-176 is currently being evaluated in clinical trials of select solid tumors (NCT03834948) and multiple myeloma (NCT04445701).

Citation Format: Benjamin J. Capoccia, Michael J. Donio, John O. Richards, Ronald R. Hiebsch, Robyn J. Puro, Arun K. Kashyap, Daniel S. Pereira. AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 954.
Abstract 965: The role of LOX-mediated FAK phosphorylation in osteosarcoma metastasis
Authors: Chen Xiang , Hicks John M. , Sarkar Poonam , Gaber Waleed M. , MAN Tsz-Kwong
Published: July 2021

Despite the use of chemotherapy and surgery, the development of metastasis remains to be the leading cause of death in patients with osteosarcoma. LOX encodes for lysyl oxidase, which is an enigmatic molecule in cancer by acting as a tumor suppressor in certain tumors, but a metastatic promoter in other tumors. To investigate the function of LOX, we generated LOX overexpression mutants in two osteosarcoma cell lines and showed that higher LOX expression promoted tumor cell proliferation and invasiveness. Using an orthotopic xenograft mouse model, we further showed that osteosarcoma cells with higher LOX expression produced a higher number of mice with pulmonary metastases than the parental cell line (n=9). To characterize the mechanism of LOX-mediated metastasis, we examined the protein expression of a panel of potential downstream targets. The results demonstrated that phospho-FAK (focal adhesion kinase) expression was increased in the LOX-overexpression mutant relative to the parental cell line. Using a small molecule inhibitor of FAK, we showed that it significantly reduced the LOX-mediated metastasis in the orthotopic xenograft model. To demonstrate the clinical significance of our findings, we analyzed the expression profiling and RNAseq datasets recently generated from the TARGET osteosarcoma study. A Kaplan-Meier analysis showed that a higher level of LOX expression significantly correlated with a poor outcome (p < 0.05) and a multivariate analysis indicated LOX remained to be significant after controlling for initial metastatic status. In addition, we have previously shown that p27 is frequently mislocalized in the cytoplasm of osteosarcoma cells and drives the development of metastasis through interacting with the PAK1-mediated actin cytoskeleton network. Our results showed that the expression of LOX was upregulated in p27-mislocalized osteosarcoma cell lines with high metastatic potential. A tissue microarray analysis showed that cytoplasmic p27 expression significantly correlated with LOX expression (p = 0.003). Together, our findings suggest that a novel link between p27 mislocalization and LOX expression. LOX plays a pivotal role in osteosarcoma metastasis by upregulating FAK phosphorylation. FAK inhibition is a potential therapeutic strategy to reduce the development of metastasis in osteosarcoma with LOX overexpression.

Citation Format: Xiang Chen, John M. Hicks, Poonam Sarkar, Waleed M. Gaber, Tsz-Kwong MAN. The role of LOX-mediated FAK phosphorylation in osteosarcoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 965.