bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 841: Risk of hepatobiliary & pancreatic cancer in inflammatory bowel disease
Authors: Yu Jingru , Refsum Erle , Helsingen Lise M. , Folseraas Trine , Ploner Alexander , Wieszczy Paulina , Barua Ishita , Jodal Henriette C. , Melum Espen , Løberg Magnus , Blom Johannes , Bretthauer Michael , Adami Hans-Olov , Kalager Mette , Ye Weimin
Published: July 2021

Background: The risk of hepatobiliary and pancreatic cancer in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC) has not been reliably quantified in large, prospective studies with long-term follow-up.

Methods: We performed a population cohort study of all patients diagnosed with IBD in Norway and Sweden from 1987 to 2015. Participants were followed through linkage to national cancer, cause of death and population registers. We calculated standardized incidence ratios (SIR) with 95% confidence intervals (CIs) and absolute risk of hepatobiliary and pancreatic cancer by PSC status and other clinical characteristics.

Results: We identified 141,960 IBD patients, 4,548 (3.2%) of these with concomitant PSC. During a median follow-up time of 10.0 years, we identified 479 biliary tract cancers (SIR 5.2, 95% CI 4.7-5.7), 127 hepatocellular carcinomas (SIR 2.1, 95% CI 1.8-2.5) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2-1.5). The relative risks were considerably higher in patients with PSC, with SIRs of 142 (95% CI 125-160) for biliary tract, 27.7 (95% CI 19.4-38.5) for hepatocellular, and 9.0 (95% CI 6.3-12.6) for pancreatic cancer. For IBD patients without PSC, we found SIRs of 2.5 (95% CI 2.2-2.9), 1.5 (1.2-1.8), and 1.2 (1.1-1.4) for biliary tract cancer, hepatocellular carcinoma, and pancreatic cancer, respectively.

Conclusion: Patients with IBD experience a substantially increased risk of biliary tract cancer. Although the risk is largely confined to patients with concomitant PSC, non-PSC patients also confer a moderate excess risk.

Citation Format: Jingru Yu, Erle Refsum, Lise M. Helsingen, Trine Folseraas, Alexander Ploner, Paulina Wieszczy, Ishita Barua, Henriette C. Jodal, Espen Melum, Magnus Løberg, Johannes Blom, Michael Bretthauer, Hans-Olov Adami, Mette Kalager, Weimin Ye. Risk of hepatobiliary & pancreatic cancer in inflammatory bowel disease [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 841.
Abstract 851: Associations of dietary calcium and magnesium intakes with lung cancer risk among low-income Americans: Results from the Southern Community Cohort Study
Authors: Yoon Hyung-Suk , Shu Xiao Ou , Cai Hui , Zheng Wei , Blot William J. , Cai Qiuyin
Published: July 2021

Background: Previous studies have suggested the potential roles of dietary intakes of calcium and magnesium in human cancer development, but little is known about their associations with lung cancer risk, especially among African Americans (AAs) and low-income populations.

Objectives: We conducted a nested case-control study to investigate the associations of dietary calcium and magnesium intakes with lung cancer risk among a low-income population of AAs and European Americans (EAs) in the Southeastern United States.

Methods: A total of 1,560 incident lung cancer cases who were diagnosed at least two years after enrollment and 5,926 matched controls from the Southern Community Cohort Study were included. Dietary calcium and magnesium intakes were assessed using a validated food frequency questionnaire at study enrollment. Multivariate logistic regression models were used to estimate odds ratios (ORs) and corresponding confidence intervals (95% CIs) for lung cancer risk associated with intakes of calcium and magnesium, and calcium/magnesium ratios after adjusting for enrollment age, education, smoking status, and pack-years, physical activity, alcohol drinking, household income, history of chronic obstructive pulmonary disease, body mass index, energy intake, and calcium or magnesium intake.

Results: Calcium intake was significantly associated with an increased risk of lung cancer among AAs but not among EAs; ORs (95% CI) for the highest compared with lowest quartiles were 1.56 (1.03-2.36) and 1.14 (0.68-1.92) for AAs and EAs, respectively (p for interaction: 0.03). Meanwhile, magnesium intake was significantly associated with a reduced risk of lung cancer risk among AAs but not among EAs; ORs (95% CI) for the highest compared with lowest quartiles were 0.55 (0.35-0.89) and 0.68 (0.39-1.18), respectively (p for interaction: 0.68). ORs (95% CI) for the highest compared with the lowest quartiles for calcium/magnesium ratios were 1.21 (0.96-1.53) for AAs and 1.17 (0.85-1.61) for EAs. These associations were more evident among men and never-smokers.

Conclusion: Our results suggest that higher dietary calcium and lower dietary magnesium intakes are associated with an increased risk of lung cancer, especially among AAs, raising the possibility that dietary factors may contribute to a higher risk of lung cancer among AA than EA men.

Citation Format: Hyung-Suk Yoon, Xiao Ou Shu, Hui Cai, Wei Zheng, William J. Blot, Qiuyin Cai. Associations of dietary calcium and magnesium intakes with lung cancer risk among low-income Americans: Results from the Southern Community Cohort Study [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 851.
Abstract 865: Genomic and evolutionary classification of lung cancer in never smokers from the Sherlock-Lung study
Authors: Zhang Tongwu , Alexandrov Ludmil B. , Zhao Wei , Sang Jian , Shi Jianxin , Zhu Bin , Gordenin Dmitry A. , Garcia-Closas Montserrat , Lan Qing , Rothman Nathaniel , Chanock Stephen J. , Wedge David C. , Landi Maria Teresa
Published: July 2021

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality, but is poorly characterized. Here we show, through high coverage whole genome sequencing of 232 tumors/blood pairs, that LCINS can be separated into three subtypes, defined by somatic copy number aberrations. While the dominant subtype (‘piano'), rarely found in lung cancer from smokers, is characterized by quiet copy number profiles, the other subtypes are associated with specific arm-level amplifications and EGFR mutations (‘mezzo-forte'), and whole genome doubling (‘forte'). Piano tumors feature somatic UBA1 mutations, germline AR variants, and stem cell-like properties, including low mutational burden, infrequent TP53 alterations, high intra-tumor heterogeneity, long telomeres, and slow growth as suggested by the occurrence of cancer driver genes decades prior to tumor diagnosis. In contrast, driver mutations in mezzo-forte and forte tumors are generally late clonal events acquired close to tumor diagnosis, thus potentially facilitating target identification with a single biopsy. The mutational signature associated with direct exposure to tobacco smoking (SBS4) was not observed in our study, even in cases with reported exposure to second-hand tobacco smoke. No significant differences of mutational spectra were found between passive and non-passive smokers. While genes within the RTK-RAS pathway have distinct impacts on survival, mutations in TP53, CHEK2, EGFR, or loss of 15q or 22q independently doubled mortality. These genomic alterations in forte and mezzo-forte subtypes, and stem cell-like features in piano tumors create avenues for personalized therapeutic strategies in LCINS.

Citation Format: Tongwu Zhang, Ludmil B. Alexandrov, Wei Zhao, Jian Sang, Jianxin Shi, Bin Zhu, Dmitry A. Gordenin, Montserrat Garcia-Closas, Qing Lan, Nathaniel Rothman, Stephen J. Chanock, David C. Wedge, Maria Teresa Landi. Genomic and evolutionary classification of lung cancer in never smokers from the Sherlock-Lung study [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 865.
Abstract 877: Use of beta blockers and death from breast cancer in New Zealand breast cancer patients
Authors: Scott Oliver William , TinTin Sandar , Cavadino Alana , Elwood Mark
Published: July 2021

Background Beta blockers (BB), used for a range of cardiovascular indications, have been associated with improved cancer outcomes in international studies. This study examines the association between the use of BBs and death from breast cancer in New Zealand women.

Methods Women who were diagnosed with breast cancer between 2007 and 2016 were identified from four population-based regional NZ breast cancer registries and linked to pharmaceutical data, hospital discharges, and death records. Median follow up time was 3.96 years. Cox proportional hazard models were used to assess the hazard of breast cancer specific death (BCD) associated with BB use.

Results Of the 14,971 women included in analysis, 21% used a BB after diagnosis. Although not significant, BB use increased the risk of BCD (adjusted hazard ratio: 1.15; 95% CI: 0.99-1.33). When considering subgroups however, the increased risk only remained in those with at least one cardiac condition, in patients under 80 years of age, and in those who were dispensed a BB in the last periods of life. When excluding dispensings in the six months prior to death/last follow up, the adjusted hazard ratio between BB use and BCD decreased to 0.95 (95% CI: 0.81-1.11). Risk was highest with short term use and decreased consistently with ever increasing doses.

Conclusions The initial increased risk is likely to be due to confounding by indication, and there was a suggestion of a protective effect of long-term BB use on BCD.

Citation Format: Oliver William Scott, Sandar TinTin, Alana Cavadino, Mark Elwood. Use of beta blockers and death from breast cancer in New Zealand breast cancer patients [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 877.
Abstract 878: Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study
Authors: Xia Yue Yin , Lubinski Jan , Rosen Barry , Moller Pal , Eisen Andrea , Ainsworth Peter , Senter Leigha , Bordeleau Louise , Neuhausen Susan L. , Singer Christian F. , Brooks Jennifer , Sun Ping , Narod Steven A. , Kotsopoulos Joanne
Published: July 2021

Background: Oral contraceptive use is associated with a significantly reduced risk of ovarian cancer among BRCA1 and BRCA2 mutation carriers. To date, there have been no prospective analyses of this relationship, and the impact of other types of contraception (e.g. intrauterine device (IUD), implant, patch, injection) on BRCA-associated ovarian cancer risk is unknown. The goal of this study is to prospectively evaluate the relationship between types of contraception and ovarian cancer incidence in women with a BRCA1 or BRCA2 mutation.

Methods: The longitudinal study included 3,298 eligible BRCA1/2 mutation carriers. Self-reported information regarding contraceptive use, including medication name, start year, end year, duration of use and method of administration were collected by biennial questionnaire. Women were classified according to history of contraceptive use (ever/never), duration of use, contraceptive method, calendar year of initiation and time since last use. Time-dependent Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of ovarian cancer associated with each contraceptive method.

Results: There were 84 incident ovarian cancer cases diagnosed over a mean follow-up period of 5.1 years. There was no significant association between ever use of an IUD (HR: 0.78; 95% CI: 0.28-2.14) and risk of ovarian cancer compared to IUD never users. Ongoing analyses will focus on the relationships between other contraceptive methods, formulations and duration of use on ovarian cancer risk, further stratified by histology and site of origin.

Conclusions: Preliminary findings from this prospective analysis suggest that IUD use may not be protective among BRCA1/2 mutation carriers. Ongoing results will elucidate the impact of contraceptive formulation and method on ovarian cancer risk to inform clinical recommendations surrounding the use of contraceptive agents for chemoprevention in high risk women.

Citation Format: Yue Yin Xia, Jan Lubinski, Barry Rosen, Pal Moller, Andrea Eisen, Peter Ainsworth, Leigha Senter, Louise Bordeleau, Susan L. Neuhausen, Christian F. Singer, Jennifer Brooks, Ping Sun, Steven A. Narod, Joanne Kotsopoulos. Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study [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 878.
Abstract 880: Development and validation of an electronic health record-based absolute risk prediction model for esophageal cancer in the primary care setting in China
Authors: Han Yuting , Yu Canqing , Guo Yu , Pei Pei , Yang Ling , Chen Yiping , Du Huaidong , Chen Junshi , Chen Zhengming , Huo Dezheng , Lv Jun , Li Liming
Published: July 2021

Background This study aims to develop a set of electronic health record (EHR)-based absolute risk prediction models for esophageal cancer (EC), which are nationally applicable and easily integrated into the EHR system in China.

Methods The study used data from China Kadoorie Biobank (CKB), a large nationwide prospective cohort recruited during 2004-2008 in ten regions. In a random two-thirds of the 510,145 participants with no prior cancer diagnoses, we developed four nested models, according to the availability of predictors in EHRs. A flexible parametric survival model was fitted to calculate a 10-year absolute risk of EC accounting for the competing risk of mortality from other diseases. Besides discrimination and calibration, we estimated a range of performance indices (e.g. sensitivity and specificity) and compared the model performance with current screening criteria in the remaining one-third.

Results During a median of 11.1 years of follow-up, we observed 2,550 EC incident cases. The most sophisticated model included EHR variable (age, sex, region risk level [of ten regions: Hui county in Henan province and Pengzhou in Sichuan province], education level, family history of cancer, smoking, alcohol drinking, body mass index), and physical activity, hot tea consumption, and fresh fruit consumption. In the validation dataset, as more predictors included, the area under the receiver-operating characteristic curve statistically increased from 0.748 (0.732-0.763) to 0.883 (0.867-0.895). We observed a great agreement between predicted and observed risk, except for a slight underestimation in the top deciles. Taking 0.40% as the 10-year risk cut-off, models had sensitivities and specificities of around 80% and largely outperformed the current screening criteria.

Conclusions Based only on non-invasive predictors, even the model including only five predictors in the EHRs exhibited excellent calibration and discrimination. Utilizing limited predictors in EHRs, our models are useful to develop nationwide risk-stratified screening strategies for esophageal cancer.

Citation Format: Yuting Han, Canqing Yu, Yu Guo, Pei Pei, Ling Yang, Yiping Chen, Huaidong Du, Junshi Chen, Zhengming Chen, Dezheng Huo, Jun Lv, Liming Li. Development and validation of an electronic health record-based absolute risk prediction model for esophageal cancer in the primary care setting in China [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 880.
Abstract 886: Prediction of outcome in Li-Fraumeni Syndrome: Development of an integrative function-based prognostic model
Authors: Fischer Nicholas , Malkin David
Published: July 2021

Li-Fraumeni Syndrome (LFS) is a highly penetrant familial cancer disorder caused by germline TP53 mutations. Hundreds of different germline TP53 mutations with a wide gradient of functional consequences have been found in association with LFS, which has a remarkably diverse clinical spectrum in terms of tumor type, age of onset, penetrance, and survival rates. Clinical tools for prognostication and risk stratification are needed to guide clinical decision making. We performed an integrated analysis combining five large-scale mutant p53 functional screens to identify three functionally distinct groups of mutations. Combined functional scores measuring multiple parameters (loss-of-function, dominant negative activity, growth inhibition, oligomeric status, and transcriptional activity) were used to classify mutations as high, intermediate, or low pathogenicity. Patients identified with germline TP53 mutations at The Hospital for Sick Children and other institutes (174 patients from 50 families) provided the discovery set. An external validation cohort included 1674 patients from 1522 families with germline TP53 mutations collected from the International Agency for Research on Cancer database. Our mutation classifications stratified carriers into three distinct risk groups with significantly different overall survival outcomes in the discovery (P=0.02) and validation cohorts (P<0.0001). In the discovery dataset, patients in the high-risk group had considerably shorter median life expectancy (28 years; n=21) compared to the intermediate-risk group (61 years; n=51) and low-risk group (median survival not reached; n=10). On average, 92% (24/26) of patients in the high-risk group developed tumors compared to only 63% (32/51) in the low-risk group (P=0.005). This model remained significant when applied to the validation cohort. In conclusion, patients at increased risk of cancer mortality can be identified to guide treatment and cancer surveillance strategies.

Citation Format: Nicholas Fischer, David Malkin. Prediction of outcome in Li-Fraumeni Syndrome: Development of an integrative function-based prognostic model [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 886.
Abstract 912: CLDN6 and CLDN9 dual targeting antibody drug conjugates for the treatment of ovarian and endometrial cancers
Authors: Du Liang , Zhang Hongyan , Jin Lina , Chen Yali , Wan Tingting , Xu Liuliu
Published: July 2021

Claudins (CLDNs) are tight junction proteins that regulate epithelial-cell barrier function and polarity. Up-regulation of certain CLDN proteins has been associated with the malignant phenotype. Embryonic, stem-cell specific CLDN6 is absent in normal adult tissues. Our in-house data showed that it is highly expressed in serous ovarian (66% cases showed 2+/3+/4+ expression of CLDN6), and testis cancers (100% cases showed 4+ expression of CLDN6) in Chinese population, and is an “ideal” target in these cancer types. CLDN9, sharing high homology with CLDN6 exhibits similar distribution patterns with CLDN6, like the absence in normal tissues and up-regulation in ovarian and endometrial cancer. We propose to simultaneously target both CLDN6 and CLDN9 for treatment of ovarian cancer and endometrial cancer to achieve better anti-tumor efficacy and expand the treatment to a larger population of patients. To this end, we designed a high-through-put antibody screening process and discovered two antibodies GB7008-03 and GB7008-05, both of which binds CLDN6 and CLDN9 with high affinity, while sparing other CLDN members. Both candidates demonstrated superior antibody-mediated antigen internalization than ASP1650, the forerunner in clinical trials. GB7008-03 and GB7008-05 also showed good ADCC potency on CLDN6 expressing tumor cell lines. Currently we are developing antibody-drug-conjugates based on these two antibodies. In vivo efficacy of these ADCs in CDX models will be presented.

Citation Format: Liang Du, Hongyan Zhang, Lina Jin, Yali Chen, Tingting Wan, Liuliu Xu. CLDN6 and CLDN9 dual targeting antibody drug conjugates for the treatment of ovarian and endometrial cancers [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 912.
Abstract 959: C/EBPβ antagonist peptide, ST101, as a therapeutic approach in breast cancer
Authors: Rotolo Jim A. , Koester Mark , Ramirez Ricardo , Ghamsari Lila , Leong Siok , Gallagher Erin , Merutka Gene , Kappel Barry J.
Published: July 2021

Breast cancer (BC) is the most common invasive cancer in women, with more than 2.1 million cases and over 626,000 deaths occurring worldwide annually. Although age-adjusted mortality from BC has been declining since 1990, the median survival for patients with metastatic disease remains at 2-3 years, and 5-year survival approximates 25%. Thus, the medical need for more effective agents in this clinical setting remains very high. CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is a transcription factor overexpressed in many cancers that regulates expression of factors that promote tumor survival, proliferation and inhibit differentiation. C/EBPβ dimers, such as with Jun/Fos and CREB/ATF family members, form via basic leucine zipper (bZIP)-driven coiled-coil interactions and are necessary for its association with DNA and transcriptional activity. Due in part to the difficulty in therapeutically targeting transcription factors, no effective C/EBPβ inhibitors are clinically available. ST101 is a novel peptide antagonist of C/EBPβ currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 was designed to bind the C/EBPβ bZIP domain, thereby preventing dimer formation and inhibiting its transcriptional activity. Here we describe ST101 non-clinical anti-tumor activity to support further development as a therapeutic approach in BC. In vitro studies in 4T1-luc triple-negative breast cancer (TNBC) and MCF7 HRPOS breast adenocarcinoma cells demonstrate ST101 dose-dependent impact of cell viability (EC50 of 4.8 and 2.1 µM, respectively), accompanied by significant impact on C/EBPβ-mediated gene expression as determined by qPCR analysis. In contrast, normal human mammary epithelial cells were not sensitive to ST101 (EC50 >100 µM). In vivo experiments indicate dose-dependent tumor growth inhibition in an orthotopic 4T1-luc model following ST101 exposure, with significant tumor growth delays observed following 25 mg/kg ST101 (p<0.05 vs. controls). Mice treated with 25 mg/kg ST101 via subcutaneous injection demonstrated significant tumor growth delay and decrease in tumor volume vs. controls. These data emphasize the potential of ST101 as a potent peptide therapeutic for HRPOS and TN BC.

Citation Format: Jim A. Rotolo, Mark Koester, Ricardo Ramirez, Lila Ghamsari, Siok Leong, Erin Gallagher, Gene Merutka, Barry J. Kappel. C/EBPβ antagonist peptide, ST101, as a therapeutic approach in 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 959.
Abstract 962: Small-molecule NSC58874 releases and activates p73 via induction of mutant p53 degradation in cancer cells
Authors: Zhang Shengliang , El-Deiry Wafik S.
Published: July 2021

The tumor suppressor p53 is the most frequently mutated gene in cancer. Mutant p53 is a challenge to target in cancer therapy due to its many mutations and the fact that it is an inactivated transcription factor. p73 is a member of the p53 family but very rarely mutated in cancer cells. Therefore, activation of p73 is one of the promising strategies to restore the p53 pathway signaling in cancer therapy. Our laboratory has reported that p73 can be activated by small molecules to restore p53 pathway signaling via induction of p73 expression or interruption of p73 interaction with mutant p53. In the present study, we explored a strategy for releasing p73 from a mutant p53 inhibitory complex by induction of mutant p53 degradation using small molecule NSC59984. We previously reported that NSC59984 induces mutant p53 degradation and restores p53 pathway signaling through p73 in p53-mutant cancer cells. To address the mechanism of whether p73 is released from a mutant p53 inhibitory complex to transcriptionally regulate p53 targets, we performed p53-RE-luc reporter assays and Chromatin Immunoprecipitation (ChIP)-PCR in cancer cells with overexpression of p73. We found NSC59984 enhances p73-mediated signaling based on p53 target (such as p21 and noxa) induction at the protein level and p53-RE-luc reporter assay. Further ChIP-PCR analysis showed that NSC59984 treatment increases p73-binding to the p21 and Noxa promoters. These results taken together suggest that NSC59984 enhances p73 transcriptional activity to restore the p53 pathway signaling. It is also well known that p73 activity is regulated through a complex mechanism such as post-translational modifications and protein-protein interactions. We found that NSC59984 can stimulate the ERK2 signaling pathway. The MEK1 inhibitor U0126 partially blocked p73 binding to the p21 and Noxa promoters and their gene expression in cells treated with NSC59984, and this correlated with the rescue of mutant p53 stabilization. These results suggest that p73 is released from mutant p53 inhibitory complex and further stimulated through ERK2 signaling, as a mechanism of tumor suppression in tumors with mutant p53.

Citation Format: Shengliang Zhang, Wafik S. El-Deiry. Small-molecule NSC58874 releases and activates p73 via induction of mutant p53 degradation in cancer cells [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 962.
Abstract 964: β-catenin antagonist peptide attenuates Wnt-dependent oncogenic activity
Authors: Rotolo Jim A. , Gallagher Erin , Ghamsari Lila , Leong Siok , Ramirez Ricardo , Koester Mark , Merutka Gene , Kappel Barry J.
Published: July 2021

β-catenin is an oncogenic transcription factor that has an essential role in cell development and biology. Increased β-catenin expression or activity has been implicated in many cancers, including breast and colorectal, and is associated with poor prognosis. Despite extensive ongoing research, β-catenin is conventionally considered ‘undruggable', and there are no current drugs available to target Wnt/β-catenin signaling. B-cell CLL/lymphoma 9 protein (BCL9) is a positive regulator of β-catenin transcriptional activity that is overexpressed in tumors. Disruption of β-catenin interaction with BCL9 has been shown genetically to suppress oncogenic Wnt/β-catenin transcription and represents a powerful approach to inhibit this previously undruggable target. Here, we describe the anti-tumor activity of a β-catenin antagonist peptide (BCAP), designed to disrupt the association of β-catenin with co-activator BCL9. Target engagement of BCAP with recombinant β-catenin was demonstrated in biophysical studies by circular dichroism spectroscopy, and inhibition of the β-catenin/BCL9 interaction was demonstrated in transiently transfected A549 cells by NanoBRET assay. Administration of BCAP to HEK293 cells stably transfected with TOPFlash reporter plasmid resulted in dose-dependent inhibition with an EC50 of 1.7 µM. Further, BCAP attenuated oncogenic gene transactivation in colorectal cancer cells (HCT116 and COLO320DM) and HRPOS breast cancer cells (MCF7), significantly decreasing the expression of Axin2 and CDK4 (p<0.05), while not impacting Axin2 or CDK4 gene expression in Wnt-independent RKO and NCI-H460 cells. Administration of BCAP to 4T1-luc triple-negative breast cancer, HCT116 and COLO320DM cells resulted in dose-dependent in vitro cytotoxicity 48 hours post exposure, with EC50 values of 1.4, 4.4 and 1.2 µM, respectively. In in vivo orthotopic 4T1-luc tumor models, administration of BCAP via subcutaneous injection resulted in dose-dependent inhibition of tumor growth and significantly reduced tumor volume compared to control tumors (p<0.05). These data demonstrate the significant in vitro and in vivo anti-cancer activity of BCAP and emphasize it's potential as a potent therapeutic for Wnt/β-catenin-dependent cancers.

Citation Format: Jim A. Rotolo, Erin Gallagher, Lila Ghamsari, Siok Leong, Ricardo Ramirez, Mark Koester, Gene Merutka, Barry J. Kappel. β-catenin antagonist peptide attenuates Wnt-dependent oncogenic activity [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 964.
Abstract 968: Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation
Authors: Tao Ran , Fang Douglas D. , Li Yuanbao , Zhang Kaixiang , Xu Chunhua , Fang Xu , Wang Qixin , Yang Dajun , Zhai Yifan
Published: July 2021

Ovarian cancer is one of the deadliest malignancies in women, and up to 70% of patients with epithelial ovarian cancer have FAK overexpression, amplification, or activation. FAK plays an important role in cellular migration, growth factor signaling, cell cycle progression, cellular survival and chemoresistance. This biomarker is also significantly associated with higher tumor stage, metastasis, and shorter overall survival in patients with ovarian cancer. Inhibition of FAK is therefore emerging as a promising treatment target.

APG-2449 is a clinical stage FAK/ALK/ROS1 multi-kinase inhibitor. In this study we investigated antitumor activity of APG-2449 combined with standard-of-care chemotherapeutics in ovarian cancer in the preclinical setting. In a mouse xenograft tumor model derived from ovarian cancer cell line OVCAR-3, which was resistant to platinum-based therapies, APG-2449 combined with paclitaxel, and paclitaxel plus carboplatin, synergistically enhanced antitumor activity, whereas the chemotherapeutics showed no activity. Synergistic antitumor activity was also observed in multiple patient-derived xenograft (PDX) models derived from women with chemoinsensitive ovarian cancer, which also frequently expresses high levels of FAK.

By comparing gene expression profiles of PDX tumors obtained from responders and nonresponders to the combined therapy, we identified CD44 (a marker for cancer stem cells) as a potentially predictive biomarker. Western blot analysis confirmed higher protein levels of CD44 in pretreated tumors of responders. Interestingly, downregulation of CD44 levels was observed in combination-treated tumors, suggesting that these combinations reduced cancer stem cell populations in ovarian cancer. Accordingly, in ovarian cancer cells exposed to APG-2449 alone or combined with paclitaxel, numbers of cells positive for CD44 or aldehyde dehydrogenase 1 (ALDH1; another marker for cancer stem cells) decreased in a dose-dependent manner.

In summary, our data suggest that FAK inhibition by APG-2449 sensitizes ovarian tumors to chemotherapeutics in preclinical tumor models of ovarian cancer. The synergistic antitumor activity was mediated by downregulation of CD44+ or ALDH1+ cancer stem cell populations. These findings encourage clinical development of APG-2449 in combination with chemotherapies for treatment of ovarian cancer.

Citation Format: Ran Tao, Douglas D. Fang, Yuanbao Li, Kaixiang Zhang, Chunhua Xu, Xu Fang, Qixin Wang, Dajun Yang, Yifan Zhai. Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation [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 968.
Abstract 975: Antitumor effect of cyclin- dependent kinase inhibitor flavopiridol in c-Myc overexpressing esophageal cancer
Authors: Hassan Md Sazzad , Awasthi Niranjan , Li Jun , Schwarz Margaret A. , von Holzen Urs
Published: July 2021

Tumors with elevated c-Myc expression often exhibit highly aggressive phenotype and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting a synthetic-lethal approach dependent on elevated c-Myc signaling is effective in treating esophageal cancer with a CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth without association with improved overall survival in esophageal cancer patients. c-Myc expression was enhanced by Wnt signaling activator (6-bromoindirubin-3′ -oxime (BIO) or pcDNA3-cMyc and c-Myc expression was depleted by c-Myc siRNAs. Interestingly, esophageal cancer cells with elevated c-Myc expression were preferentially more sensitive to induction of apoptosis by CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combinations with chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth with significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to CDK inhibitor flavopiridol and flavopiridol alone or in combination with cytotoxic or targeted agents can be a potential therapy for c-Myc overexpressing esophageal cancer.

Citation Format: Md Sazzad Hassan, Niranjan Awasthi, Jun Li, Margaret A. Schwarz, Urs von Holzen. Antitumor effect of cyclin- dependent kinase inhibitor flavopiridol in c-Myc overexpressing esophageal 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 975.
Abstract 986: Induction of lytic cycle of Epstein-Barr virus by a novel organic compound through activation of the c-Jun N-terminal kinase pathway
Authors: Dorothea Mike , Yiu Stephanie PT , Hui Kwai Fung , Chiang Alan K. S.
Published: July 2021

The reactivation of lytic cycle of Epstein-Barr Virus (EBV) is an important component of the emerging lytic induction therapy to specifically target the virus in EBV-associated malignancies. The potency of the lytic induction is central to the effectiveness of the lytic induction therapy. It is hampered by cancer cells that are refractory to lytic induction. This study aims to elucidate novel pathways involved in inducing EBV lytic cycle in epithelial cancer cells using a small organic compound, E11 intermediate (E11.1), and develop new drug combinations to overcome the refractoriness of the cancer cells to lytic induction. E11.1 was found to be the active component in the original E11 compound which has a superior lytic induction capability in both gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC) cells. Timepoint and dose dependent studies were performed to characterize E11.1's lytic reactivation kinetics of EBV in AGS-BDneo cells. Reactive oxygen species (ROS) scavengers and chemical pathway inhibitors were used to investigate the involvement of ROS and major cellular pathways in inducing lytic cycle of EBV by E11.1. Concomitant drug treatment of E11.1 and histone deacetylase (HDAC) inhibitor (suberoylanilide hydroxamic acid or romidepsin) was tested for synergistic action in lytic induction and cell death. E11.1 elicited a rapid kinetics of lytic induction through the activation of c-Jun N-terminal kinase (JNK) pathway in GC and NPC cells and induced the production of ROS and cell death at later timepoints. The combination of E11.1 and HDAC inhibitor reactivated the lytic cycle of EBV synergistically in both GC and NPC lines at 48 hours of treatment. In conclusion, we provided the evidence of activation of JNK pathway in the induction of EBV lytic cycle by E11.1 in EBV-positive epithelial malignancies. E11.1 and HDAC inhibitor induced the lytic cycle of EBV in EBV-positive epithelial cancer cells synergistically resulting in enhanced cell death.

Citation Format: Mike Dorothea, Stephanie PT Yiu, Kwai Fung Hui, Alan K. S. Chiang. Induction of lytic cycle of Epstein-Barr virus by a novel organic compound through activation of the c-Jun N-terminal kinase pathway [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 986.
Abstract CT150: Humanized CD19 CAR-T cells in the treatment of relapsed and refractory diffuse large B-cell lymphoma: A case report
Authors: Li Tan , Wang Yi , Li Bin , Hu Xueying , Liu Liu , Bao Yangyi , Li Qiao , Yang Lin , Li Hongxia
Published: July 2021

The authors did not submit an updated abstract. The original abstract should be considered final.

Citation Format: Tan Li, Yi Wang, Bin Li, Xueying Hu, Liu Liu, Yangyi Bao, Qiao Li, Lin Yang, Hongxia Li. Humanized CD19 CAR-T cells in the treatment of relapsed and refractory diffuse large B-cell lymphoma: A case report [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 CT150.
Abstract CT155: Role of Time intensity & density curve for detecting early changes in pancreatic adenocarcinoma
Authors: Rahmanuddin Syed , Cridebring Derek , Korn Ron , Brase Jordyn , Motarjem Pejman , Kai Wenli , Chung Vincent , Borazanci Erkut , Goel Ajay , Von Hoff Daniel
Published: July 2021

Purpose: Pancreatic cancer has limited options for early detection and this study tried to tackle that issue using TIDC (Time Intensity Density Curve), 3D volumetric and perfusion imaging. Experimental Design: This quantitative study was done by analyzing multi-phase CT images of patients undergoing treatment of different stages of pancreatic ductal adenocarcinoma (PDAC). Using advanced 3D imaging software we identified the perfusion and radiodensity of tumors at different stages. This analysis was done using 41 adult patients with unresectable treatment-naïve PDAC who were either enrolled in a clinical trial at HonorHealth Research Institute (Scottsdale, AZ) or treated at the City of Hope Comprehensive Cancer Center (Duarte, CA) as standard of care non study patients between 2015-2019. All patients were over the age of 18 and had been diagnosed with PDAC. We divided the participant sample into two groups, labeled Cohort 1 and Cohort 2. For image acquisition in both groups, we required to have multiphase CT images for the collection of images at both locations. Results: TIDC, 3D volumetric measurements and perfusion imaging proved useful in the quantification of tumor aggressiveness. Our results showed that perfusion in PDAC displayed delays in the venous phase which may be linked to vascular growth related activity and exhibits the active and viable part of the tumor. 3D volumetric analysis of the patient's multi-phase CT scan showed clear changes in arterial and venous perfusion and correlated with how rapidly patients progressed (e.g. tumor aggressiveness). Conclusion: TIDC and 3D volumetric analysis could play a significant role in defining the aggressiveness of the pancreatic ductal adenocarcinoma.

Citation Format: Syed Rahmanuddin, Derek Cridebring, Ron Korn, Jordyn Brase, Pejman Motarjem, Wenli Kai, Vincent Chung, Erkut Borazanci, Ajay Goel, Daniel Von Hoff. Role of Time intensity & density curve for detecting early changes in pancreatic 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 CT155.
Abstract CT213: NEON-1: a first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies
Authors: Voskoboynik Mark , Moser Justin C. , Lakhani Nehal , Millward Michael , Davar Diwakar , Harb Wael A. , Yang Jing , Means Gary , Manjarrez Kristi , Tercero Almudena , Zayed Hany , Hillson Jan , Dela Cruz Christine , Perez Graciela , Peng Stanford L.
Published: July 2021

BACKGROUND: Checkpoint inhibitors (CPI) targeting the PD-1 and CTLA-4 pathways have demonstrated significant clinical benefit in multiple tumors, but the majority of patients exhibit or develop resistance, at least in part due to insufficient activation and/or excessive exhaustion of tumor-specific T cells. Strong preclinical rationale exists to combine CPIs with T cell costimulatory agonists, but such approaches have not yet translated into significantly improved clinical benefit. The majority of these approaches, though, have not targeted CD28, a critical T cell costimulator recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. As monotherapy, ALPN-202 has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating a favorable safety profile in preclinical toxicology studies.

METHODS: This is a cohort-based, open-label dose escalation and expansion study in adults with advanced solid tumors or lymphoma (NCT04186637). The objectives of this study are to evaluate the safety, efficacy, pharmacokinetics, anti-drug antibodies, and pharmacodynamics of ALPN-202. Subjects who are refractory or resistant to standard therapy (including approved CPIs), or without available standard or curative therapy are eligible. ALPN-202 is administered by IV infusion. After two single-subject cohorts (0.001 mg/kg, 0.01 mg/kg), a standard 3+3 dose escalation (0.1-20 mg/kg) has been implemented with two dose schedules in parallel, Q1W and Q3W. Thereafter, expansion cohorts are planned to enroll subjects at a selected dose regimen(s) in selected indications. Biomarkers include tumor measurements of PD-L1, CD28, CD80 and CD86 to explore the possible relationship between baseline expression and outcomes. Other pharmacodynamic analyses include target saturation, inflammatory cytokines and immunophenotyping of circulating leukocytes. As of January 2021, the trial is continuing as planned; no DLTs have been observed through the 0.3 mg/kg cohorts (dose level 4).

Citation Format: Mark Voskoboynik, Justin C. Moser, Nehal Lakhani, Michael Millward, Diwakar Davar, Wael A. Harb, Jing Yang, Gary Means, Kristi Manjarrez, Almudena Tercero, Hany Zayed, Jan Hillson, Christine Dela Cruz, Graciela Perez, Stanford L. Peng. NEON-1: a first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies [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 CT213.
Abstract LB009: Dynamic changes in the compositions of cancer associated-fibroblasts correlate with clinical outcome in breast cancer
Authors: Friedman Gil , Levi-Galibov Oshrat , David Eyal , Bornstein Chamutal , Giladi Amir , Dadiani Maya , Mayo Avi , Halperin Coral , Pevsner-Fischer Meirav , Lavon Hagar , Mayer Shimrit , Nevo Reinat , Stein Yaniv , Balint-Lahat Nora , Barshack Iris , Ali H. Raza , Caldas Carlos , Gal-Yam Einav Nili , Alon Uri , Amit Ido , Scherz-Shouval Ruth
Published: July 2021

Cancer associated fibroblasts (CAFs) are prevalent in carcinomas. CAFs are also heterogeneous and perform various tumor-promoting tasks. Understanding whether distinct CAF-subsets exert specific functions, and how the composition of CAFs changes as tumors evolve could improve the accuracy of cancer treatment. Here, we analyzed thousands of CAFs by single-cell RNA-sequencing and index-sorting at several timepoints along breast tumor progression in mice, revealing distinct CAF-subsets. We discovered that the transcriptional programs of these subsets change over time, shifting from an immune-regulatory program at earlier timepoints to wound-healing and antigen-presenting programs at later timepoints, indicating that the composition and functions of CAFs are dynamic. We also found the two main CAF subsets in human breast tumors, wherein their ratio was associated with disease outcome. This association was particularly correlated with BRCA mutations in triple-negative breast cancer. Our findings indicate that the diverse composition of CAFs in breast cancer changes over time as tumors progress, and that these changes are linked to disease outcome.

Citation Format: Gil Friedman, Oshrat Levi-Galibov, Eyal David, Chamutal Bornstein, Amir Giladi, Maya Dadiani, Avi Mayo, Coral Halperin, Meirav Pevsner-Fischer, Hagar Lavon, Shimrit Mayer, Reinat Nevo, Yaniv Stein, Nora Balint-Lahat, Iris Barshack, H. Raza Ali, Carlos Caldas, Einav Nili Gal-Yam, Uri Alon, Ido Amit, Ruth Scherz-Shouval. Dynamic changes in the compositions of cancer associated-fibroblasts correlate with clinical outcome in 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 LB009.