bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3237: Development of direct inhibitors of KRAS mutants for the treatment of cancer
Authors: Tian Xiaohong , Geng Guoyan , Wu Jian Hui
Published: July 2017

Oncogenic KRAS mutations occur in ~ 30% of all human cancer. All attempts to develop inhibitors of oncogenic KRAS have failed to reach the clinic for decades and promote the perception of ‘undruggable’ KRAS proteins. Given the recent advances in understanding of mechanism of oncogenic KRAS, there is renewed enthusiasm toward development of direct inhibitors of KRAS. In a recent breakthrough, Shokat et al. discovered a “pocket," where they designed a series of mutant-specific small molecular inhibitors that are covalently binding to the mutant Cys 12 in KRAS protein (KRAS G12C). In human cancer, G12C, G12D and G12V are the predominant KRAS mutants. The G12C mutation accounts for 29,700 new diagnoses annually (lung, colon and pancreatic). The G12D and G12V, annually account for 53,700 and 39,100 new cancer diagnoses, respectively, occurring most frequently in Pancreatic ductal adenocarcinoma (PDAC) (51% G12D and 30% G12V) and colorectal cancer (45% G12D and 27% G12V). Thus, there is an urgent need to develop direct inhibitor of KRAS 12D and 12V mutants. By computer-aided drug design techniques, we have discovered a series of novel chemical inhibitors that potently inhibit KRAS G12D mutant in reporter assays using HEK293 cells and in Western blot analysis using PANC10.05 and SNU-C2B cells, which express endogenous KRAS G12D mutant. The direct binding of our compounds with KRAS G12D mutant was confirmed by Surface Plasmon Resonance (SPR) analysis. Our compounds also inhibit KRAS G12V mutant. Chemical optimization of these initial hits as direct inhibitors of multiple KRAS mutants is in progress.

Citation Format: Xiaohong Tian, Guoyan Geng, Jian Hui Wu. Development of direct inhibitors of KRAS mutants for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3237. doi:10.1158/1538-7445.AM2017-3237
Abstract 3245: Preclinical evaluation of the imipridone family of small molecules, including analogues of clinical-stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212
Authors: Wagner Jessica , Kline C. Leah , Olson Gary , Nallaganchu Bhaskara , Pottorf Richard , Prabhu Varun , Stogniew Martin , Allen Joshua , El-Deiry Wafik
Published: July 2017

We previously identified a novel, potent anti-cancer small molecule ONC201, which upregulates the integrated stress response (ISR) through ATF4/CHOP/DR5 and acts as a dual inactivator of Akt and ERK, leading to TRAIL gene activation. After completing a first-in-human phase I clinical trial that revealed exceptional safety, therapeutic pharmacokinetic (PK) profile and tumor engagement, ONC201 is under investigation in several advanced cancer Phase I/II trials. Given the unique imipridone core chemical structure of ONC201, we synthesized a family of analogues in an effort to identify additional chemical family members with distinct therapeutic properties. Based on in vitro potency improvements in human cancer cell lines and therapeutic window approximations with normal human fibroblasts, select analogues were investigated in animals for toxicity, maximum tolerated dose (MTD), and antitumor efficacy. ONC212 is one of the most promising new imipridones that was further evaluated to establish the PK profile, oral bioavailability, and efficacy in tumor types that are less sensitive to ONC201. Compared to ONC201, we noted distinct and more rapid kinetics of activity as well as improved potency in multiple human cancer cell lines in vitro. ONC212 has a broad therapeutic window, an acceptable PK profile, and is orally well-tolerated in mice. With no evidence of toxicity at efficacious doses in both colon and triple negative breast cancer, we have begun further evaluation of antitumor efficacy studies in ONC201-resistant tumor types. Efficacy studies with ONC212 are ongoing in melanoma models that are sensitive to ONC212 but less sensitive to ONC201 in vitro. Preliminary data indicates potent tumor growth reduction by ONC212 in vivo in ONC201-resistant melanoma xenografts. With a wide safety margin, potent antitumor activity in ONC201-insenstive tumors, and drug-like characteristics, ONC212 is being further developed as a drug candidate from the new imipridone class of compounds that complements the spectrum of activity of ONC201.

Citation Format: Jessica Wagner, C. Leah Kline, Gary Olson, Bhaskara Nallaganchu, Richard Pottorf, Varun Prabhu, Martin Stogniew, Joshua Allen, Wafik El-Deiry. Preclinical evaluation of the imipridone family of small molecules, including analogues of clinical-stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3245. doi:10.1158/1538-7445.AM2017-3245
Abstract 325: Pediatric relapsed acute lymphoblastic leukemia patients display enrichment of the PI3K/mTOR pathway and respond to the dual PI3K/mTOR inhibitor PKI-587
Authors: Gazi Mohiuddin , Moharram Sausan A. , Marhäll Alissa , Shah Kinjal , Kazi Julhash U.
Published: July 2017

Although significant improvements have been observed in the treatment of acute lymphoblastic leukemia, there is a substantial subset of high-risk T-ALL patients with relatively poor prognosis. T-cell acute lymphoblastic leukemia (T-All) is a hematopoietic malignancy affecting lymphoblast of T-cell lineage which cause lots of hematopoietic cancer related deaths every year all over the world. The current overall cure rates of newly diagnosed childhood ALL are more than 80% in Europe, but approximately 20% of patients relapse due to treatment failure in childhood ALL. Like other leukemia types, alterations of PI3K/mTOR pathway are predominant in T-ALL which is also responsible for treatment failure and relapse. In this study, two different gene expression data sets of relapsed patients also displayed enrichment of the PI3K/mTOR pathway. Out of 88 different inhibitors targeting multiple components of this pathway, we observed that PKI-587 was the most selective to the T-ALL cell line CCRF-CEM. Thus, we characterized the activity of the novel dual PI3K/mTOR pathway inhibitor PKI-587 using CCRF-CEM and Molt3 cells. We observed that PKI-587 blocked proliferation, colony formation and induced apoptosis in the T-ALL cell lines and selectively abrogated PI3K/mTOR without affecting the MAPK signaling. In vivo PI3K/mTOR inhibition delayed tumor progression, and reduced tumor load in a NSG/SCID xenograft mouse model. Since no deceptive body weight decrease was noticed, our conclusion is that this dose is effective and well tolerated. The beneficial effects of PKI-587 on T-ALL cells that has been observed in this study both in vitro and in vivo warrant further investigation.

Citation Format: Mohiuddin Gazi, Sausan A. Moharram, Alissa Marhäll, Kinjal Shah, Julhash U. Kazi. Pediatric relapsed acute lymphoblastic leukemia patients display enrichment of the PI3K/mTOR pathway and respond to the dual PI3K/mTOR inhibitor PKI-587 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 325. doi:10.1158/1538-7445.AM2017-325
Abstract 3255: Circulating adipose stromal cells (CASCs) as a potential biomarker of response to weight loss interventions in obese women at high risk for breast cancer
Authors: Baker Hailey , Kreutzjans Amy L. , Nydegger Jennifer L. , Phillips Teresa L. , Hasting Richard C. , Dixon Dan A. , Kimler Bruce F. , Fabian Carol J.
Published: July 2017

Background Obesity is a modifiable risk factor for breast cancer in the United States. White adipose tissue is increased in obese (BMI ≥ 30 kg/m2) women, releasing estrogens and pro-inflammatory cytokines. Adipose stromal cells play a key role in releasing estrogens, while circulating adipose stromal cells (CASCs, characterized as CD34+CD31-CD45-) home to tumor sites and promote angiogenesis and vascularization. CASCs have been correlated with BMI in both cancer and non-cancer patients. However, BMI alone as a marker of adiposity has its limitations. We examined whether CASCs correlate with additional measures of adiposity in women who are at high risk for development of breast cancer.

Methods Women at high risk for development of breast cancer but without prior breast cancer were recruited for random periareolar fine needle aspiration (RPFNA), DEXA body composition, anthropomorphic assessment, and non-fasting venous blood collection. Mononuclear cells were isolated and the frequency of CD34brightCD31-CD45- cells was assessed by flow cytometry.

Results CASC frequency ranged from 0 to 0.018% (median 0.001%) for 13 non-obese and 20 obese women. There was no association between CASC frequency and BMI (range 19 - 46 kg/m2), either as a linear correlation or when dichotomized at a BMI of 30 kg/m2. However, there were tendencies for greater CASC frequencies in pre-menopausal women, women with greater waist circumference (p<0.050), and women with visceral fat mass greater than 50%. With limited numbers, there was no apparent association of CASC frequency with cytology or proliferation (Ki-67) of benign breast epithelial cells acquired by RPFNA.

Conclusions This is the first study to investigate CASC frequency in a cohort of women at high-risk for development of breast cancer. Our results to date do not show an association between CASC frequency and obesity (BMI). However, associations with other indices of visceral fat suggest that evaluation of circulating adipose stromal cells could have value as a biomarker of response in clinical trials of obese breast cancer survivors and high risk women undergoing weight loss (especially fat mass) interventions.

Citation Format: Hailey Baker, Amy L. Kreutzjans, Jennifer L. Nydegger, Teresa L. Phillips, Richard C. Hasting, Dan A. Dixon, Bruce F. Kimler, Carol J. Fabian. Circulating adipose stromal cells (CASCs) as a potential biomarker of response to weight loss interventions in obese women at high risk for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3255. doi:10.1158/1538-7445.AM2017-3255
Abstract 3269: Impact of gender on survival of the patients with esophageal squamous cell carcinoma at a single institute in China
Authors: Lu Jian Liang , Lu Jian Liang , Xu Rui Ping , Li Bei , Wan Li Xin , Chen Ming Yao , Liu Chun Jiang , Han Zhan Qiang , Shen Fang Fang , Zhao Jian Bo , Guo Hai Zhou , Cao Wei , Fan Bing Yu , Wang Li Dong
Published: July 2017

Esophageal cancer (EC) has been well documented with predominant occurrence in male and with major histopathological type of esophageal squamous cell carcinoma (ESCC) in China. However, the influence by gender on ESCC survival is largely unknown in China. The present study was thus undertaken to elucidate the impact by gender on survival of Chinese patients with ESCC. A total of 17,969 ESCC patients was enrolled in this study, including 11,127 males with a mean age of 60.2±8.6 and 6842 females with a mean age of 61.0±8.4.All the patients were from ESCC database in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University (1975 to 2015). Only the patients with T2–4N0–1M0–1 were enrolled in this study. Based on the diagnosed time, the patients were classified into two groups, group I (1996–2005, 6885/38.3%) and group II (2006–2015, 11084/61.7%). The followed–up was undertaken until October, 2016. Kaplan–Meier models were for describing the survival curves and Cox proportional hazards models were undertaken to observe the risk of death of male and female. The results demonstrated that the male patients had a poor survival than female (X2=58.17, P<0.001). Furthermore, similar results were observed for the two different periods of 1996–2005 (X2=21.08, P<0.001) and 2006–2015 (X2=34.67, P<0.001). The present results indicate that gender is an independent survival factor for ESCC and the female patients with ESCC have a dramatic prolonged survival than male patients in China. [Supported by Doctoral Team Foundation of the First Affiliated Hospital of Zhengzhou University (2016-BSTDJJ-03), Natural Science Foundation of Henan

Province (20161110) and Correspondening author: Li Dong Wang, email:ldwang2007@126.com]

Note: This abstract was not presented at the meeting.

Citation Format: Jian Liang Lu, Jian Liang Lu, Rui Ping Xu, Bei Li, Li Xin Wan, Ming Yao Chen, Chun Jiang Liu, Zhan Qiang Han, Fang Fang Shen, Jian Bo Zhao, Hai Zhou Guo, Wei Cao, Bing Yu Fan, Li Dong Wang. Impact of gender on survival of the patients with esophageal squamous cell carcinoma at a single institute in China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3269. doi:10.1158/1538-7445.AM2017-3269
Abstract 327: EpCAM/EpEX regulate tumor progression through EGFR signaling in colon cancer cells
Authors: Liang Kang-Hao , Lai Jun-Kai , Kuan I-I , Tso Hsien-Cheng , Wu Han-Chung
Published: July 2017

Epithelial cell adhesion molecule (EpCAM) is highly expressed in advanced epithelial cancers and tumor-initiated cells (TICs), but its roles in cancer progression remain to be elucidated. Here, we showed that the extracellular domain of EpCAM (EpEX) could bind to EGFR through EGF-like domain I, and subsequently activated its downstream molecules, ERK1/2 and Akt. EGFR inhibitor and knockdown of EGFR by shRNA ablated EpEX-induced ERK1/2 phosphorylation. Regulated intramembrane proteolysis (RIP) of EpCAM was induced similarly by EpEX and EGF through EGFR-dependent activation of ERK pathway. MEK inhibitor, U0126, could abolish ADAM17 and PS2 phosphorylation induced by EpEX. EpAb2-6, an anti-EpEX neutralizing monoclonal antibody, inhibits EpEX-activated EGFR-PI3K-AKT pathway in detached colon cancer cells. Moreover, intracellular domain of EpCAM (EpICD), the product of RIP-induced cleavage of EpCAM, is necessary for nuclear accumulation of β-catenin, and their target gene expressions in vitro and in mouse xenograft models. We also found that an increase of nuclear EpICD observed in CRCs predicted metastasis and poor prognosis in CRC patients. Finally, in animal model studies, EpAb2-6 therapy exhibited an enhanced antitumor effect and markedly extended the survival time of mice with human colorectal cancer in metastatic and orthotopic models. These results demonstrate that EpEX works as a growth factor in activating EGFR-mediated signaling, and as a potential target for treatment of colon cancer. This research was supported by grants from Academia Sinica and Ministry of Science and Technology [MOST 104-0210-01-09-02,MOST 105-0210-01-13-01], and the National Science Council (NSC103-2321-B-001-064), Taiwan (to H-C Wu).

Citation Format: Kang-Hao Liang, Jun-Kai Lai, I-I Kuan, Hsien-Cheng Tso, Han-Chung Wu. EpCAM/EpEX regulate tumor progression through EGFR signaling in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 327. doi:10.1158/1538-7445.AM2017-327
Abstract 3276: Impact of the different treatments on the survival of advanced esophageal squamous cell carcinoma
Authors: Cheng Rang , Zhou Fu You , Wang Neng Chao , Wang Ran , Wang Wei Peng , Wang Xian Zeng , Yue Wen Bin , Zhou Jian Wei , Miao Zhan Hui , Ding Guang Cheng , Bu De Chao , Wang Li Dong
Published: July 2017

Esophageal squamous cell carcinoma (ESCC) remains one of the leading cause of cancer-related death in China. Moreover, more than 90% of the ESCC patients have been in the advanced stage when diagnosed, the 5-year survival is very poor even though the medical techniques have been improved in the past decades. Although the accumulated evidences have suggested the crucial role of genetic changes in esophageal carcinogenesis, the target therapy based on these genetic changes is largely in the very beginning, and radical esophagectomy and radiochemotherapy remain the chief choice for ESCC treatment at present. The present study was thus designed to evaluate the efficacy of the present treatment methods in China to provide more information for optimal choice in advanced ESCC treatment. The enrolled 20,712 ESCC patients in this study were from the ESCC database in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University. Of the patients, there were 12,818 males with a mean age of 59.59±8.2 and 7,894 females with a mean age of 60.34±8.3. All the 20,712 patients were confirmed by histopathology as ESCC at II to IV stage (advanced stage) and classified into three groups based on the treatment methods: radical esophagectomy (R0) alone (17,577, 84.8%), R0 plus radiochemotherapy (2,510, 12.1%) and radiochemotherapy alone (625, 3.1%). The followed-up was undertaken until 2016. The SPSS21.0 software and Kaplan-Meier survival analysis and Log Rank test were used to evaluate the efficiency of different treatments. The results demonstrated that the overall median survival time for the three groups was 5.81 years, 4.82 years and 2.85 years, respectively (P<0.001). Moreover, compared with surgery alone, R0 plus radiochemotherapy did not prolong survival of the advanced patients. Obviously, much efforts, especially combined with genetic application are much desirable to improve the survival for the advanced ESCC patients. [Supported by National High-Tech Research and Development Program of China (SQ2015AA0202183), Project for Characteristic and Advantage Discipline of Henan Province (20151208) and Correspondence to: Li Dong Wang, Email: ldwang2007@126.com]

Note: This abstract was not presented at the meeting.

Citation Format: Rang Cheng, Fu You Zhou, Neng Chao Wang, Ran Wang, Wei Peng Wang, Xian Zeng Wang, Wen Bin Yue, Jian Wei Zhou, Zhan Hui Miao, Guang Cheng Ding, De Chao Bu, Li Dong Wang. Impact of the different treatments on the survival of advanced esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3276. doi:10.1158/1538-7445.AM2017-3276
Abstract 328: PARP inhibitors suppress growth of EGFR-mutant cancers by targeting nuclear PKM2
Authors: Li Nan , Lin Steven H.
Published: July 2017

Poly(ADP-robose) polymerase-1 (PARP1) or ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) is the most abundant and the best understood member of the 17 PARP family proteins. PARP1 binds to both single strand breaks (SSBs) and double-strand breaks (DSBs) and participates in the recognition, excision and repair of DNA damage. The most extensively studied role of PARP1 is its involvement in base excision repair (BER) and PARP inhibition induced-trapping of PARP1 during BER. Moreover, suppression of PARP1/2 leads to synthetic lethality in BRCA1/2-defecient tumors, indicating that PARP1-dependent BER and BRCA-dependent homologous repair pathway have overlapping and redundant functions in DNA repair. Recent studies have also pointed to a broader utility of PARP inhibitors beyond hereditary BRCA-deficient cancers. Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme that converts phosphoenolpyruvate (PEP) into pyruvate. Up-regulation of PKM2 has been shown recently to be an important feature of tumorigenesis. In tumor cells, PKM2 forms a dimmer that is catalytically inactive as a glycolysis enzyme, but provides advantage for tumor progression due to Warburg effect. In this report, we demonstrated that poly-ADP-ribose (PAR) is required for nuclear retention and nuclear function of PKM2. PKM2 translocates into nucleus and binds to PAR upon EGF stimulation. PARP inhibition, or the PKM2-C/A mutant, which abolishes the PKM2/PAR interaction, suppresses the nuclear function of PKM2. In addition, PARP inhibition also diminishes the nuclear PKM2-dependent glycolysis and tumor growth. Moreover, we showed that nuclear localization of PKM2 correlates with PAR expression in EGFR-mutant human lung cancer tissues. Interestingly, PARP inhibition leads to growth suppression of some EGFR-mutant lung cancer cells, which are resistant to EGFR inhibitor. These data together support an unexpected function of PARP inhibition in tumor suppression and indicate that nuclear PKM2 may serve as a promising biomarker for the further development of PARP inhibitor-based therapies.

Note: This abstract was not presented at the meeting.

Citation Format: Nan Li, Steven H. Lin. PARP inhibitors suppress growth of EGFR-mutant cancers by targeting nuclear PKM2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 328. doi:10.1158/1538-7445.AM2017-328
Abstract 3288: Effects of concomitant metformin and statins on overall survival of pancreatic cancer patients: results from SEER-Medicare data analyses
Authors: E Jian-Yu , Lu Shou-En , Lin Yong , Graber Judith M. , Rotter David , Zhang Lanjing , Petersen Gloria M. , Demissie Kitaw , Lu-Yao Grace , Tan Xiang-Lin
Published: July 2017

Purpose: Growing mechanistic and epidemiologic evidence suggests that both metformin and statins have anti-cancer effects and are associated with reduced pancreatic cancer mortality. However, the joint effect of combination statin/metformin on pancreatic cancer mortality is unknown. By applying a robust analytic approach, we aim to examine the association between metformin and/or statin use and overall survival in a large cohort of patients with primary pancreatic adenocarcinoma (PDAC). Patients and Methods: 12,572 elderly patients with primary PDAC diagnosed between 2008 and 2012 were identified by using the Surveillance, Epidemiology, and End Results (SEER), and the detailed information on metformin and statin use was extracted from Medicare Part D. A Cox proportional hazard model with time-varying covariate adjusted for the propensity score was applied to assess the association of metformin and /or statin use with overall survival while controlling for potential confounders. Results: Of total 12,572 PDAC patients (median age = 76 years), 11,526 (91.77%) patients died before the study ended with a median follow-up of 3.8 months (interquartile range: 1.4-10.1). By the time-varying covariate analysis, statin use was significantly associated with an improved overall survival [Hazard ratio (HR), 0.938; 95% confidence interval (CI), 0.898 to 0.979], and more pronounced in post-diagnosis statin users (HR, 0.693; 95% CI, 0.555 to 0.864). However, metformin use was not significantly associated with overall survival (HR, 1.011; 95% CI, 0.939 to 1.091), neither in pre-diagnosis users (HR, 1.015; 95% CI, 0.970 to 1.061) nor in post-diagnosis users (HR, 0.990; 95% CI, 0.866 to 1.131). Additionally, no superior beneficial effect was observed for dual users (HR, 0.998; 95% CI, 0.947 to 1.053). Conclusions: Exposures to statin, not metformin, was significantly associated with reduced overall mortality of PDAC, indicating potential benefits of statin use on improving survival among PDAC patients. Further prospective validation is required to confirm these findings.

Citation Format: Jian-Yu E, Shou-En Lu, Yong Lin, Judith M. Graber, David Rotter, Lanjing Zhang, Gloria M. Petersen, Kitaw Demissie, Grace Lu-Yao, Xiang-Lin Tan. Effects of concomitant metformin and statins on overall survival of pancreatic cancer patients: results from SEER-Medicare data analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3288. doi:10.1158/1538-7445.AM2017-3288
Abstract 3290: Cancer mortality by antiarrhythmic drug use in a population-based cohort of Finnish men
Authors: Kaapu Kalle J. , Murtola Teemu , Talala Kirsi , Taari Kimmo , Tammela Teuvo , Auvinen Anssi
Published: July 2017

Introduction: In-vitro studies have suggested that antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. A non-selective beta-blocker sotalol has similar effect on K+-channels. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study.

Materials and methods: The study population consists of 78,615 men originally identified for the Finnish Randomized Study for Screening of Prostate Cancer. Men were 55-69 years old at baseline. Prevalent prostate cancer cases were excluded; no exclusions were made based on other cancer types. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used Cox regression method to analyze the overall cancer mortality and individually mortality from the most common causes of cancer death.

Results: A total of 8,064 men (10.3%) had used antiarrhythmic drugs. Of these 5,668 had used digoxin and 2,540 had used sotalol. During the median follow-up of 16.9 years after baseline 26,790 (34.1%) men died, of these 8,225 (30.7% of deaths) due to cancer. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.25, 95% CI 1.12-1.40). Similar results were observed for digoxin (HR 1.44, 95% CI 1.26-1.63) but not for sotalol (HR 0.92, 95% CI 0.68-1.24). Furthermore, the antiarrhythmic drug use was associated with elevated risk of lung-cancer death (HR 1.76 95% CI 1.46-2.14). However, the risk associations disappeared in long-term use. When we restricted the analysis to cancer cases only, no differences were observed in survival after the cancer diagnosis for any cancer type.

Conclusion: Cancer mortality was elevated among users of antiarrhythmic drugs compared to non-users. This association is probably due to the differences between users and non-users as it was related to short-term use, and disappeared in long-term use. Use of digoxin or sotalol was not associated with improved cancer-specific survival.

Citation Format: Kalle J. Kaapu, Teemu Murtola, Kirsi Talala, Kimmo Taari, Teuvo Tammela, Anssi Auvinen. Cancer mortality by antiarrhythmic drug use in a population-based cohort of Finnish men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3290. doi:10.1158/1538-7445.AM2017-3290
Abstract 3297: Survival predictors of Burkitt's lymphoma in children, adults and elderly in the United States during 2000-2013
Authors: Mukhtar Fahad , Boffetta Paolo , Risch Harvey A. , Park Jong Y. , Bubu Omonigho M. , Womack Lindsay , Tran Thuan V. , Zgibor Janice C. , Luu Hung N.
Published: July 2017

Background. Burkitt’s Lymphoma (BL) has three peaks of occurrence, in children, adults and elderly, at 10, 40 and 70 years respectively. To the best of our knowledge, no study has been conducted to assess predictors of survival in the three age groups. We hypothesized that the predictors of survival may differ by age group. We, therefore, sought to determine the predictors of survival for BL in these three groups: children (<15 years of age), adults (40-70 years of age) and elderly (>70 years of age).

Methods. Using the Surveillance, Epidemiology, and End Results (SEER) database covering the years 2000-2013, we identified 797 children, 1,994 adults and 757 elderly patients newly diagnosed with BL. We used Cox proportional hazards regression models to determine prognostic factors for survival for each age group.

Results. Five-year relative survival in BL for children, adults and elderly were 90.4%, 47.8%, and 28.9%, respectively. Having at least stage II disease and multiple primaries were associated with higher mortality in the elderly group. In adults, multiple primaries, stage III or IV disease, African American race and bone marrow primary were associated with increased mortality whereas stage IV disease and multiple primaries were associated with worse outcome in children.

Conclusion. These findings demonstrate commonalities and differences in predictors of survival that may have implications for management of BL patients.

Financial Support: This work was supported by the US National Institutes of Health/National Cancer Institute 1P20CA210300-01 (PI: Shu XO, Tran T/Sub-contract-PI: Luu HN) and the University of South Florida start-up grant (PI: Luu HN).

Note: This abstract was not presented at the meeting.

Citation Format: Fahad Mukhtar, Paolo Boffetta, Harvey A. Risch, Jong Y. Park, Omonigho M. Bubu, Lindsay Womack, Thuan V. Tran, Janice C. Zgibor, Hung N. Luu. Survival predictors of Burkitt's lymphoma in children, adults and elderly in the United States during 2000-2013 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3297. doi:10.1158/1538-7445.AM2017-3297
Abstract 3299: Radiation induced p53-dependent cytoprotective autophagy fails to reduce radiation sensitivity in H460 non-small cell lung cancer cells
Authors: Xu Jingwen , Saleh Tareq , Tyutynuk-Massey Liliya , Wu Yingliang , Gewirtz David A.
Published: July 2017

Our previous studies showed that radiation-induced autophagy could be either cytoprotective or nonprotective in A549 non-small cell lung cancer cells, HN30 and HN6 head and neck cancer cells and 4T1 breast tumor cells, and that this functional difference was related to the status of p53 in the cells (i.e. cytoprotective autophagy in p53 wild type (wt) cells and nonprotective autophagy in cells with mutant or null p53) [1]. Despite the fact that inhibition of autophagy has been proposed as a strategy to overcome resistance to radiation and chemotherapy, there is little direct information in support of the premise that the induction of autophagy confers resistance. As an example, studies in HCT-116 cells that are either wt or null in p53 demonstrate essentially identical radiation sensitivity [2], although the nature of radiation induced autophagy was not determined in these cell lines. To address this question, p53 wt and p53 null H460 cell lines were utilized to evaluate whether cytoprotective autophagy actually suppressed radiation sensitivity. Acridine orange staining, flow cytometric analysis and western blotting (LC3B, p62, Atg5) showed that following exposure to 6 Gy of radiation wtp53 and p53-null H460 cells exhibited a significant induction of autophagy. p53 wt H460 cells showed sensitization to radiation upon pharmacological autophagy inhibition and Atg5 knock down. However, pharmacological inhibition of autophagy and knock down of Atg5 genes failed to influence sensitivity to radiation in p53-null H460 cells. Furthermore, clonogenic survival assays showed that while exposure to radiation induced a dose-dependent (2, 4, 6, 8 Gy) decrease in clonogenicity in both p53wt and p53-null H460 cells, radiation sensitivity was not decreased in the p53 wt cells. Taken together, these findings indicate that cytoprotective autophagy may not actually alter the nature of radiation (and possibly chemotherapeutic) sensitivity in tumor cells. [1] Chakradeo, S, et al. Mol Pharm (2015): [2] Lindgren, T, et al. Int J Rad Biol (2015). Acknowledgments We would like to thank Dr. Santiago Lima (Virginia Commonwealth University) for the H460 p53-null cells.

Citation Format: Jingwen Xu, Tareq Saleh, Liliya Tyutynuk-Massey, Yingliang Wu, David A. Gewirtz. Radiation induced p53-dependent cytoprotective autophagy fails to reduce radiation sensitivity in H460 non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3299. doi:10.1158/1538-7445.AM2017-3299
Abstract 330: SGK1 activation is essential for PI3K-dependent tumor development
Authors: Orlacchio Arturo , Cristofano Antonio Di
Published: July 2017

The PI3K signaling cascade is frequently activated in human cancer, with AKT being commonly considered its major transforming conduit.

Conditional deletion of Pten in the mouse thyroid epithelium induces constitutive activation of the PI3K pathway, which causes thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. Concomitant loss of p53 or activation of KRAS dramatically accelerates the development of aggressive and lethal tumors.

The PDK1 kinase plays a key role in the PI3K signaling cascade, directly activating, in a PI3K-dependent manner, not only AKT but also a set of additional AGC kinases, including, S6K, PKC, and SGK.

Using in vivo, ex vivo, and in vitro genetic and pharmacological approaches, we now show that AKT activation is not sufficient to transform thyroid epithelial cells. Concomitant activation of additional PDK1-dependent pathways is absolutely required to develop neoplastic lesions in vivo, and to induce cell proliferation ex vivo, in mouse models based on Pten loss, alone and in combination with additional genetic alterations.

In particular, we show that one member of the SGK family, SGK1, is an essential mediator of the transformation process downstream of PI3K.

Genetic and pharmacological SGK1 inhibition strongly reduces cell proliferation in Pten-/-and PIK3CA-mutant cell lines.

Moreover we show that concomitant SGK inhibition significantly increases the efficacy of inhibitors targeting AKT or PI3K.

Taken together, our data identify an essential and druggable signaling cascade that critically cooperates with AKT activation to transform thyroid epithelial cells.

Citation Format: Arturo Orlacchio, Antonio Di Cristofano. SGK1 activation is essential for PI3K-dependent tumor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 330. doi:10.1158/1538-7445.AM2017-330
Abstract 3304: Inhibition of autophagy enhances mitochondria-mediated apoptosis in malignant mesothelioma cells by cisplatin and sulforaphane
Authors: Lee Yoon Jin , Lee David M. , Nam Hae , Lee Sang
Published: July 2017

Drug resistance to current chemotherapy regimens has been considered a cell survival adaptive response in malignant mesothelioma cells. Therefore, new strategies to enhance the apoptotic signal and overcome resistance to chemotherapeutics are necessary to improve treatment outcomes for this deadly disease. Here, the effect of sulforaphane, an isothiocyanate compound derived from glucoraphanin present in cruciferous vegetables, on enhancing anticancer role of cisplatin was investigated in malignant mesothelioma cells. At concentrations showing little toxicity in normal human mesothelial MeT-5A cells, the combined treatment with both compounds exhibited synergistic growth-inhibiting and apoptosis-promoting effects, as demonstrated in a series of pro-apoptotic events including reactive oxygen species (ROS) accumulation, loss of mitochondrial membrane potential, up-regulation of p53, increased Bax/Bcl-2 ratio, activation of caspase-3, and the occurrence of a sub-G0/G1 peak with an increase in the cells with pyknotic and fragmented nuclei, Annexin V-PE(+), and G2/M phase transition delay in the cell cycle. The levels of phosphorylation of both Akt and mTOR were decreased by the combined treatment, which was accompanied by a significant increase in the level of autophagosomal marker protein LC3-II and the accumulation of acidic vesicular organelles. Furthermore, scavenging of ROS by antioxidant N-acetylcysteine inhibited both the apoptosis and autophagy, while the inhibition of autophagy by bafilomycin A1 potentiated apoptotic cell death following the combination treatment of sulforaphane and cisplatin, indicating the cytoprotective role of autophagy counteracts apoptosis of malignant mesothelioma cells. Considering the pro-oxidant-based combinational approach, our data provide a rationale for targeting cytoprotective autophagy as a potential therapeutic strategy for malignant mesothelioma.

Citation Format: Yoon Jin Lee, David M. Lee, Hae Nam, Sang Lee. Inhibition of autophagy enhances mitochondria-mediated apoptosis in malignant mesothelioma cells by cisplatin and sulforaphane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3304. doi:10.1158/1538-7445.AM2017-3304
Abstract 3315: Cancer cells upregulate autophagy as a survival mechanism in response to tumor treating fields (TTFields)
Authors: Porat Yaara , Shteingauz Anna , Giladi Moshe , Schneiderman Rosa S. , Voloshin Tali , Munster Mijal , Blat Roni , Kirson Eilon D. , Weinberg Uri , Palti Yoram
Published: July 2017

Tumor treating fields (TTFields) are an established anti-neoplastic treatment modality in patients with glioblastoma. TTFields are delivered via noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to the region of the tumor. Previous studies have shown that TTFields treatment lead to increased cellular granularity, which is often associated with autophagy. Autophagy has been shown to regulate cell survival and proliferation under stress conditions and to influence cellular response to cytotoxic drugs. This study evaluated the role of autophagy in cancer cells treated with TTFields.

Immunoblot analysis showed significant elevations in levels of lipidated Microtubule Associated Protein Light Chain (LC3-II) in TTFields-treated glioma and lung cancer cells. Increased autophagy following TTFields application in these cell lines was also detected using fluorescence microscopy, where punctate distribution of LC3-II was observed. TEM micrographs demonstrated the presence of autophagy typical, autophagosome-like structures in TTFields-treated U-87 MG cells. Combination of TTFields with autophagy inhibitors, chloroquine and melfoquine, resulted in a significant dose-dependent reduction in cell growth compared with TTFields treatment alone. Inhibition of autophagy with chloroquine triggered apoptosis as indicated by elevated levels of AnnexinV/7AAD double staining. Increased levels of autophagic flux in TTFields-treated cells were not associated with reduced mTOR activity, which was monitored by p70S6K phosphorylation immunoblot analysis.

TTFields are known to exert anti-mitotic effects by disrupting highly dipolar structures that play critical roles in mitosis. Our results demonstrate that TTFields additionally induce cellular autophagy by an mTOR-independent mechanism. TTFields- treated cell lines appear to utilize autophagy as a survival mechanism. Thus, inhibition of autophagy sensitizes tumor cells to TTFields treatment, resulting in elevated apoptotic cell death.

Future studies are warranted to examine the extent to which TTFields-elicited autophagy may affect treatment outcomes and to investigate the therapeutic implications of combining TTFields with autophagy inhibitors in vivo.

Citation Format: Yaara Porat, Anna Shteingauz, Moshe Giladi, Rosa S. Schneiderman, Tali Voloshin, Mijal Munster, Roni Blat, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Cancer cells upregulate autophagy as a survival mechanism in response to tumor treating fields (TTFields) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3315. doi:10.1158/1538-7445.AM2017-3315
Abstract 3316: Mieap, the mitochondria-eating protein, induces cell death by eating unhealthy mitochondria
Authors: Nakamura Yasuyuki , Tsuneki Masayuki , Yamamoto Makoto , Arakawa Hirofumi
Published: July 2017

Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. Mieap suppresses murine intestinal tumor via its mitochondrial quality control (1). Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer (2). To explore the role of the Mieap-regulated mitochondria quality control function in human colorectal cancer tissues, we examined the Mieap expression in primary colorectal cancer tissues by performing immunohistochemical analysis with anti-human Mieap antibody. Mieap expression was very low in normal colorectal epithelial cells, whereas the strong expression of the Mieap protein was detected in the hypoxic cell death regions of colorectal adenoma and adenocarcinoma, suggesting the role of Mieap in hypoxic cell death. Overexpression of Mieap in vitro induced large vacuole structures (MIV: Mieap-induced vacuole) in HCT116 colorectal cancer cells (Mieap-deficient colorectal cancer cells). MIV engulfed and degraded unhealthy mitochondria, leading to caspase-dependent cancer cell death. Re-expression of Mieap in HCT116 cells resulted in striking suppression of tumor growth in vivo. These results suggest that Mieap plays a critical role in hypoxic tumor cell death via lysosomal degradation of unhealthy mitochondria.

(1) Tsuneki et al. Mieap suppresses murine intestinal tumor via its mitochondrial quality control. Sci. Rep. 5: 12472 (2015). (2) Kamino et al. Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer. Oncogenesis 5: e181 (2016).

Citation Format: Yasuyuki Nakamura, Masayuki Tsuneki, Makoto Yamamoto, Hirofumi Arakawa. Mieap, the mitochondria-eating protein, induces cell death by eating unhealthy mitochondria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3316. doi:10.1158/1538-7445.AM2017-3316
Abstract 332: Loss of primary cilia promotes LPA-driven proliferation in glioblastoma
Authors: Loskutov Yuriy
Published: July 2017

Glioblastoma is one of the most common brain cancers with a median survival of 13 months. Therapeutic approaches for this type of cancer are very limited, creating an urgent need to develop new strategies for the treatment. Recently several groups reported that glioblastoma have a drastic decrease in primary cilia, suggesting that loss of cilia might be important for glioblastoma biology. The primary cilium is a ubiquitous microtubule based organelle presented on most of human cells. It plays significant role in embryonic development and tissue homeostasis, serving as a hub for multiple signaling cascades including RTK, Sonic Hedgehog, Wnt and Hippo. Here we report that loss of primary cilia in immortalized astrocytes stimulate cell proliferation and drastically change ERK1/2 activation in response to serum. These changes depend on lysophosphotidic acid (LPA), a water-soluble lipid metabolite, implicated in chemotactic and proliferative signaling. The receptor to LPA type 1 tends to accumulate in the primary cilia, indicating its potential role in inhibition/restriction of LPA-dependent mitogenic signaling via dynamic changes in primary cilium. Loss of primary cilia can lead to LPA receptors 1 redistribution to the plasma membrane and switch cellular response for the LPA, allowing it to act as mitogen. Inhibition of LPA receptors with a small molecule inhibitor, Ki16425, is significantly decreasing the growth of glioblastoma PDXs. Overall, our findings clearly indicate that loss of primary cilia is sufficient to severely change mitogen-driven signal transduction and point towards the new therapeutic target for glioblastoma.

Citation Format: Yuriy Loskutov. Loss of primary cilia promotes LPA-driven proliferation in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 332. doi:10.1158/1538-7445.AM2017-332
Abstract 3326: Identification of a novel androgen receptor co-regulator in prostate cancer
Authors: Shatnawi Aymen A. , Malkaram Sridhar Acharya , Tsouko Efrosini , Frigo Daniel E.
Published: July 2017

Prostate cancer (PC) is one of the most frequently diagnosed tumors in the United States, affecting one in six men during their lifetime and second only to lung cancer as a cause of cancer death in men. One of the major drivers of prostate cancer is the androgen receptor (AR). It has been shown that deregulation of AR co-regulators play a crucial role in PC through modulating the transcriptional activity of the receptor. While the importance of the AR complex is well established, there is still an incomplete understanding of what all the associated co-regulators are and how they modulate AR signaling. Here, we have identified that the inhibitor of growth family member 4 (ING4), a protein that has been implicated in the pathogenesis of several solid tumors such as gastric and breast cancer, is a novel AR co-regulator. Overexpression of ING4 increased AR activity in an androgen-dependent manner as assessed using luciferase reporter gene assays. Supporting a role as a potential AR co-activator, RNA Next-Generation Sequencing of prostate cancer cells with ING4 knocked down revealed a repression of endogenous AR/R1881-activated genes and expression of AR/R1881 suppressed genes. Further, mining of existing clinical datasets revealed that the ING4 gene expression is de-regulated in PCs compared relative to normal tissue and tracks with poor patient prognosis. Collectively, the current findings strongly support the involvement of ING4 in AR signaling and PC progression and development.

Citation Format: Aymen A. Shatnawi, Sridhar Acharya Malkaram, Efrosini Tsouko, Daniel E. Frigo. Identification of a novel androgen receptor co-regulator in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3326. doi:10.1158/1538-7445.AM2017-3326