bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 856: Combination of crizotinib and radiation in the treatment of ALK-positive and cetuximab-resistant lung cancer
Authors: Li Chunrong , Huang Shyhmin , Walters Noah , Armstrong Eric A. , Harari Paul M.
Published: May 2015

Approximately 4% of patients with non-small cell lung carcinoma (NSCLC) carry the EML4-ALK chromosomal rearrangement. Crizotinib, a c-MET and ALK inhibitor, has shown significant therapeutic benefit as a single agent with FDA approval for the treatment of patients with ALK-positive NSCLC. Since radiation commonly plays a key role in lung cancer treatment, we sought to evaluate the potential of crizotinib as a radiation sensitizer and the role of ALK in cellular radiation sensitivity. We examined the effect of crizotinib in combination with radiation on ALK signaling, cell proliferation, cell cycle distribution and radiosensitivity in ALK-positive NSCLC cell lines H3122 and H2228 in vitro. We also examined the in-vivo effects of crizotinib in combination with radiation in H3122 and H2228 xenograft models.

Crizotinib blocked phosphorylation of ALK and its downstream effectors and inhibited cell proliferation in a dose-dependent manner. The combination of crizotinib and radiation resulted in increased inhibition of cell growth. Although cells were sensitized to radiation by crizotinib, molecular knockdown of ALK by siRNA had only modest impact on cell radiosensitivity. Cell cycle analysis by flow cytometry showed that ALK-siRNA induced G1 arrest. Interestingly, low dose crizotinib induced G1 arrest, while doses above 2µM induced G2 arrest. Combination treatment induced arrest in G1 and G2 phases and decreased the cell population in S-phase. Moreover, in xenograft tumor models, we observed combined treatment to produce additive tumor growth inhibition over that observed with either drug or radiation alone.

We further examined the capacity of crizotinib overcome cetuximab resistance in our established in vitro resistance models. Compared with parental cells, cetuximab-resistant cells showed cross-resistance to radiation. Crizotinib inhibited the growth of cetuximab-resistant cells and resensitized cells to radiation. Compared with single-agent treatment, the combination of crizotinib and erlotinib resulted in increased growth inhibition and further re-sensitization to radiation.

These data suggest that crizotinib in combination with radiation can enhance the inhibitory effect on ALK-positive tumor cell growth in vitro and in-vivo and also suggest the potential value of using crizotinib in combination with other EGFR-targeting therapeutics. Ultimately however, the potential value of crizotinib as a radiation sensitizer requires systematic clinical investigation.

Citation Format: Chunrong Li, Shyhmin Huang, Noah Walters, Eric A. Armstrong, Paul M. Harari. Combination of crizotinib and radiation in the treatment of ALK-positive and cetuximab-resistant lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 856. doi:10.1158/1538-7445.AM2014-856
Abstract 86: Heterozygous expression of an oncogenic Pik3ca mutation during murine development results in fatal embryonic and extra-embryonic defects
Authors: Hare Lauren M. , Schwarz Quenten , Gurung Rajendra , Montgomery Karen G. , Mitchell Christina , Phillips Wayne A.
Published: May 2015

The PI3K/Akt signalling pathway regulates many important cellular functions including proliferation, migration, survival and angiogenesis. The PIK3CA gene, encoding the p110α catalytic subunit of the PI3K enzyme, is somatically mutated in a range of human cancers and overgrowth syndromes. We have previously described a novel mouse model with a Cre-recombinase (Cre)-mediated knock-in of the common cancer-associated Pik3ca(H1047R) mutation that can be targeted to selected tissues using various Cre-expressing mouse strains. As the mutation is knocked in to the endogenous gene, the mutant protein is expressed at normal physiological levels.

We have used the Cre-deleter mouse to induce expression of the Pik3ca(H1047R) mutation ubiquitously from the 2-cell stage of development. This results in embryonic lethality by E10.5 with embryos at E9.5 demonstrating stunted growth, failed ‘turning’ and abnormal cardiovascular development in both the embryo proper and extraembryonic yolk sac. These tissues also showed increased expression of vascular endothelial growth factor (VEGF) family proteins. We then selectively targeted the mutation to the endothelial cells of the developing embryo using the Tie2-Cre mouse strain. No Tie2-Cre:Pik3ca(H1047R) mutant embryos survived to E11.5 and at E10.5, while successfully turned, embryos were severely underdeveloped and no longer viable. At E9.5, vascular remodelling was disorganised and truncated in the embryo proper and yolk sacs. Development of the heart was also affected with clear disruption to anterior cardinal vein and dorsal aorta development.

Our results demonstrate the importance of PI3K/Akt signalling in embryonic development and cardiovascular formation in the mouse. The observed cell autonomous role in vessel development was further confirmed upon targeted expression to endothelial cells while the increased expression of various VEGF family proteins suggests probable crosstalk between the PI3K/Akt and VEGF signalling pathways during cardiovascular development. The lethality associated with expression of Pik3ca(H1047R) mutation during development likely explains the lack of inherited germline PIK3CA mutations in humans.

Citation Format: Lauren M. Hare, Quenten Schwarz, Rajendra Gurung, Karen G. Montgomery, Christina Mitchell, Wayne A. Phillips. Heterozygous expression of an oncogenic Pik3ca mutation during murine development results in fatal embryonic and extra-embryonic defects. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 86. doi:10.1158/1538-7445.AM2014-86
Abstract 863: Clinical significance of mucinous production in rectal cancer after preoperative chemoradiotherapy
Authors: Kaneko Kensuke
Published: May 2015

Background: Mucinous adenocarcinoma (MA) is a relatively rare histological subtype of colorectal cancer, in which more than 50% of the tumor is occupied by extracellular mucin. MA has been reported to be associated with poor response to neoadjuvant chemoradiotherapy (CRT), but the prognostic significance still remains to be evaluated. Here, we aimed to analyze the prognostic significance of mucin production in the response of rectal cancer to neoadjuvant CRT.

Methods: The medical records of 141 consecutive patients receiving rectal resection after neoadjuvant CRT for the treatment of rectal cancer at our institution, in the period between October 2003 and December 2012, were retrospectively reviewed. For the histological evaluation, Hematoxylin-Eosin (HE) and Periodic Acid Schiff/Alcian Blue (PAS/AB) stainings were used. Mucin production was evaluated according to the proportion of the tumor area occupied by extracellular mucin, and cases were sorted, according to the mucin occupancy rate, into three groups, namely, low (0 - 5%), medium (5 - 25%) and high (>25%).

Results: The number of patients in the low, medium and high mucin rate groups was 89 (63.1%), 28 (19.9%) and 24 (17.0%), respectively. Only advanced tumor stage out of histological features had a significant correlation with the high mucin rate group. Compared to the low mucin rate group, patients in the high group had a worse prognosis in disease free survival, and also a worse prognosis in distant recurrence free survival, compared to the medium group, while no significant difference was observed among the three groups in overall and local recurrence-free survivals. Multivariate analysis showed that the high mucin rate group had an independent association with shorter disease-free survival, and those advanced stage tumors (T3 and T4) with a high mucin rate had an independent association with shorter distant recurrence-free survival.

Conclusion: Mucinous production in rectal cancer may be associated with resistance to neoadjuvant CRT. Thus, careful histological analysis for the presence of extracellular mucin should be indicated for rectal patients receiving neoadjuvant CRT, and those cases with high mucin rate (> 25% mucinous component) should be closely followed-up.

Citation Format: Kensuke Kaneko. Clinical significance of mucinous production in rectal cancer after preoperative chemoradiotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 863. doi:10.1158/1538-7445.AM2014-863
Abstract 866: Identification of novel early detection candidate protein biomarkers for ER+/PR+ invasive ductal breast carcinoma using pre-clinical plasma from the Women's Health Initiative Observational Study
Authors: Buas Matthew F. , Zhang Yuzheng , Rho Junghyun , Pepe Margaret , Lampe Paul , Li Christopher
Published: May 2015

Estrogen receptor (ER)-positive/progesterone receptor (PR)-positive invasive ductal carcinoma accounts for approximately 45% of all invasive breast cancers (BC) diagnosed in the United States each year. While mammography screening and adjuvant hormonal therapy have played key roles in reducing breast cancer mortality, an important challenge remains the development of clinically useful blood-based biomarkers for early detection. The objective of this study was to identify and initially validate novel candidate markers for ER+/PR+ ductal BC, using pre-clinical plasma samples collected up to 12.5 months before diagnosis from 121 cases, 121 matched controls, and 201 non-matched controls from the Women's Health Initiative Observational Study. These specimens were equally divided into training and testing sets and interrogated by a customized antibody array, which included over 3,000 antibodies targeting more than 2,000 proteins. In the training set, statistically significant differences in matched case versus control signals were observed for 374 (11.4 %) antibodies at P<0.05, with 42 of these 374 candidates confirmed in the testing set (P<0.05). Four markers remained significant in the pooled matched pairs sample set after Bonferroni correction for multiple comparisons (P<0.05/3286=1.52x10-5). Areas under the curve for the full list of candidates ranged from 0.55 to 0.66, when assessed in an expanded sample including non-matched controls. With specificity set at 95%, sensitivity ranged from 4 to 19%, with six candidates having a sensitivity of ≥15% at 95% specificity and ≥20% at 90% specificity. The majority of these putative markers did not overlap with those identified in a parallel analysis of triple-negative BC from the same cohort population, suggesting the potential for BC sub-type specificity at the level of the pre-clinical plasma proteome. Additional studies are needed to validate these findings in larger sample sets and further explore their biologic implications in relation to ER+/PR+ BC etiology.

Citation Format: Matthew F. Buas, Yuzheng Zhang, Junghyun Rho, Margaret Pepe, Paul Lampe, Christopher Li. Identification of novel early detection candidate protein biomarkers for ER+/PR+ invasive ductal breast carcinoma using pre-clinical plasma from the Women's Health Initiative Observational Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 866. doi:10.1158/1538-7445.AM2014-866
Abstract 868: Characterization of LASEP3 as a serological and prognostic biomarker and a therapeutic target for lung cancer
Authors: Takano Atsushi , Nakamura Yusuke , Daigo Yataro
Published: May 2015

This study aims to identify novel biomarkers or therapeutic targets for lung cancers. We used cDNA microarrays for screening genes encoding transmembrane/secretory proteins that are up-regulated in lung cancers. During this process, we identified a secreted protein, LASEP3 (lung cancer-associated serum protein 3) as a candidate. Immunohistochemical staining of LASEP3 showed that LASEP3 expression was observed in 198 (54.8%) of 361 NSCLCs (non-small cell lung cancer) that had undergone curative surgery. High level of LASEP3 expression was associated with poor prognosis for NSCLC patients. (P=0.0183 by log-rank test). Serum LASEP3 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP3-positive cases was 160 (61.8%) of 259 NSCLCs (49.4% for stage I-II, 67.4% for stage III-IV), while 6 (5.5%) of 109 healthy volunteers were falsely diagnosed. Moreover serum LASEP3 levels were significantly higher in breast and colon cancer patients than in healthy volunteers. LASEP3 protein was overexpressed in breast and colon cancer tissues. Furthermore, reduction of LASEP3 by siRNA suppressed lung cancer cell proliferation and invasion. Flow cytometric analysis of these tumor cells transfected with siRNAs for LASEP3 revealed a significant increase of the cells at the G1 phase. Furthermore, subsequent microarray analysis of these cancer cells identified several candidate downstream genes of LASEP3 that relate to cell growth signals. These data suggest that LASEP3 is a possible diagnostic and prognostic biomarker and therapeutic target for lung and various types of solid cancer.

Citation Format: Atsushi Takano, Yusuke Nakamura, Yataro Daigo. Characterization of LASEP3 as a serological and prognostic biomarker and a therapeutic target for lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 868. doi:10.1158/1538-7445.AM2014-868
Abstract 872: APE1/Ref-1 as a serological biomarker for the detection of bladder cancer
Authors: Choi Sunga , Shin Ju Hyun , Lee Yu Ran , Park Myoung Soo , Yim Chang Nam , Na Young Gil , Lim Jae Sung , Jeon Byeong Hwa
Published: May 2015

Apurinic/apyrimidinic endonuclease1/redox factor-1 (APE1/Ref-1) is a DNA repair enzyme whose expression is increased in several forms of cancerous cells. We investigated whether serum APE1/Ref-1 is elevated in patients with bladder cancer. Tumor tissue and serum from patients with bladder cancer who had not received chemotherapy or radiotherapy (n=51) and non-tumor healthy controls (n=55) was used. In immunohistochemistry, and immunoblot analysis, the APE1/Ref-1 protein level of bladder tissues was increased in patients with bladder cancer. The serum APE1/Ref-1 levels were significantly elevated in bladder cancer patients than in those of non-tumor healthy controls and its levels were correlated with tumor staging and grading. The ROC curve of APE1/Ref-1 showed an excellent area under the ROC curve of 0.824. In this study, the optimal combination of sensitivity and specificity were determined as 93% and 59% for a cut-off value of serum APE1/Ref-1 of 2.83 ng/100 μl, respectively. The serum APE1/Ref-1 levels are increased in patients with bladder cancer with recurrence. These data indicate serum APE1/Ref-1 may help to identify patients with bladder cancer and it can be used as a serological marker of bladder cancer.

Citation Format: Sunga Choi, Ju Hyun Shin, Yu Ran Lee, Myoung Soo Park, Chang Nam Yim, Young Gil Na, Jae Sung Lim, Byeong Hwa Jeon. APE1/Ref-1 as a serological biomarker for the detection of bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 872. doi:10.1158/1538-7445.AM2014-872
Abstract 878: Identification and characterization of tumor-associated antigens as biomarkers in human prostate cancer
Authors: Li Jitian , Dai Liping , Casiano Carlos A. , Zhang Jianying
Published: May 2015

Autoantibodies against intracellular antigens are commonly found in a number of systemic autoimmune diseases. Their utility in providing insights into molecular and cellular biology and in the differential diagnosis of autoimmune diseases is well documented. Autoimmune phenomena manifested as antibodies to cellular components have been described in many types of cancer. Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the second leading cause of male cancer deaths in the United States. PCa also presents the greatest racial disparity in this country, with an incidence and mortality in African-American men that is 3 times higher than in White and Latino men. Reducing these disparities would require a multi-faceted approach that includes developing more effective screening method for the early detection of PCa. The objective of this study is to analyze the frequency and specificity of autoantibodies in PCa patients, and further to identify and characterize the targeted tumor-associated antigens. In this study, 34 sera from PCa patients, and 30 sera from normal human individuals were examined for autoantibodies using indirect immunofluorescence (IIF) assay and western blotting. Autoantibodies were detected in 18 of 34 (52.9%) PCa sera by IIF, which was significantly higher than that in normal human sera. Of the interest is that of 34 PCa sera, 9 (26.5%) sera were identified by western blotting analysis containing antibodies against an unknown 70kDa cellular protein and 23.5% PCa patients showed antibody to 45 kDa protein. No reactivity with 70KDa and 45kDa proteins was detected in 30 normal human sera. In the further study, these cellular proteins targeted by serum antibodies in PCa were identified by using two-dimensional gel electrophoresis (2DE) and liquid chromatography-tandem-mass spectrometry (LC-MS/MS). This preliminary data supports that autoimmune responses to certain cellular proteins maybe a by-product in the transformation to PCa, and further studies of novel targeted proteins in PCa may provide insights into how these proteins might be involved in malignancy.

Citation Format: Jitian Li, Liping Dai, Carlos A. Casiano, Jianying Zhang. Identification and characterization of tumor-associated antigens as biomarkers in human prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 878. doi:10.1158/1538-7445.AM2014-878
Abstract 879: New serum biomarkers for prostate cancer diagnosis
Authors: Chadha Kailash C. , Miller Austin , Nair Bindukumar B. , Schwartz Stanley A. , Trump Donald L. , Underwood Willie
Published: May 2015

Prostate-specific antigen (PSA) is currently used as a biomarker for the early diagnosis and management of prostate cancer (CaP). However, PSA generally lacks the sensitivity and specificity desired of an effective diagnostic biomarker. The goal of this study was to identify an additional biomarker or a panel of biomarkers that is more sensitive and specific than PSA in differentiating benign vs. malignant prostate disease and/or localized CaP vs. metastatic CaP.

Concurrent measurements of circulating IL-8, TNF-alpha (TNF-α) and sTNFR1 were obtained from four groups of men: (1) controls (2) men with elevated PSA with a negative prostate biopsy (eIPSA_negBx) (3) men with clinically localized CaP and (4) men with castration resistant CaP (CRPC). TNF-α (AUC=0.93) and sTNFR1 (AUC=0.97) were strong predictors of elPSA_negBx vs CaP). The best predictor of elPSA_negBx vs prostate cancer was sTNFR1 and IL8 combined (AUC=0.997). The strongest single predictors of localized versus metastatic CaP were TNF-α (AUC=0.992) and PSA (AUC=0.963) levels. Conclusions: The specificity and sensitivity of a PSA-based CaP diagnosis can be significantly enhanced by concurrent serum measurements of IL-8, TNF-α and sTNFR1. In view of the concerns about the ability of PSA to distinguish clinically relevant CaP from indolent disease, assessment of these biomarkers in larger cohort consisting of Caucasians and African Americans is warranted.

Citation Format: Kailash C. Chadha, Austin Miller, Bindukumar B. Nair, Stanley A. Schwartz, Donald L. Trump, Willie Underwood. New serum biomarkers for prostate cancer diagnosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 879. doi:10.1158/1538-7445.AM2014-879
Abstract 882: Non-invasive diagnostic testing for lung cancer in a prospective cohort
Authors: Tobi Martin , Sayre Joe , Rambus MaryAnn , Antaki Fadi , Schwartz Ann , Lawson Michael J.
Published: May 2015

Monoclonal antibody Adnab-9 recognizes the p87 antigen, a constituent of putatively activated pulmonary type 2 pneumocytes. p87 shed into sputum and swallowed may be a potential tumor marker detectable by the Adnab-9 stool test. We describe prospectively collected stool and colonic effluent ELISA results in a cohort of urban patients enrolled in a colorectal cancer screening study. Methods: Prospectively, 1,132 American patients in Metropolitan Detroit submitted stool in a CRC prospective screening study from 1996 to 2013. Eleven patients free of any significant colorectal neoplasia or other cancer, but who had died from non-cancer-related causes, served as controls. Patients and controls were approximately 50-80 years old and the male to female ratios were similar (30:1 and 10:1). Sixty-seven percent of patients and 45 % of controls were African American. Results: 64 patients of 1,132 contracted lung cancer during the 17 year period of follow-up (5.7%). Of these 64 patients, 34 (52%) had stool or effluent Adnab-9 binding tests on retrospective review. We found that over half the patients ultimately diagnosed with lung cancer had either stool/effluent ELISA or Western blot positivity for Adnab-9 compared to only 1 of 11 controls (OR = 11.3, CI 1.3-97.9, p=0.014). The median time from stool submission to diagnosis of lung cancer was 4.4 (0.7-10.3) years. Lung Cancer Tumor types were adenocarcinoma in 23%; squamous in 33%; other in 20%; large cell cancer in 9%; small cell cancer in 8%; and unknown in 7%. At the last time of follow-up, 70% of patients subsequently diagnosed with lung cancer were deceased. Median survival time was 2.1 years from the time of clinical diagnosis. Conclusion: Adnab-9 sensitivity in this cohort was 52% with specificity of 90.9% for lung cancer and could lead to the diagnosis of lung cancer 4.4 years before clinical diagnosis was made. This supports the notion that accessible, early non-invasive testing combined with effective follow-up studies may lead to earlier diagnosis and treatment of lung cancer, the World's most frequent cancer.

Citation Format: Martin Tobi, Joe Sayre, MaryAnn Rambus, Fadi Antaki, Ann Schwartz, Michael J. Lawson. Non-invasive diagnostic testing for lung cancer in a prospective cohort. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 882. doi:10.1158/1538-7445.AM2014-882
Abstract 885: Using immunomic approach to enhance tumor-associated autoantibody detection in diagnosis of hepatocellular carcinoma
Authors: Dai Liping , Liu Mei , Zhu Qing , Liu Xinxin , Chai Yurong , Ren Pengfei , Wang Kaijuan , Song Chunhua , Wang Peng , Wang Mingan , Tan Eng M. , Zhang Jianying
Published: May 2015

Many studies demonstrated that the immune system can recognize the antigenic changes in cancer cells, and further develop autoantibodies against these antigens which have been called tumor-associated antigens (TAAs). During transition from chronic liver disease to hepatocellular carcinoma (HCC), autoantibodies can appear which are not detected in the pre-malignant conditions. In order to explore the possibility and usefulness of using a mini-array of multiple TAAs as an approach in the diagnosis of HCC, a total of 14 TAAs, including IMP1, IMP2/p62, IMP3/Koc, p53, Survivin, p16, CAPERα, CIP2A/p90, RalA, NPM1, MDM2 and 14-3-3 ζ, c-Myc and CyclinB1, were selected for expression of full-length recombinant proteins. Antibodies against 14 TAAs in 30 sera from patients with chronic hepatitis, 30 sera from patients with liver cirrhosis and 76 sera from patients with HCC as well as sera from 16 HCC patients with serial bleeding samples were detected by enzyme-linked immunosorbent assay (ELISA). Positive results were also confirmed by Western blotting. Antibody frequency to any individual TAA in HCC varied from 6.6% to 21.1%. With the successive addition of TAAs to the panel of TAAs, there was a stepwise increase of positive antibody reactions. According to the evaluation indexes for accuracy of screening test, the sensitivity and specificity in using a panel of 14 TAAs for immunodiagnosis of HCC was 69.7% and 83.0%, respectively. The interesting finding was that these anti-TAA autoantibodies could be detected at least one year before the diagnosis of HCC, suggesting that using a penal of 14 TAAs for enhancing autoantibody detection would be a valuable approach in the early diagnosis of HCC. The mini-array of 14 TAAs can identify 43.8% HCC patients who shows serum alpha-fetoprotein (AFP) negative. This study deals with the concept of “cancer immunomics” which allows a global analysis of the auto-antibodies against antigens in a neoplasm. It also determinates that malignant transition to HCC is associated with increased autoantibody responses to certain cellular proteins. In summary, the data from this study further support the hypothesis that a customized TAA array can constitute promising and powerful tool for enhancing the serological anti-TAA antibody detection of HCC, especially in patients with serum AFP negative.

Citation Format: Liping Dai, Mei Liu, Qing Zhu, Xinxin Liu, Yurong Chai, Pengfei Ren, Kaijuan Wang, Chunhua Song, Peng Wang, Mingan Wang, Eng M. Tan, Jianying Zhang. Using immunomic approach to enhance tumor-associated autoantibody detection in diagnosis of hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 885. doi:10.1158/1538-7445.AM2014-885
Abstract 887: Proteome scale identification of autoantibody biomarkers in colorectal cancer
Authors: Demirkan Gokhan , Soderberg Leah , Wallstrom Garrick , Szeto Emily , Barker Kristi , Wang Jie , LaBaer Joshua , Lindor Noralane M. , Qiu Ji
Published: May 2015

It is widely appreciated that early detection is the key to making inroads in the fight against cancers. Despite the availability of endoscopic screening, compliance is poor. The diagnosis of CRC is often made in advanced stages, and the consequence is a dismal 50% five year survival across all CRC. There is urgent need for biomarkers with performance that can meet the need of early diagnosis. Like most cancers, colorectal cancers (CRCs) express tumor antigens that can induce humoral immune response. The identification of the autoantibodies against tumor antigens may facilitate early diagnosis of CRC. The goal for this pilot project was to demonstrate the feasibility of discovering autoantibody biomarkers for colorectal cancer using Nucleic Acid Programmable Protein Arrays (NAPPA). Autoantibodies in serum samples collected from 40 patients with DNA mismatch repair proficient colorectal cancer who had died of their cancer within 18 months of their blood draw and from 40 age-gender matched healthy controls were profiled on NAPPA arrays with randomly selected 2000 human protein. The fact that p53, a tumor antigen that has been previously reported to be related to various cancers including CRC, was one of the top candidates based on the statistical analysis demonstrates the validity of our discovery platform. Besides p53, thirty-one candidate antigens were identified to have sensitivity greater than or equal to 25% at 95% specificity and fifty-one candidate antigens had an area under the ROC curve (AUC) equal to or greater than 0.6. Validation of the combined 83 unique genes selected based on these two different data analysis methods in an independent sample set in a blind fashion is on-going. This pilot study using late stage cancer samples demonstrates the feasibility and power of an immunoproteomics study using protein arrays. This approach may rapidly lead to identification of markers that could have relevance in monitoring disease progression as well as in early cancer detection.

Citation Format: Gokhan Demirkan, Leah Soderberg, Garrick Wallstrom, Emily Szeto, Kristi Barker, Jie Wang, Joshua LaBaer, Noralane M. Lindor, Ji Qiu. Proteome scale identification of autoantibody biomarkers in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 887. doi:10.1158/1538-7445.AM2014-887
Abstract 888: Development of a urine DNA based marker panel for early detection of liver cancer
Authors: Chen Sitong , Jain Surbhi , Lin Selena , Su Ying-Hsiu , Song Wei
Published: May 2015

Hepatocellular carcinoma (HCC) or liver cancer is an aggressive disease and one of the fastest growing cancers in incidence in the United States. The 5 year survival rate drops dramatically from a poor 26% in early stages to a mere 2% in later stages of the disease. Currently, the only available biomarker for early detection is serum alpha-fetoprotein which can identify only 40-60% of cases. We aim to improve the poor disease prognosis by developing a screening test capable of detecting liver cancer in its earlier stages. Since cancer is a disease of the genome and epigenome, if we can detect these underlying genetic mutations and epigenetic modifications in the periphery, we should be able to effectively detect cancer early. We have previously shown that urine contains fragmented, cell-free, cancer related DNA, both mutated and methylated, derived from the circulation of cancer patients. We have also demonstrated that the concentration of tumor-derived DNA in plasma and in urine is similar in patients with tumors. Hence, we propose the use of a panel of HCC-associated genetic and epigenetic methylation DNA biomarkers to develop a sensitive, noninvasive urine screening test for HCC. In order to detect these markers in the circulation derived urine DNA, we developed short amplicon (∼50 bp) PCR based assays targeting HCC-associated mutations in TP53, CTNNB1, hTERT genes and HCC associated methylation in GSTP1, RASSF1A and CDKN2A. Urine DNA isolated from hepatitis, cirrhosis and HCC patients were tested in each of the assays and analyzed. Panel performance parameters such as sensitivity, specificity and area under the receiver operating curve were calculated for individual markers and then as a group in order to evaluate their ability to distinguish HCC patients from hepatitis and cirrhosis subjects. The potential of this urine test in the early detection of HCC is discussed.

Citation Format: Sitong Chen, Surbhi Jain, Selena Lin, Ying-Hsiu Su, Wei Song. Development of a urine DNA based marker panel for early detection of liver cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 888. doi:10.1158/1538-7445.AM2014-888
Abstract 892: Potential of urinary MMP-9/NGAL complex as a novel biomarker for the early detection of gastric cancer
Authors: Shimjura Takaya , Dagher Adelle , Ebi Masahide , Yamada Tamaki , Yamada Tomonori , Joh Takashi , Moses Marsha A.
Published: May 2015

The early diagnosis of gastric cancer (GC) provides the opportunity for curative endoscopic resection. However, although endoscopy is a standard diagnostic method for this disease, comprehensive screening endoscopy would be invasive, expensive and could result in significant complications. To date, there is a significant lack of useful GC biomarkers. In fact, serum tumor markers such as CEA and CA19-9 have not been recommended as GC diagnostics due to their low sensitivity and specificity. With the goal of discovering non-invasive biomarkers for the early diagnosis of GC, we have conducted a pilot case-control study utilizing urine samples from individuals with gastric cancer vs. healthy control samples. A cohort of 70 patients composed of 35 patients with gastric cancer and 35 age- and sex-matched healthy controls was analyzed. Baseline clinical characteristics were tightly controlled and no significant differences were noted. Since changes in the microvasculature have been described in the very early stages of GC, we conducted an angiogenesis protein array analysis to identify potential candidate biomarkers. Three proteins, IL-8, PECAM-1, MMP-9, were found to be elevated in the urine of GC patients compared to controls by this method. In confirming the elevated levels of urinary MMP-9 by gelatin zymography, we determined that MMP-9/NGAL complex was also significantly elevated in the GC urines compared to control samples. We therefore tested all samples for the presence of IL-8, PECAM-1, MMP-9 and MMP-9/NGAL complex using monospecific ELISAs. We were able to confirm that urinary levels of MMP-9/NGAL complex were significantly higher in the GC group compared to the healthy control group (Median, 85 pg/ml (IQR, 43-224) vs. 0 pg/ml (IQR, 0-213), respectively, P=0.020). Urinary MMP-9/NGAL complex could distinguish between healthy control samples and GC samples with an area under the curve of 0.657(95%CI, 0.527-0.789) in a receiver operating characteristics analysis. A cut-off value of urinary MMP-9/NGAL complex was established and the statistical performance characteristics of this urinary biomarker were also determined. In summary, urinary MMP-9/NGAL complex emerged as a significant non-invasive biomarker for gastric cancer including early stage disease. Ongoing studies are focused on the large scale validation of these findings.

Citation Format: Takaya Shimjura, Adelle Dagher, Masahide Ebi, Tamaki Yamada, Tomonori Yamada, Takashi Joh, Marsha A. Moses. Potential of urinary MMP-9/NGAL complex as a novel biomarker for the early detection of gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 892. doi:10.1158/1538-7445.AM2014-892
Abstract 895: Discriminant, identifiable plasma metabolites in pancreatic cancer-associated diabetes - candidate early-detection biomarkers
Authors: Urayama Shiro , Tolstikov Vladimir
Published: May 2015

Background: Pancreatic cancer (PDAC) has been associated with development of glucose intolerance and dysregulation. Based on our previous report of strong potential for existence of metabolite biomarkers for PDAC detection, in this study, we have pursued initial characterization of plasma metabolites for discriminating PDAC cases among diabetic patients as a means to delineate further subset of patients who may benefit from screening protocol.

Methods: IRB-approved prospectively collected database and corresponding plasma from UC Davis Pancreas Registry was searched for appropriate cases: PDAC patients with recent-onset diabetes (≤3yrs prior to the index PDAC diagnosis) (Grp 1) and non-PDAC patients with long history of diabetes mellitus (>3 yrs) (Grp 2).

The plasma was processed and non-targeted GC/MS and targeted LC/MS were performed to assay for identifiable plasma metabolites. The data was processed and the peak intensity levels were normalized, scaled and identifiable metabolites were analyzed via metabolomics specific multivariate & bootstrap methods as well as ROC evaluation (Metaboanalyst & ROCCET) for visualization and biomarker development.

Results: We have identified 36 patients in Grp 1 and 22 patients for Grp 2. The metabolite specific multivariate and ROC analyses revealed specific features such as elaidic acid, uric acid, 2,3-propanediol, arachidonic acid, docosahexanoic acid, 5-oxo-EET, lysine, LysoPC(18:2), 9(10)-EpOME, LysoPC(16:0), sphingosine-1-phosphate and others as strong discriminators for recent-onset diabetic patients with pancreatic cancer. Such set yielded AUC of 0.964 with 15 features [CI=0.876-1].

Conclusion: We have demonstrated that an identifiable set of plasma metabolite biomarkers exists for discriminating diabetic patients with developing pancreatic cancer. These features could be utilized in a larger set of new-onset diabetic population for further validation in near-future study.

Citation Format: Shiro Urayama, Vladimir Tolstikov. Discriminant, identifiable plasma metabolites in pancreatic cancer-associated diabetes - candidate early-detection biomarkers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 895. doi:10.1158/1538-7445.AM2014-895
Abstract 900: Computing tumor growth rate across pre- and post-treatment periods uncovers anti-tumor activity in patients treated by a pan-CDK inhibitor (BAY1000394)
Authors: Hollebecque Antoine , Ferte Charles , Nitenberg Gerard , Felices Mathieu , Durand-Salmon Alexandre , Ocker Matthias , Soria Jean-Charles
Published: May 2015

Background: Recent studies suggest that tumor shrinkage as measured by RECIST 1.1 criteria may not be adequate to assess early signs of anti-tumor activity in phase I trials. The value of Tumor Growth Rate (TGR) evaluation in this context has been suggested. Methods: We analyzed the TGR of solid tumors from patients prospectively enrolled in a dose-escalation phase I trial investigating the pan-CDK inhibitor BAY1000394 on a 3 days on/4 days off 21 day treatment cycle. Only patients who had tumor imaging evaluation at least one month before the onset of the experimental treatment, a baseline tumor imaging, and at least one tumor evaluation after 2 cycles of treatment were eligible. Patient consent was obtained prior to analysis. We computed the TGR across the pre- (REFERENCE) and post-treatment (EXPERIMENTAL) evaluation, as described by Ferté et al (Clin Cancer Res, 2013) and compared these results to RECIST-based response evaluation. Each patient was used as his/her own control.Results: A total of twelve patients were eligible for both RECIST and TGR evaluation. At the time of first evaluation, 9 patients were classified as progressive disease (PD) and 3 as stable disease (SD) using RECIST. Conversely, TGR decreased in 6 out of 12 patients (median: - 9.8 %; CI 95% - 27.4 to 2.3), suggesting antitumor activity by the investigational drug. However, these 6 patients were classified as PD due to the occurrence of new lesions and then discontinued from the trial. They had small cell lung, colorectal, thymic, and bladder cancer. Interestingly, two patients suffering from ovary adenocarcinoma with durable SD (10 treatment cycles) had almost no tumor growth rate change between the REFERENCE and the EXPERIMENTAL period, suggesting no anti-tumor activity, and could potentially have been discontinued earlier from the trial. Conclusion: Computing the variation of TGR in the context of a phase 1 trial investigating a pan-CDK inhibitor reveals early signs of antitumor activity in specific patients, not previously identified by RECIST. Its use to guide the “go/no go” decision-making in the early drug development context is promising.

Citation Format: Antoine Hollebecque, Charles Ferte, Gerard Nitenberg, Mathieu Felices, Alexandre Durand-Salmon, Matthias Ocker, Jean-Charles Soria. Computing tumor growth rate across pre- and post-treatment periods uncovers anti-tumor activity in patients treated by a pan-CDK inhibitor (BAY1000394). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 900. doi:10.1158/1538-7445.AM2014-900
Abstract 912: P21-activated kinase 4 (PAK4) as a predictive marker for gemcitabine in pancreatic cancer cell line
Authors: Moon Sung Ung , Kim Jin Won , Sung Ji Hea , Kang Mi Hyun , Chang Hyun , Lee Jeong Ok , Kim Yu Jung , Lee Keun Wook , Kim Jee Hyun , Bang Soo Mee , Lee Jong Seok
Published: May 2015

Pancreatic cancer is a highly lethal disease. Although gemcitabine is activelyused in pancreatic cancer, modest activity and relativeresistanceare revealed.P21-activated kinases(PAKs) are involved in cytoskeletal reorganization, gene transcription, cellproliferation and survival, and oncogenic transformation.The gene amplification and protein overexpression of PAK1 and PAK4were reported in pancreatic cancer, which were associated with K-ras mutation, MUC13 and Smad4. Therefore, we hypothesized that PAKs could predict the drug-sensitivity of gemcitabine in pancreatic cancer and could be a therapeutic target. Using cell viability assay of human pancreatic cancer cell lines (Capan1, Capan2, MIA-paca2, PANC1, Aspc1, SNU213, SNU410) for gemcitabine, Capan-2, PANC-1 and SNU-410 cell lines was identifiedas resistant cell lines for gemcitabine. Through western blots of molecules related with down-steam pathway and drug-sensitivity, higher expression of PAK4 and lower expression of human equilibrative nucleoside transporter 1 (hENT1) were associated with the resistance for gemcitabine. PAK4 down-regulation through siRNA induced the up-regulation of hENT1, which is well-known as predictive marker for gemcitabine activity. In resistance cell lines (Capan-2, PANC-1, SNU-410), down-regulation of PAK4 through siRNArestored the drug-sensitivity for gemcitabine. In conclusion, PAK4 can be a potential predictive marker and therapeutic target in gemcitabine chemotherapy for pancreatic cancer.

Citation Format: Sung Ung Moon, Jin Won Kim, Ji Hea Sung, Mi Hyun Kang, Hyun Chang, Jeong Ok Lee, Yu Jung Kim, Keun Wook Lee, Jee Hyun Kim, Soo Mee Bang, Jong Seok Lee. P21-activated kinase 4 (PAK4) as a predictive marker for gemcitabine in pancreatic cancer cell line. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 912. doi:10.1158/1538-7445.AM2014-912
Abstract 917: Post-treatment changes in levels of TNF family ligands and XIAP may predict sensitivity to IAP antagonist CUDC-427
Authors: Atoyan Ruzanna , Samson Maria Elena S. , Hantzis Brianne , Ma Anna W. , Yin Ling , Borek Mylissa , Dellarocca Steven , Zifcak Brian , Xu Guangxin , Wang Jing
Published: May 2015

Inhibitors of apoptosis (IAP) proteins are a novel target for cancer therapy. Antagonists of IAP proteins have been shown to synergize with TNF receptor family signaling as well as with standard-of-care chemotherapeutics and targeted therapies. CUDC-427 is a potent, oral, monovalent IAP antagonist poised for more advanced clinical testing after completion of phase 1 trials using two different dosing schedules. Predictive biomarkers of response to CUDC-427 are expected to inform clinical development as monotherapy and in combination with other agents. In this study, we sought to identify potential markers of sensitivity to single-agent CUDC-427. Screening of more than 100 breast, ovarian and hematologic cancer cell lines using a viability assay identified several that are sensitive to CUDC-427 treatment. This sensitivity to CUDC-427 was associated with treatment-induced expression of TNFα or TRAIL in cell lines lacking basal levels of these TNF family ligands. In sensitive cell lines that express high basal levels of TNF family ligands prior to CUDC-427 treatment, induction of apoptosis was independent of NFκB signaling but dependent on caspase 8. Our results also confirmed that the addition of exogenous TNFα sensitized some but not all cell lines to CUDC-427 treatment, as previously reported by others. Interestingly, co-culture with stromal cells also sensitized certain hematologic cancer cell lines to CUDC-427 treatment. In addition, a decrease in XIAP levels was detected in cell lines that were highly sensitive to CUDC-427. These results suggest the potential for using TNF family ligand or XIAP levels pre- and post-treatment as predictive biomarkers of response to CUDC-427.

Citation Format: Ruzanna Atoyan, Maria Elena S. Samson, Brianne Hantzis, Anna W. Ma, Ling Yin, Mylissa Borek, Steven Dellarocca, Brian Zifcak, Guangxin Xu, Jing Wang. Post-treatment changes in levels of TNF family ligands and XIAP may predict sensitivity to IAP antagonist CUDC-427. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 917. doi:10.1158/1538-7445.AM2014-917
Abstract 919: BIM as a predictive biomarker for VEGFR inhibitor in metastatic renal cell carcinoma
Authors: Kim Jee Hung , Lee Hoi Young , Kwon Woo Sun , Park Kyu Hyun , Lim Ho-yeong , Ahn Joong Bae , Chung Hyun Cheol , Rha Sun Young
Published: May 2015

Angiogenesis is an important target for metastatic renal cell carcinoma(mRCC), resulting in several VEGFR tyrosine-kinase inhibitors(TKIs)in clinical practice. Approximately 35% of mRCC patients do not get the benefit from TKIs treatment, including sunitinib, sorafenib or the other VEGF pathway blockers, due to resistance and/or drug induced toxicities. Despite these initial insights, no validated biomarkers that identify which mRCC patients benefit most from antiangiogenic therapy have been discovered. Pro-apoptotic Bcl-2 family member (BIM) is a particularly critical mediator of targeted therapy-induced apoptosis in solid tumors. BIM upregulation is required for TKI to induce apoptosis in tyrosine kinase driven cancer. According to recent several studies, BIM deletion polymorphism was identified as one of the primary resistant mechanisms of various TKIs in EGFR mutated NSCLC or CML. However, there has been no study that confirms germline BIM deletion could confer the resistance to several VEGFR TKIs in treatment with mRCC. Here, we evaluated the possibility of germline and tumor tissue BIM deletion as a potential biomarker for VEGFR TKI resistance in mRCC. BIM deletion polymorphism status of gDNA from 55 formalin fixed paraffin embedded(FFPE) tumor tissues and 98 peripheral blood mononucleated cells (PBMC) of mRCC patients was determined by separated PCR. BIM protein expression level was evaluated by immunohistochemistry. Among these samples, 19 samples overlapped FFPE and PBMC and these sample results were exactly the same comparing either wild type or deletion. BIM deletion(heterozygous) accounted for 18.2% of the 121 total mRCC patients.We observed these patients with BIM deletion showed poor prognosis with TKIs treatments (response rate of treatment with sunitinib in BIM wild group and BIM deletion group : 24.6% versus 16.7%). Our study identified BIM a possible genetic biomarker that can predict the efficacy to VEGFR TKIs treatment in mRCC patients. Especially, as germline BIM deletion in the PBMC showed the concurrdence with tissue polymorphysim, it might be feasible to predict the response to antiangiogenic agent therapy simply through simple blood sampling. In conclusion, BIM deletion polymorphism might be a useful candidate marker for selecting mRCC patients for TKIs treatment.

Citation Format: Jee Hung Kim, Hoi Young Lee, Woo Sun Kwon, Kyu Hyun Park, Ho-yeong Lim, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha. BIM as a predictive biomarker for VEGFR inhibitor in metastatic renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 919. doi:10.1158/1538-7445.AM2014-919