bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2623: PI3K/mTOR dual inhibitor PF-5212384 inhibits aberrant NF-kB activation and exhibits activity in combination with MEK inhibitor PD-325901 and docetaxel in human head and neck squamous cell carcinoma
Authors: Mohan Suresh , Broek Robert J. Vander , Saleh Anthony D. , Pierce Matthew L. , Coupar Jamie F. , Eytan Danielle F. , Chen Zhong , Waes Carter Van 
Published: May 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and standard treatment with surgery or chemoradiation has significant morbidity, with 5 year survival of &lt;50%. Personalized targeted therapies with small molecule inhibitors have gained interest following identification of genetic drivers from The Cancer Genome Atlas (TCGA). TCGA data shows &gt;60% of head and neck tumors harbor genomic alterations in the RTK-PI3K-mTOR and MAPK pathways important in cell growth and survival. In this study, we determined the effects of the novel PI3K-mTOR inhibitor PF-5212384 (PF-384) on molecular targets and HNSCC growth in preclinical models. PF-384 IC50s of 0.75nM-133nM were found in 12 HNSCC lines by XTT cell density assays and treatment resulted in increased sub-G0 cell death and G0/G1 phase blockade by DNA flow cytometry. PF-384 strongly inhibited direct targets of PI3K-mTOR, aberrant NF-kB transactivation and induced cytokines, but only partially inhibited MEK pathway targets. Transient siRNA knockdown of PIK3CA inhibited NF-kB activity, supporting PI3K-mTOR as an important driver and target for inhibition of NF-kB prosurvival signaling in HNSCC. PF-384 partially inhibited UMSCC1 tumor xenografts in vivo. PF-384 with MEK inhibitor PD-325901 or docetaxel revealed combinatorial activity. Given the high proportion of HNSCC patients with aberrations in the PI3K pathway and combinatorial activity observed, PF-384 with PD-901 or docetaxel merit further investigation in HNSCC.
Supported by NIH Medical Research Scholars Program (SM, RVB, DFE) and NIDCD intramural projects ZIA-DC-000016, 73 and 74 (AS, JC, ZC, CVW).
Citation Format: Suresh Mohan, Robert J. Vander Broek, Anthony D. Saleh, Matthew L. Pierce, Jamie F. Coupar, Danielle F. Eytan, Zhong Chen, Carter Van Waes. PI3K/mTOR dual inhibitor PF-5212384 inhibits aberrant NF-kB activation and exhibits activity in combination with MEK inhibitor PD-325901 and docetaxel in human head and neck squamous 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 2623. doi:10.1158/1538-7445.AM2014-2623
Abstract 2625: Increased sensitivity to Wnt/beta-catenin inhibitors in hepatocellular carcinoma cells harboring activating mutation of beta-catenin
Authors: Lin Hsiao-Hui , Feng Wen-Chi , Lu LI-Chun , Hsu Ta-Wen , Cheng Ann-Lii , Hsu Chih-Hung 
Published: May 2015

Abstract
[Background] The WNT/β-catenin signaling pathway is a major oncogenic pathway of human hepatocellular carcinoma (HCC). More than 50% of HCCs have aberrant activation of WNT/β-catenin signaling, which are caused by genetic alterations, ligand activation, or cross-activation by other signaling pathways. We hypothesized that activating mutation of CTNNB1, the coding gene of β-catenin, may confer sensitivity to WNT/β-catenin inhibitors in HCC cells.
[Materials and Methods] SNU398 is a human HCC cell line harboring a missense somatic mutation in exon 3 of CTNNB1 gene, resulting in S37C mutation. Huh7, HepG2, PLC5, and Hep3B are HCC cells containing no somatic mutations in exon 3 of CTNNB1 gene. HCC cells were treated with various types of WNT/β-catenin pathway inhibitors, including ICG-001 which down-regulates β-catenin/TCF transcriptional activity by interfering the binding of β-catenin with its transcriptional activation complex, XAV939 which targets tankyrases and facilitates degradation of β-catenin, and LGK974 which inhibits Porcupine, an acyltransferase responsible for palmitoylation and secretion of Wnt ligands, and evaluated for in vitro viability by MTT.
[Results] ICG-001 as a single agent showed significantly greater anti-proliferation effect in SNU398 than other HCC cells. The 50%-inhibitory concentrations (IC50s) of ICG-001 were 5 μM and &gt;10 μM for SNU398 and other HCC cells, respectively. ICG-001 also induced a more potent suppression of colony- formation, and a more significant increase of subG1 fraction detected by flow cytometry in SNU398 cell than other HCC cells. XAV939 up to 20 μM induced only modest anti-proliferative effect in all HCC cells. However, SNU398 remained the one showing the greatest sensitivity to the growth suppression induced by XAV939. The anti-proliferative effect of LGK974 was modest and showed no significant difference among different HCC cells.
[Conclusion] The activating mutation of β-catenin may confer sensitivity to certain WNT/β-catenin pathway inhibitors, such as ICG-001, in HCC cells. (This study was supported by grants NRPB-100CAP1020-2).
Citation Format: Hsiao-Hui Lin, Wen-Chi Feng, LI-Chun Lu, Ta-Wen Hsu, Ann-Lii Cheng, Chih-Hung Hsu. Increased sensitivity to Wnt/beta-catenin inhibitors in hepatocellular carcinoma cells harboring activating mutation of beta-catenin. [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 2625. doi:10.1158/1538-7445.AM2014-2625
Abstract 2632: Casein kinase II inhibitors regulate cell cycle progression in leukemia
Authors: Gowda Chandrika , Song Chunhua , Sachdev Mansi , Pan Xiaokang , Ding Yali , Payne Kimberley , Dovat Sinisa 
Published: May 2015

Abstract
Casein Kinase II (CK2) is an oncogenic kinase that is overexpressed in leukemia. The molecular mechanism by which CK2 exerts its oncogenic function is largely unknown. We have previously demonstrated that CK2 directly phosphorylates the Ikaros tumor suppressor in vivo at multiple, evolutionarily conserved amino acids. CK2-mediated phosphorylation of Ikaros results in reduced DNA binding affinity, loss of pericentromeric localization and impaired Ikaros transcriptional repression. We hypothesize that the pro-oncogenic activity of CK2 in leukemia involves functional inactivation of Ikaros, and that CK2 inhibition will result in restoration of the tumor suppressor function of Ikaros and an anti-leukemia effect. To test this hypothesis, we have tested the effect of specific CK2 inhibitors on Ikaros function as a transcriptional regulator of genes that promote cell cycle progression. Using quantitative Chromatin Immunoprecipitation (qChIP), we have shown that Ikaros binds to the promoters of two genes that are essential for mitosis, ANAPC1 and ANAPC7, in leukemia cell lines and in primary leukemia cells. Increased expression of Ikaros via retroviral transduction was associated with increased binding of Ikaros to the promoters of ANAPC1 and ANAPC7 and their transcriptional repression. Luciferase reporter assay was used to confirm that Ikaros can directly repress transcription of both ANAPC1 and ANAPC7. These data suggest that Ikaros negatively regulates cell cycle progression during mitosis and that Ikaros function as a repressor of ANAPC1 and ANAPC7 is impaired in leukemia. We tested the ability of CK2 inhibition to restore Ikaros repressor activity in leukemia. We evaluated the pre-B acute lymphoblastic leukemia (B-ALL) cell line, Nalm6 treated with a specific CK2 inhibitor, TBB as well as in a murine preclinical xenograft model of B-ALL. CK2 treatment resulted in increased Ikaros binding to promoters of ANAPC1 and ANAPC7, along with transcriptional repression of both genes. This was associated with prolonged survival of B-ALL xenograft mice that were treated with CK2 inhibitors. These data suggest that CK2 inhibitors can regulate cell cycle progression in leukemia cells by restoring the transcriptional repressor function of Ikaros. Our results demonstrate efficacy of CK2 inhibitors as a novel treatment for leukemia.
Citation Format: Chandrika Gowda, Chunhua Song, Mansi Sachdev, Xiaokang Pan, Yali Ding, Kimberley Payne, Sinisa Dovat. Casein kinase II inhibitors regulate cell cycle progression in leukemia. [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 2632. doi:10.1158/1538-7445.AM2014-2632
Abstract 2633: TP53 loss creates therapeutic vulnerability in cancer
Authors: Liu Yunhua , Lu Xiongbin 
Published: May 2015

Abstract
TP53, a well-known tumor suppressor gene, is frequently inactivated by mutation or deletion in a majority of human tumors. Theoretically, targeting the p53 pathway would lead to successful anti-cancer treatments. However, no effective p53-based anti-cancer therapy has been developed due to the complexity of the p53 regulators and their poor drugability. Here we demonstrate that focal deletion of TP53 often encompasses neighboring essential genes, rendering cancer cells with hemizygous p53 deletion highly vulnerable to further suppression of such genes. One such gene, POLR2A, encodes the largest subunit of RNA polymerase II complex. We found that its expression correlates with copy number changes and suppression of POLR2A with its inhibitors, alpha-amanitin or short-hairpin RNA, selectively inhibits growth, survival and tumorigenic potential in colon cancer cells with hemizygous TP53 loss, suggesting an novel and effective strategy for cancers with such genomic alternations.
Note: This abstract was not presented at the meeting.
Citation Format: Yunhua Liu, Xiongbin Lu. TP53 loss creates therapeutic vulnerability in 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 2633. doi:10.1158/1538-7445.AM2014-2633
Abstract 2646: Building a powerful ADCs discovery and development platform with novel dolastatin/auristatin payloads
Authors: Hu Shanghui , Zhao Lucy X. , Liu Xu , Li Chao , Hu Wei , Wang Zunrong , Tian Xufang 
Published: May 2015

Abstract
A family of novel warheads derived from dolastatins or auristatins were designed and synthesized. They showed similar or better antitumor activities against several typical cancer cell lines compared with dolastatin 10 or monomethylauristatin E or F. The conjugated ADCs with Trastuzumab have showed potent activities against Her2 breast cancer cell lines. The validated platform with novel cytotoxins can be potentially used to ADCs discovery and development.
Citation Format: Shanghui Hu, Lucy X. Zhao, Xu Liu, Chao Li, Wei Hu, Zunrong Wang, Xufang Tian. Building a powerful ADCs discovery and development platform with novel dolastatin/auristatin payloads. [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 2646. doi:10.1158/1538-7445.AM2014-2646
Abstract 2649: Development of an antibody-drug conjugate targeting TIM-1 for the treatment of ovarian and renal cell carcinoma
Authors: Thomas Lawrence J. , Vitale Laura , O'Neill Thomas , Dolnick Ree , Wallace Paul K. , Minderman Hans , Gergel Lauren E. , Forsberg Eric M. , Boyer James M. , Storey James R. , Hammond Russell A. , Widger Jennifer , Sundarapandiyan Karuna , Crocker Andrea , Marsh Henry C. , Keler Tibor 
Published: May 2015

Abstract
T cell immunoglobulin and mucin domain 1 (TIM-1) is a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury. Tim-1 expression is also upregulated in several human cancers, most notably in renal cell and ovarian carcinomas, but has very restricted expression in healthy tissues thus representing a promising target for antibody mediated therapy. To this end we have developed a fully human monoclonal IgG1 antibody specific for extracellular domain of TIM-1. This antibody was shown to bind purified recombinant chimeric TIM-1-Fc protein and TIM-1 expressed on a variety of transformed cell lines, including Caki-1 (human renal clear cell carcinoma), IGROV-1 (human ovarian adenocarcinoma) and ACHN (human renal cell adenocarcinoma). Internalization studies using confocal microscopy revealed the antibody was rapidly internalized by cells in vitro, and the internalization was confirmed by quantitative imaging flow cytometry using ImageStream. An antibody-drug conjugate (ADC) was produced with the anti-TIM-1 antibody covalently linked to a potent cytotoxin, monomethyl auristatin E (MMAE), and designated CDX-014. The ADC was shown to exhibit in vitro cytostatic or cytotoxic activity against a variety of TIM-1 expressing cell lines, but not on TIM-1 negative cell lines. Using the Caki-1 and IGROV-1 xenograft models, CDX-014 showed significant anti-tumor activity in the range of 75-300 μg/dose given every four days for a total of four doses. Activities are on-going to support the manufacturing and IND-enabling studies in order to advance CDX-014 towards clinical studies in renal cell carcinomas and potentially other TIM-1 expressing tumors.
Citation Format: Lawrence J. Thomas, Laura Vitale, Thomas O'Neill, Ree Dolnick, Paul K. Wallace, Hans Minderman, Lauren E. Gergel, Eric M. Forsberg, James M. Boyer, James R. Storey, Russell A. Hammond, Jennifer Widger, Karuna Sundarapandiyan, Andrea Crocker, Henry C. Marsh, Tibor Keler. Development of an antibody-drug conjugate targeting TIM-1 for the treatment of ovarian and 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 2649. doi:10.1158/1538-7445.AM2014-2649
Abstract 266: How many epidemiological types of breast cancer: Two, three, four, or more
Authors: Anderson William F. , Rosenberg Philip S. , Prat Aleix , Perou Charles M. , Sherman Mark E. 
Published: May 2015

Abstract
Background: Breast cancer is a heterogeneous disease, divisible into a variable number of clinical subtypes depending upon the analytical approach. A fundamental question is how many etiological subtypes underlie the spectrum of clinical breast tumors? A clinical subtype represents a grouping according to prognosis (outcome) or prediction (expected treatment response), whereas an etiological subtype reflects a common set of causes.
Methods: We initiated a systematic literature review to examine the historical, epidemiological, biostatistical, and molecular evidence for breast cancer etiology. Information sources included CANCERLIT, Index Medicus, and PubMed. Data resources included the Surveillance, Epidemiology, and End Results program.
Results: A bimodal age distribution at diagnosis was a fundamental characteristic of breast cancer for important tumor characteristics, risk factor profiles, molecular markers, and prognosis; suggestive of a ‘mixture’ of two main etiological subtypes in varying proportions in different populations. The first breast cancer tended to arise early in life with modal age-at-diagnosis near 50 years and generally behaved aggressively. The second breast cancer occurred later in life with modal age near 70 years, and usually portended a more indolent clinical course.
Conclusion: Epidemiological and molecular patterns suggest that breast cancer etiology reflects a bimodal breast cancer mixture model, possibly emerging from two stem cells of origin. Notwithstanding, the potential added value of more detailed categorizations and personalized approaches for the targeted treatment of breast cancer, we suggest that the development of criteria to better identify the two proposed main etiologic types would advance etiologic research and the prevention of breast cancer.
Citation Format: William F. Anderson, Philip S. Rosenberg, Aleix Prat, Charles M. Perou, Mark E. Sherman. How many epidemiological types of breast cancer: Two, three, four, or more. [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 266. doi:10.1158/1538-7445.AM2014-266
Abstract 2666: Monoclonal antibodies specific for the oncofetal antigen - immature laminin receptor: Tumor selectivity, rapid internalization and in vivo efficacy
Authors: McClintock Shannon D. , Dame Michael K. , Aslam Muhammad N. , Ali Saqib , Knibbs Randall N. , Warner Roscoe L. , Varani James 
Published: May 2015

Abstract
A series of murine monoclonal antibodies were generated using recombinant oncofetal antigen - immature laminin receptor protein (OFA/iLRP) as the immunogen. Several of the antibodies detected the 37kD OFA/iLRP but did not recognize the structurally related 67kD mature laminin receptor protein (LRP), as determined by western blot analysis. Additional antibodies demonstrated reactivity with both proteins. Those antibodies specific for the 37kD moiety bound to recombinant OFA/iLRP with high affinity (Kaff = 1-2 x 10-10M; Biacore technology). These antibodies also reacted with native OFA/iLRP on the surface of human tumor cells with high affinity (Kaff = 1-2 x 10-9M) but did not show significant reactivity with normal human epithelial cells or fibroblasts. In contrast, antibodies that interacted with both 37kD OFA/iLRP and 67kD mature LRP were reactive with both tumor cells and normal cells. Antibodies specific to OFA/iLRP were internalized upon binding to the target protein on human tumor cells. Two monoclonal antibodies from this group were tested for anti-tumor activity in a murine model of B-cell leukemia. BALB/c mice were injected with A20 leukemia cells either intramuscularly or intravenously. Mice were given a total of six intraperitoneal 100µg antibody injections over a two-week period following tumor initiation. Both antibodies slowed growth of the intramuscular primary tumor by approximately 45%. More importantly, in the intravenous tumor model, the treatments reduced systemic blood tumor levels by greater than 70% and suppressed liver tumor formation by up to 46%. These high affinity tumor-selective antibodies potentially provide a front-line or adjuvant therapy for hematological malignancies.
Citation Format: Shannon D. McClintock, Michael K. Dame, Muhammad N. Aslam, Saqib Ali, Randall N. Knibbs, Roscoe L. Warner, James Varani. Monoclonal antibodies specific for the oncofetal antigen - immature laminin receptor: Tumor selectivity, rapid internalization and in vivo efficacy. [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 2666. doi:10.1158/1538-7445.AM2014-2666
Abstract 2668: RG7116, a novel humanized anti-HER3 antibody with superior preclinical in vitro and in vivo efficacy in combination with, everolimus and other anti-cancer agents
Authors: Bossenmaier Birgit , Friess Thomas , Weisser Martin , Lechner Stefanie , Abraham Esther , Hoch Monika , Mirschberger Christian 
Published: May 2015

Abstract
HER3 is a member of the Human Epidermal Growth Factor Receptor (HER) family. HER3 is a kinase dead receptor, but by forming heterodimers with other HER family receptors, HER3 works as amplifier for PI3 kinase driven tumorigenesis. It has been reported that tumors treated with EGFR-, HER2-, cMET-or mTOR targeted therapies can escape via HER3 activation or upregulation. HER3 is expressed in a large variety of tumors for example in non-small cell lung cancer (NSCLC), head and neck, colorectal, gastric, pancreatic, breast, ovarian, thyroid and prostate cancer. Anti-HER3 antibodies can work via various mechanisms including: (1) blocking ligand (HRGs) binding to the receptor, (2) blocking heterodimerization with other HER family members (HER1, 2 and 4), (3) downregulation of the receptor from the cell surface, and (4) engaging immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC). The first three mechanisms lead to inhibition of HER3 phosphorylation and downstream signaling thereby resulting in tumor cell growth inhibition, while ADCC is a mechanism of direct target cell killing triggered by cross-linking of Fc receptors on immune effector cells (e.g. NK cells, macrophages).
RG7116 is a novel humanized and glycoengineered IgG1 antibody currently in clinical development, that binds to HER3 with high affinity. This antibody prevents ligand binding and receptor heterodimerization, thereby blocking receptor phosphorylation. In various tumor xenograft models monotherapy treatment with this antibody leads to substantial tumor growth inhibition. Only in a few cases monotherapy treatment resulted in complete tumor remission. Most of the models initially show convincing efficacy, but tumors regrow after a while. Combination therapy with other HER targeted therapies such as pertuzumab, cetuximab or erlotinib, lead to complete remission in preclinical models. The combination of RG7116 with downstream signaling inhibitors like: everolimus (mTOR) andand other anti-cancer agents leads to increased efficacy.
Citation Format: Birgit Bossenmaier, Thomas Friess, Martin Weisser, Stefanie Lechner, Esther Abraham, Monika Hoch, Christian Mirschberger. RG7116, a novel humanized anti-HER3 antibody with superior preclinical in vitro and in vivo efficacy in combination with, everolimus and other anti-cancer agents. [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 2668. doi:10.1158/1538-7445.AM2014-2668