bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2581: Pancreatic cancer immunotherapy with chitosan/IL-12
Authors: Perlow Haley K. , Yang Lirong , Zaharoff David 
Published: May 2015

Abstract
Pancreatic cancer is difficult to treat due to its late diagnoses and limited treatment options. Strategies capable of reducing tumor mass so that patients are eligible for tumor resection, i.e. the Whipple procedure, and strategies for reducing metastatic deposits with immunotherapy are needed. New immunotherapy techniques can provide an alternative to modern chemotherapy, radiation, or surgical options which have not been able to reduce pancreatic cancer mortality. IL-12 has been discovered to be a potent agent in the development of anti-tumor immunity through its ability to stimulate the activities of cytotoxic T lymphocytes, NK cells, and macrophages while promoting Th1 differentiation. We have previously discovered that a bioadhesive chitosan/IL-12 combination can aggressively eliminate implanted tumors in murine models. Chitosan is a non-toxic and degradable polysaccharide derived from crustacean shells that shows great potential for use in immunotherapy models due to its unique binding properties. Here, ability of chitosan/IL-12 vaccinations to slow the growth of a pancreatic adenocarcinoma cells in vivo was investigated. C57BL/6 mice received subcutaneous inoculations with Panc02 cells. After Panc02 tumors became visible, the mice received 4 weekly intratumoral immunotherapy treatments with either saline or chitosan/IL-12. There was a prominent delay in the tumor growth of the chitosan/IL-12 group at all stages of the treatment. Seven days after the second treatment, control mice had an average tumor volume of 180mm3 and treatment mice tumors became undetectable. Seven days after the fourth treatment, the control mice had an average tumor volume of 743mm3 and treatment mice had an average tumor volume of 221mm3. Cell proliferation assays showed that IL-12 had no direct effect on the Panc02 cell line. However, interferon-γ, a cytokine whose production is induced by IL-12, reduced the growth of Panc02 cells in vitro. These data shows that chitosan/IL-12 may be an effective immunotherapy for pancreatic cancer and also that IL-12 is not directly cytotoxic, but rather, it initiates an effector response capable of inhibiting pancreatic tumors.
Citation Format: Haley K. Perlow, Lirong Yang, David Zaharoff. Pancreatic cancer immunotherapy with chitosan/IL-12. [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 2581. doi:10.1158/1538-7445.AM2014-2581
Abstract 2594: Adjuvant cationic nanoliposomes induce anti-cancer immunity in a murine model of breast cancer
Authors: Meraz Ismail M. , Savage David J. , Gu Jianhua , Rhudy Jessica , Serda Rita E. 
Published: May 2015

Abstract
Nanoparticles, such as liposomes, provide opportunities to simultaneously present antigens and immune modulators. Using a 4T1 murine model of breast cancer, a cationic nanoliposomal formulation containing monophosphoryl lipid A and the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane induced anti-tumor activity following intratumoral administration. Addition of recombinant interleukin-12 (IL-12) further suppressed tumor growth and augmented T helper-1 cell (Th-1) polarization, with enhanced tumor infiltration by cytotoxic T cells, dendritic cells, and M1 macrophages, and amplification of interferon gamma secretion. Mice bearing dual tumors displayed arrest of tumor growth in treated tumors as well as distal, untreated tumors following combination therapy with adjuvant nanoliposomes and IL-12. In summary, adjuvant MPL-liposomes combined with localized IL-12 therapy block tumor growth, stimulate a Th-1 bias of the tumor microenvironment, and induce cancer-specific immune responses.
Citation Format: Ismail M. Meraz, David J. Savage, Jianhua Gu, Jessica Rhudy, Rita E. Serda. Adjuvant cationic nanoliposomes induce anti-cancer immunity in a murine model of breast 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 2594. doi:10.1158/1538-7445.AM2014-2594
Abstract 2597: Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices
Authors: Leshchiner Elizaveta , Bellairs Joseph , Bird Gregory H. , Opoku-Nsiah Kwadwo , Godes Marina , Walensky Lored D. 
Published: May 2015

Abstract
Activating mutations in KRAS represent the most frequent oncogenic driving force among the RAS homologs K-, N- and H-RAS, and are associated with poor prognosis and chemoresistance. KRAS mutations are present in approximately 30% of tumors, and at even higher frequencies in cancers of the pancreas, lung, thyroid gland, colon, and liver. In pancreatic ductal adenocarcinomas (PDAC), which carries a 5-year survival rate of less than 5%, activating KRAS mutations are present in over 90% of tumors. Moreover, these mutations have been causally linked to the initiation and progression of PDAC. Despite the mechanistic insights into KRAS-mediated oncogenesis, development of high affinity targeted inhibitors remains a formidable challenge. Here, we report the synthesis and application of hydrocarbon-stapled peptides as prototype therapeutics for blocking wild type and mutant KRAS in vitro and in cancer cells. Stabilized Alpha-Helices of SOS1 (SAH-SOS1) were generated by inserting hydrocarbon staples into SOS1 peptide sequence to recapitulate the alpha-helical structure of the native KRAS-interaction domain. SAH-SOS1 peptides, but not negative control analogs, bound to a variety of KRAS constructs with nanomolar affinity, inhibiting nucleotide exchange. This sequence-specific biochemical activity correlated with impairment of KRAS-driven cancer cell viability and signal transduction. These studies provide proof-of-concept for the utility of SAH-SOS1 peptides in dissecting and targeting the oncogenic KRAS pathway in human cancer.
Citation Format: Elizaveta Leshchiner, Joseph Bellairs, Gregory H. Bird, Kwadwo Opoku-Nsiah, Marina Godes, Lored D. Walensky. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. [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 2597. doi:10.1158/1538-7445.AM2014-2597
Abstract 2599: KDM3A tyrosine phosphorylation by Ack1 promotes tamoxifen-resistance in breast cancer
Authors: Mahajan Kiran , Bandyopadhyay Sayantani , Mahajan Nupam 
Published: May 2015

Abstract
Hormone therapy with the selective estrogen-receptor modulator tamoxifen (TAM) provides palliative benefit for patients with breast cancer. However, estrogen receptor α (ER hereafter) positive breast tumors with high expression of HER2 receptor tyrosine kinase often develop significant resistance to tamoxifen therapy. Thus, precise understanding of activation of Estrogen (E2)-independent ER regulated gene transcription in tamoxifen-resistant breast tumors could open new therapeutic avenues to target drug-resistance and ameliorate poor prognosis. The non-receptor tyrosine kinase, Ack1 (also known as TNK2) has emerged as a major integrator of signaling from various receptor tyrosine kinases including HER2. Here we demonstrate that heregulin promoted ER activity at Estrogen Response Element (ERE) in the presence of tamoxifen, which was significantly downregulated upon Ack1 knockdown. We observed that Ack1 phosphorylated the ER co-activator, KDM3A, a H3K9 demethylase, at evolutionary conserved tyrosine 1114 in heregulin dependent manner in the presence of tamoxifen. KDM3A demethylates H3 mono- and dimethyl-K9 in vitro and in vivo. Heregulin mediated Ack1 activation resulted in significant decrease in the level of monomethyl-H3K9, while, monomethyl-H3K27 levels remained unchanged. Further, inhibition of Ack1 by small molecule inhibitor AIM-100 or Dasatinib resulted in significant increase in the level of monomethyl-H3K9. Therefore by its ability to regulate the activity of ER co-activator such as KDM3A, activated Ack1 may modulate ER target gene expression in the absence of estrogen and confer TAM-resistance to cancer cells. Thus, Ack1 inhibitors hold the potential as novel therapeutics to treat a subset of tamoxifen resistant breast cancers.
Citation Format: Kiran Mahajan, Sayantani Bandyopadhyay, Nupam Mahajan. KDM3A tyrosine phosphorylation by Ack1 promotes tamoxifen-resistance in breast 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 2599. doi:10.1158/1538-7445.AM2014-2599
Abstract 26: MUC1 enhances neuropilin-1 signaling in pancreatic ductal adenocarcinoma
Authors: Zhou Ru , Curry Jennifer , Grover Priyanka , Roy Lopamudra Das , Leung TinChung , Mukherjee Pinku 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all cancers and is the 4th leading cause of cancer-related deaths in the United States. Mucin1 (MUC1) is a transmembrane glycoprotein over-expressed in more than 60% of PDA and its expression correlates with high metastases and poor prognosis. In PDA, there is a correlation between blood vessel density, tumor levels of VEGF, and disease progression. We have recently discovered a novel association between MUC1 and neuropilin-1 (NRP-1) expression. Neuropilin-1 (NRP-1) is a co-receptor for VEGF165 and blockade of NRP-1-VEGF165 interaction has been shown to inhibit angiogenesis and tumor growth in several other cancer types. Thus, we hypothesize that MUC1 induces a pro-angiogenic tumor microenvironment by increasing levels of VEGF and NRP-1, thus enhancing disease progression and metastases. We have generated Muc1-expressing KC and Muc1-null KCKO mouse PDA cell lines for this study. Compared to KCKO, KC cells secrete more VEGF and express higher levels of NRP-1 as well as VEGF receptors (1/2/3). Although the cell culture supernatants from KC do not alter the NRP-1 level on the endothelial line 2H11 cells, they significantly promote the 2H11 cell tube formation. Consistent with the in vitro results, tumor lysates from KC-bearing mice have higher levels of NRP-1 and VEGFR2 and its phosphorylations at Tyr residues 951, 996, and 1175. In human PDA cell lines, inhibition of MUC1 expression by specific siRNA reduced NRP-1 level while overexpression of full-length MUC1 increases NRP-1 expression. This suggests a direct regulation of NRP-1 by MUC1. Furthermore, the over-expression of MUC1 in BxPC3 human PDA cell line induces strong angiogenesis and promotes tumor metastasis in a zebrafish tumor xenograft model. Finally, we report that inhibition of NRP-1 by its specific blocking peptide suppresses BxPC3.MUC1 tumor growth in vivo. Taking together, MUC1 in PDA cells can enhance their own NRP-1 levels and promote the VEGF-VEGFR-NRP-1 signaling, which may favor the creation of a pro-angiogenic microenvironment for tumor growth and metastases. Our findings highlight the potential for MUC1 targeted blockade of VEGF-NRP-1 interaction in PDA by conjugating the NRP-1 inhibitory agents to a MUC1 targeting antibody.
Citation Format: Ru Zhou, Jennifer Curry, Priyanka Grover, Lopamudra Das Roy, TinChung Leung, Pinku Mukherjee. MUC1 enhances neuropilin-1 signaling in pancreatic ductal adenocarcinoma. [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 26. doi:10.1158/1538-7445.AM2014-26
Abstract 2612: ljm716, an anti her3 antibody that inhibits her3 dimerization, displays anti-tumor activity in esophageal squamous cell cancer
Authors: Sheng Qing , Wang Hui-Qin , das rita , chen yan , liang jinsheng , Xu Fiona , Wang zongyao , Cao Z. Alexander , Wang youzhen , huang alan 
Published: May 2015

Abstract
Background: Esophageal cancer is the eighth most common cancer and the sixth most common cause of cancer related death in the world. Squamous cell carcinoma is the predominant histologic subtype of esophageal cancer, particularly in Asia. Currently, no targeted therapy has been approved for treating this type of disease. Platinum-based combination chemotherapy remains to be the standard care for first line treatment of advanced or metastatic esophageal cancer with limited efficacy. Activation of EGFR/HER3/PI3K pathway is frequently observed in esophageal cancer, however, their therapeutic value remains to be further tested.
Methods: In this study, we evaluated the anti-tumor activity of LJM716, a fully human anti-HER3 antibody, either alone or in combination with anti-EGFR antibody cetuximab or PI3K alpha subunit inhibitor BYL719 in esophageal squamous cancer. LJM716, cetuximab and BYL719 single agent as well as their pair-wised combination activity were assessed in 24 esophageal squamous cancer cell (ESCC) lines using the CellTiter-Glo® Luminescent Cell Viability Assay. Single agent and combination anti-tumor activities of these reagents were also tested in selected cell line xenograft and patient derived xenograft mouse models.
Results: NRG1 expression (60%), PIK3CA mutation (8%), moderate PIK3CA (30%) and EGFR (30%) amplification were detected in a panel of 24 ESCC lines. Anti-HER3 antibody LJM716 potently inhibited HER3 phosphorylation and decreased pAKT level in these cell lines. In vitro, LJM716 inhibited proliferation of a sub-set of ESCC lines. LJM716 further enhanced and broadened the anti-tumor activities of both BYL719 and cetuximab in ESCC lines. In mouse xenograft models, LJM716 single agent treatment induced tumor stasis while combination with either BYL719 or cetuximab induced model dependent tumor regression.
Conclusion: NRG1-HER3-PI3K pathway activation is commonly observed in esophageal squamous cell cancer. Activation of HER3 is a potential mechanism leading to resistance to EGFR or PI3K targeted therapies, and combining anti-HER3 therapies with therapies targeting PI3K/EGFR may provide new therapeutic strategy for patients with esophageal squamous cell cancer.
Citation Format: Qing Sheng, Hui-Qin Wang, rita das, yan chen, jinsheng liang, Fiona Xu, zongyao Wang, Z. Alexander Cao, youzhen Wang, alan huang. ljm716, an anti her3 antibody that inhibits her3 dimerization, displays anti-tumor activity in esophageal squamous cell 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 2612. doi:10.1158/1538-7445.AM2014-2612
Abstract 2615: Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells
Authors: Ishida Michihiro , Kagawa Shunsuke , Shimoyama Kyoko , Takehara Kiyoto , Noma Kazuhiro , Tanabe Shunsuke , Tazawa Hiroshi , Matsuoka Junji , Kobayashi Hisataka , Fujiwara Toshiyoshi 
Published: May 2015

Abstract
Introduction: Humanized anti-HER2 monoclonal antibody, trastuzumab, has provided survival benefit to patients with HER2 positive breast cancer and advanced gastric cancer. However, the treatment with trastuzumab was limited due to low or heterogeneous HER2 positivity, insufficient effects as single agent and acquisition of resistance. To overcome these problems, we employed the adenoviral vector expressing HER2-extracellular domain (HER2-ECD), Ad/ HER2-ECD, which is designed to tag cancer cells with HER2-ECD and to sensitize them to trastuzumab, and a novel photoimmunotherapy (PIT). PIT consists of trastuzumab-conjugated with a photosensitizer, IR700 (Tmab-IR700) and irradiation with near-infrared light, induces a strong cytotoxicity on HER2 positive cancer cells. We assessed the effect of Ad/HER2-ECD and Tmab-IR700 mediated PIT in HER2 negative cancer cells.
Methods: HER2 negative breast cancer cells (MCF7, MDA-MB-231) and gastric cancer cells (MKN1 and MKN45) were infected with Ad/ HER2-ECD. They were treated with Tmab-IR700 mediated PIT. We evaluated the HER2-ECD expression induced by Ad/ HER2-ECD and the cytotoxic effects of Tmab-IR700 mediated PIT.
Results: Ad/HER2-ECD efficiently expressed HER2 protein on the surface of the cancer cells. HER2-ECD expressing cells were selectively and rapidly killed by Tmab-IR700 mediated PIT, which was morphologically captured as bleb formation of cellular membrane.
Conclusions: We demonstrated that Ad/ HER-ECD combined with Tmab-IR700 mediated PIT could induce target-selective, immediate cell death in HER2 negative cancer cells. The combination therapy of adenoviral gene transfer of HER2-ECD and the molecular-target PIT is effective for cancer cells regardless of HER2 expression.
Citation Format: Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Hiroshi Tazawa, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara. Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells. [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 2615. doi:10.1158/1538-7445.AM2014-2615
Abstract 2619: Meausuring PIP3 reveals the unexpected role of p110B in luminal breast cancers
Authors: Costa Carlotta , Ebi Hiromichi , Faber Anthony C. , Nishtala Madhuri , Song Youngchul , Benes Cyril H. , Engelman Jeffrey A. 
Published: May 2015

Abstract
The phosphatidylinositol 3-kinase (PI3K) family of lipid kinases plays a prominent role in the growth and survival of several types of cancer, including breast cancers where the PI3K pathway is altered in up to 70% of cases. Due to the technical challenges of measuring the PI3K product, PIP3 directly, the phosphorylation of the downstream effector AKT has historically been used to indirectly assess the activity of class I PI3K. While this approach has proven to be rather useful, it is based on the assumption that this readout is proportional to the levels of PIP3, which is likely to apply only to a limited range of activation levels and within specific contexts. Indeed, evaluation of the efficacy of PI3K inhibitors with such indirect measurements may approximate and oversimplify the complex transduction mechanism of PI3K. During time course experiments using the p110A selective inhibitor, BYL719, we observed that both PIP3 and p-AKT levels were similarly restored after 24 hours in HER2 amplified breast cancer cells, while the rebound of p-AKT was minimal and did not correlate with increased PIP3 levels in PIK3CA mutant breast cancer models. Both p110B inhibition and p110B depletion were effective in blocking the PIP3 rebound observed. Consistent with this, the combination of p110A and p110B inhibitors decreased cell growth and induced a better apoptotic response compared to BYL719 alone. We further demonstrated that only the combination of p110A and p110B inhibitors induced tumor regression. Importantly, PIP3 levels correlated with efficacy more reliably than p-AKT in a PIK3CA mutant model in vivo. These data suggest that measurement of PIP3 levels following treatment may serve as a more effective biomarker than p-AKT levels to predict response to PI3K inhibitors within this subset of breast cancers.
Citation Format: Carlotta Costa, Hiromichi Ebi, Anthony C. Faber, Madhuri Nishtala, Youngchul Song, Cyril H. Benes, Jeffrey A. Engelman. Meausuring PIP3 reveals the unexpected role of p110B in luminal breast cancers. [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 2619. doi:10.1158/1538-7445.AM2014-2619
Abstract 262: The PROFILE feasibility study: Genetic prostate cancer risk stratification for targeted screening
Authors: Eeles Rosalind , Kote-Jarai Zsofia , Antoniou Antonis , Kumar Pardeep , Mikropoulos Christos , Dadaev Tokhir , Taylor Natalie , Bancroft Elizabeth 
Published: May 2015

Abstract
Introduction & Objectives: Prostate cancer (PC) screening is controversial and a better assessment of individualized PC risk is needed. Several single nucleotide polymorphisms (SNPs) conferring a cumulative risk of PC have been identified. We have explored the potential role of genetic markers for targeted screening in a population with increased risk of PC due to family history (FH).
Material & Methods: PROFILE was developed as a pilot study to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. We also evaluated the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools. 116 men aged 40-69 with FH of PC were enrolled between October 2009 and December 2012. Cumulative SNP risk scores were calculated by summing 59 risk alleles for each locus using the weighted effect (log-additive model). DW-MRI was performed in 50 patients. Participants were asked to undergo a 10 core PB regardless of baseline PSA.
Results: Median age 53 yrs (40-69) and median PSA was 1.15. One hundred and two men accepted to undergo a PB as primary PC screening. Twenty-three tumours were found (22.5% of biopsies) as well as seven men diagnosed with atypical small acinar proliferation (ASAP) (6.8%) and 8 men with high-grade prostatic intraepithelial neoplasia (HG-PIN) (7.8%). In total 37.1% received an abnormal result. Of those diagnosed with PC, 41% were intermediate or high risk and required treatment (compared to 24% in general population screening). The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed best in men with a ‘normal’ PSA (&lt;3 ng/ml - AUC 0.63). Analyses of a 78 SNP profile incorporating the new 23 recently identified SNPs is underway.
Conclusions: Our results indicate that PB used for PC screening in men with FH of PC identified a higher proportion of clinically significant PCs. The high AUC for DW-MRI would warrant a larger study. The incidence of ASAP is higher in this group than the general population.The SNP risk score was more predictive in men with PSA&lt;3 where PB would not normally be undertaken, therefore an expanded study to investigate the role of genetic profiling in directing PB in PC screening is indicated.
Citation Format: Rosalind Eeles, Zsofia Kote-Jarai, Antonis Antoniou, Pardeep Kumar, Christos Mikropoulos, Tokhir Dadaev, Natalie Taylor, Elizabeth Bancroft. The PROFILE feasibility study: Genetic prostate cancer risk stratification for targeted screening. [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 262. doi:10.1158/1538-7445.AM2014-262