bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2577: Aurora kinase inhibitors require PUMA to induce apoptosis and preferentially kill KRAS-mutant colon cancer cells
Authors: Sun Jing , Knickelbein Kyle , He Kan , Chen Dongshi , Yu Jian , Zhang Lin 
Published: August 2015

Abstract
Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells. Inhibition of aurora kinases results in mitotic arrest and death of cancer cells, and has been explored as an anti-cancer strategy. However, how aurora inhibition kills cancer cells is poorly understood. In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of p53-upregulated modulator of apoptosis (PUMA), a BH3-only BCL-2 family protein, in colorectal cancer cells irrespective of p53 status. Deficiency in PUMA increased polyploidy and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors. In response to aurora kinase inhibition, PUMA was directly activated by p65 through the canonical NF-kB pathway following AKT inhibition. Interestingly, aurora kinase inhibitors were found to preferentially kill KRAS-mutant colon cancer cells, which is associated with enhanced induction of PUMA and another BH3-only protein NOXA. Furthermore, PUMA was necessary for the chemo-sensitization and in vivo anti-tumor effects of aurora kinase inhibitors in colon cancer cells. These results suggest that PUMA induction mediates the apoptotic response to mitotic arrest imposed by aurora kinase inhibition, and may be a useful indicator for the anti-cancer activity of aurora kinase inhibitors.
Citation Format: Jing Sun, Kyle Knickelbein, Kan He, Dongshi Chen, Jian Yu, Lin Zhang. Aurora kinase inhibitors require PUMA to induce apoptosis and preferentially kill KRAS-mutant colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2577. doi:10.1158/1538-7445.AM2015-2577
Abstract 2582: Gefitinib [epidermal growth factor receptor (EGFR) inhibitor] plus etoricoxib (COX-2 inhibitor) versus oral methotrexate in advanced, recurrent head and neck squamous cell carcinoma (HNSCC): results of a randomized pilot study
Authors: Malhotra Hemant , Joshi Archit , Jasuja Sandeep , Yadav Ajay 
Published: August 2015

Abstract
Background: There are very few options for the treatment of patients of SCCHN who relapse after surgery and/or radiotherapy and/or chemotherapy other than best supportive care (BSC). Over expression of the EGFR has been demonstrated in more than 80% of patients with SCCHN. In the present study, we compared the response rates, overall survival, toxicity profile and quality of life in patients of recurrent SCCHN receiving oral methotrexate versus a combination of EGFR inhibitor (Gefitinib) + COX II inhibitor (Etoricoxib).
Patients and Methods: Twenty five patients of Advanced and Recurrent HNSCC were included in each group. Patients were randomly assigned to receive Gefitinib (250 mg twice a day before meals) plus Etoricoxib (120 mg/day) [Group A] or Oral Methotrexate (15 mg/week) [Group B]. All patients received BSC. Patients were follow-up 4 weekly with routine blood investigations and quality of life questionnaires - QLQ C-30 and QLQ H & N-35. CT scan of Head and Neck was done every 8 weeks. EGFR mutation studies were not performed.
Results : Partial Response (PR) was seen in 6.25% of patients in group-A; and 0% from group-B. Stable Disease (SD) observed in 25% of patients from group-A and 10% patients from group-B. At the end of study, mean overall survival (OS) in group-A was 107.15 days; whereas mean overall survival in group-B was 73.95 days. The difference in survival was statistically significant (P&lt;0.05). Comparing the QOL between two groups by EORTC QLQ C-30 and EORTC H & N-35 at 4 and 8 weeks, patients of group-A had better quality of life. No dose-limiting toxicities were seen in group-A or B. Most common toxicity observed in group A were skin rash and diarrhoea while on group B it was mucositits.
Conclusions: In this small pilot study, in patients with advanced and recurrent SCCHN, dual targeted treatment (EGFR and COX II) with combination of Gefitinib plus Etoricoxib improved response rates, quality of life and overall survival as compared to oral methotrexate. The combination was well tolerated with minor side-effects and should be considered in this poor prognostic subset of patients. Larger, multi-centric studies are needed to confirm these results.
Citation Format: Hemant Malhotra, Archit Joshi, Sandeep Jasuja, Ajay Yadav. Gefitinib [epidermal growth factor receptor (EGFR) inhibitor] plus etoricoxib (COX-2 inhibitor) versus oral methotrexate in advanced, recurrent head and neck squamous cell carcinoma (HNSCC): results of a randomized pilot study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2582. doi:10.1158/1538-7445.AM2015-2582
Abstract 259: Ibrutinib enhances the anti-tumor efficacy of CTLA-4 blockade in lymphoma and colon cancer models
Authors: Ng Patrick , Lu Daniel , Chang Betty 
Published: August 2015

Abstract
The anti-CTLA-4 antibody ipilimumab was the first immune checkpoint blockade antibody to show significant clinical efficacy. However, only a subset of the treated melanoma patients had long-term survival benefits (Schadendorf, D., et al. ECCO 2013). Combining ipilimumab with an agent that modulates immunity by a different mechanism may improve efficacy. Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase (Btk), an essential enzyme in the B-cell receptor signaling pathway. Ibrutinib also inhibits the interleukin-2-inducible Tec kinase (Itk) that is required for the activation/survival of Th2 T cells. This activity is consistent with preclinical studies that demonstrated ibrutinib could potentiate Th1 immunity (Dubovsky, JA., et al. Blood 2013). We investigated whether ibrutinib could enhance the anti-tumor effect of CTLA-4 blockade using the A20 B-cell lymphoma and the CT26 colon carcinoma mouse models. BALB/c mice (9-11/group) were implanted with tumor cells subcutaneously on the hind flanks. Animals bearing 80-100 mm3 (D x d2 x 0.4) tumors were dosed daily with oral ibrutinib (24 mg/kg) with or without the anti-mouse CTLA-4 antibody 9D9 (100 μg/mouse) given every 2 days by intraperitoneal injections. Animals in the lymphoma and colon cancer models were treated for 13 and 37 days, respectively. Tumor volume was measured and survival recorded for up to 2 months after tumor inoculation. Neither the A20 tumors, which express Btk, nor the CT26 tumors were inhibited by ibrutinib. In the A20 model, although 9D9 alone resulted in complete tumor regression in 7 of 9 treated animals, tumors in 2 of the 7 mice relapsed after treatment had ended. In contrast, 9D9 in combination with ibrutinib led to rapid, complete, and durable responses in 7 of 9 treated animals that lasted until the end of the study. In the CT26 model, treatment with 9D9 alone had minimal effects on tumor growth, but the addition of ibrutinib led to complete tumor regression in 6 of 10 treated animals. Thus, ibrutinib enhanced the anti-tumor efficacy of an anti-CTLA-4 antibody in B-cell lymphoma and colon carcinoma mouse models. The mechanism of tumor eradication by the combination therapy is under investigation and will be discussed at presentation.
Citation Format: Patrick Ng, Daniel Lu, Betty Chang. Ibrutinib enhances the anti-tumor efficacy of CTLA-4 blockade in lymphoma and colon cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 259. doi:10.1158/1538-7445.AM2015-259
Abstract 2607: Antitumor activity of the selective RAF inhibitor HM95573 in solid tumors and hematologic malignancies
Authors: Lee Young-Mi , Bae InHwan , Gwang Mo Namgoong , Lee Jae Ho , Kim Suhyeon , Song Ji Yeon , Lee Kyu Hang , Song Tae Hun , Ahn Young Gil , Kim Young Hoon , Suh Kwee Hyun 
Published: August 2015

Abstract
The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of tumor cells. Activation of the MAPK pathway due to mutations in BRAF, NRAS and KRAS is considered one of the causes of solid tumors (NSCLC, CRC,HCC, andthyroid cancers) and hematologic malignancies.
HM95573 is a novel, highly potent RAF kinase inhibitor. Biochemically assayed for over 120 kinases, HM95573 showed the high selectivity toward BRAF mutant and CRAF kinases. The half maximal inhibition concentrations (IC50) of HM95573 against BRAFWT, BRAFV600E and CRAF kinases were 41nM, 7nM and 2nM, respectively. The strongly inhibited kinases subsequent to RAF kinases appeared to be CSF1R (44nM), DDR1 (77nM) and DDR2 (182 nM).
HM95573 potently inhibited the growth of BRAFmutation CRC cell lines (e.g. IC50: 118nM for Colo-205) and thyroid cancer cell lines (43nM for B-CPAP); KRAS mutation NSCLC cell lines(297nM for Calu-6),CRC cell lines(65nM for HCT-116) and thyroid cancer cell lines(479nM for CAL-62); and NRAS mutation HCC cell lines(28nM for HepG2) andleukemia cell lines (39nM for HL-60). HM95573 effectively inhibited the phosphorylations of MEK and ERK, downstream kinases associated with cell proliferation in tumor cell lines mutated in BRAF, KRAS and NRAS. In addition, the phosphorylation of downstream kinases of RAF such as MEK and ERK was effectively inhibited with treatment of HM95573 in mutant KRAS NSCLC and CRC cells.
HM95573 showed the excellent antitumor activity in mouse models xenografted with BRAF mutation cell line (Colo-205), KRAS mutation cell lines (Calu-6 and HCT-116)and NRAS mutation cell line (HepG2)two RAF inhibitors approved in melanoma which were effective to only BRAF mutation cell lines under conditions tested. The in vivo antitumor activity of HM95573 was potentiated with MEK inhibitors.
Now, HM95573 is currently in phase I development in patients with advanced solid tumors including KRAS mutation NSCLC in Korea.
Citation Format: Young-Mi Lee, InHwan Bae, Namgoong Gwang Mo, Jae Ho Lee, Suhyeon Kim, Ji Yeon Song, Kyu Hang Lee, Tae Hun Song, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Antitumor activity of the selective RAF inhibitor HM95573 in solid tumors and hematologic malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2607. doi:10.1158/1538-7445.AM2015-2607
Abstract 261: Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice
Authors: Sanmamed Miguel F. , Rodriguez Inmaculada , Oñate Carmen , Azpilikueta Arantza , Rodriguez-Ruiz Maria E. , Morales-Kastresana Aizea , Labiano Sara , Perez-Gracia Jose L. , Martín-Algarra Salvador , Alfaro Carlos , Schalper Kurt A. , Mazzolini Guillermo , Sarno Francesca , Hidalgo Manuel , Korman Alan J. , Jure-Kunkel Maria , Melero Ignacio 
Published: August 2015

Abstract
To evaluate the pharmacodynamics effects and antitumor activities of immunostimulatory mAb, we have developed a “humanized” murine model in which the receptors targeted by such mAbs become expressed. Human lymphocytes transferred into immunodeficient mice undergo activation and redistribute to organs with surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations result in lethal xenograft-versus-host disease, which is aggravated when mice are given clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab) mAbs. In mice engrafted with either a human colorectal carcinoma cell line (HT-29) and allogeneic human PBMCs or a primary gastric carcinoma and PBMCs from the patient, urelumab and nivolumab significantly slowed tumor growth (p&lt;0.01). Increased activated human T lymphocytes producing IFN-ϒ and decreased human regulatory T lymphocytes in the xenografted tumors may explain such therapeutic activities. These mouse models permit surrogate analyses to test and make predictions on immunotherapy strategies encompassing immunostimulatory mAbs and their combinations.
Citation Format: Miguel F. Sanmamed, Inmaculada Rodriguez, Carmen Oñate, Arantza Azpilikueta, Maria E. Rodriguez-Ruiz, Aizea Morales-Kastresana, Sara Labiano, Jose L. Perez-Gracia, Salvador Martín-Algarra, Carlos Alfaro, Kurt A. Schalper, Guillermo Mazzolini, Francesca Sarno, Manuel Hidalgo, Alan J. Korman, Maria Jure-Kunkel, Ignacio Melero. Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 261. doi:10.1158/1538-7445.AM2015-261
Abstract 2619: Synergistic anticancer effect of Noscapine and Camptothecin is mediated through apoptosis and cell cycle arrest in A549 lung cancer
Authors: Doddapaneni Ravi , Patel Ketan , Singh Mandip 
Published: August 2015

Abstract
Background:
The aim of this study was to evaluate the anticancer activity of a natural product Noscapine (Nos) and Camptothecin (CMP) combination (Nos+CMP) against non-small cell lung cancer (NSCLC) and to elucidate the underlying mechanism of action.
Methods: A549 cells were treated with Nos, CMP or their combination and combination index (CI) values were calculated using isobolographic method. The apoptotic proportion of the cells and cell cycle effects were analyzed using flow cytometry. The expression of apoptotic proteins was detected by western blot analysis such as anti-apoptotic protein Bcl2, cell survival marker survivin, extracellular matrix proteins like MMP-2, MMP-9 and cell cycle regulatory proteins like p21 and cyclin dependent kinase 2 (CDK2).
Results: The CI values (&lt;0.61) were suggestive of synergistic behavior between Nos and CMP. To investigate the underlying mechanism of the Nos antiproliferative effect, cell cycle-analysis was conducted with A549 cells. Nos+CMP treatment group induced G2/M phase arrest (using the the fluorescence-activated cell sorting analysis) and the number of apoptotic cells were also increased significantly in a dose-dependent manner compared to Nos and CMP alone and control treatments. Furthermore, western blot analysis revealed that Nos+CMP treatment significantly upregulated 0.9 fold (p&lt;0.05) the expression of tumor suppressor protein p21 Waf1/Cip1 (suggesting inhibition of cell cycle progression) compared to single agent treated and control groups. Expression of CDK2 (an important component of cell machinery) and cyclin D1 (another important regulator of cell cycle progression) was significantly downregulated 1.03 fold (p&lt;0.05) and 0.7 fold (p&lt;0.05) respectively in Nos+CMP compared to other groups. Also, expression of Bcl2, survivin, MMP-2 and MMP-9 was significantly downregulated in Nos+CMP treated cells (p&lt;0.05). Further, investigations are currently being conducted to evaluate the synergistic anticancer effect of Nos and CMP in lung tumor xenografts in nude mice.
Conclusion: Nos potentiated the anticancer activity of CMP in an additive to synergistic manner against lung cancer via cell cycle and apoptotic pathways. These findings suggest potential benefit for use of Nos+CMP in treatment of lung cancer.
Citation Format: Ravi Doddapaneni, Ketan Patel, Mandip Singh. Synergistic anticancer effect of Noscapine and Camptothecin is mediated through apoptosis and cell cycle arrest in A549 lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2619. doi:10.1158/1538-7445.AM2015-2619
Abstract 2627: Lapatinib promotes promoted the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes
Authors: Dai Chunling , Ma Shaolin , Chen Zhesheng , To Kenneth , Fu Liwu 
Published: August 2015

Abstract
Purpose: Lapatinib has been used in combination with capecitabine or paclitaxel in treating patients with progressive HER2-overexpressing metastatic breast cancer. Unfortunately, an increased hepatotoxicity had been found in the combinational therapy. The aim of this study was to investigate the potential mechanism of the increased hepatotoxicity during the combination treatment of lapatinib and chemotherapeutic agent.
Experimental design: The incidence of hepatotoxicity was analyzed in the patients and Swiss mice with combinational treatment of lapatinib and paclitaxel or doxorubicin. Pharmacokinetic studies of paclitaxel and doxorubicin were carried out in mice. The chemotherapeutic agent accumulation was performed in ABCB1 overexpressing hepatocellular cancer cells and normal liver tissues.
Results:The patients received lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those received paclitaxel alone. The in vivo experiments showed that the subjects in group of lapatinib plus chemotherapeutic agent had significantly higher levels of alanine aminotransferase and serious hepatocyte injury compared with that in group of single drug. Pharmacokinetic studies revealed that lapatinib could increase the exposed level of paclitaxel and doxorubicin without inhibiting the activity of CYP 3A4. Further study demonstrated that lapatinib could increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1.
Conclusion: The higher incidence of hepatotoxicity during the treatment of lapatinib plus chemotherapeutic agent was due to the increased agent accumulation in liver cells via inhibiting the function of ABC transporters inhibited by lapatinib. This is important information direction for the design of combinational therapy in clinic.
Citation Format: Chunling Dai, Shaolin Ma, Zhesheng Chen, Kenneth To, Liwu Fu. Lapatinib promotes promoted the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2627. doi:10.1158/1538-7445.AM2015-2627
Abstract 2648: A novel dual inhibitor for AKT and EGFR signaling inhibits the growth of lung cancer cells
Authors: Papu John Arokya Mary Sashi , Ankem Murali , Damodaran Chendil 
Published: August 2015

Abstract
Lung cancer is the leading cause of deaths worldwide due to cancer, of which non-small cell lung cancer is more common making up about 80 percent of lung cancer cases. Although early detection of lung cancer is feasible, targeted therapies importance are growing for advanced lung cancer. EGFR inhibitor is one of the potent options for non-small cell lung cancer (NSCLC), either alone or in combinations with chemotherapy drugs, erlotinib, gefitinib and afatinib; however the complete remission is not yet achieved. Hence, our goal is to dissect the role behind EGFR resistance in NSCLC.
Our results suggested a concomitant activation of AKT which was also evident in EGFR expressed of NSCLC. So, we hypothesized that inhibiting both AKT as well as EGFR signaling, could be a promising strategy for treatment of lung cancer. Recently we identified a small molecule, 6-dimethyl, dihydro pyranone (6ddp), that inhibits both AKT (pAKTser473) and EGFR signaling in NSCLC, which resulted growth inhibition of A549 and H460 lung cancer cell lines. Interestingly, the IC50 concentrations were at 1.5nm and 0.3nm in both the lung cancer cell lines. Inhibition of both pro-survival signaling by a small molecule, activated induction of apoptosis by up regulating caspase mediated pro-apoptotic signaling (cleaved caspase) in NSCLC cells. Interestingly, the potent molecule inhibits epithelial-mesenchymal transition (EMT) in A549 and H460 cells by modulating the kinetics of E-Cadherin, β-Catenin expression. Currently, we are planning to validate these interesting findings in animal models, which is essential to translate into clinics.
Citation Format: Arokya Mary Sashi Papu John, Murali Ankem, Chendil Damodaran. A novel dual inhibitor for AKT and EGFR signaling inhibits the growth of lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2648. doi:10.1158/1538-7445.AM2015-2648
Abstract 2669: Chaetoglobosin K, an Akt pathway inhibitor, prevents proliferation and migration of prostate carcinoma cells
Authors: Ali Amna , Caggia Silvia , Matesic Diane F. , Khan Shafiq A. 
Published: August 2015

Abstract
Chaetoglobosin K (ChK) is an indolylcytochalasin isolated from the fungus Diplodia macrospora that has shown anti-tumorigenic effects in multiple human lung and ovarian carcinoma cell lines. We have previously reported that ChK decreases Akt activation and modulates key downstream Akt/mTOR pathway effectors in tumorigenic cells. The down-regulation of Akt activation by ChK is independent of class I PI3K enzyme inhibition or the upstream mediators PDK1, PTEN, and mTORC2. The purpose of these studies was to investigate the effect of ChK on the proliferation and migration of prostate carcinoma cells of various metastatic potential and PTEN status. The activation of Akt was monitored to assess the ability of ChK to inhibit Akt in prostate carcinoma cells. In these studies, MTT assays were used to measure the number of viable PC3, DU145, and LNCaP cells treated with ChK. Scratch wound and transwell migration assays were utilized to examine the effect of ChK on cell migration. To assess Akt activation, western blot analysis was performed to measure changes in Akt phosphorylation at the ser473 and thr308 sites after cells were treated with ChK or vehicle. ChK was found to inhibit the number of viable PC3, DU145, and LNCaP cells with IC50 values in the 3-5μM range. ChK inhibited migration of PC3 cells into the wound space at 1μM by approximately 60% after 72 hours as compared to vehicle treated controls. ChK inhibited transwell migration of PC3 cells by greater than 90% compared to controls after 5 hours. Additionally, ChK treatment lowered Akt phosphorylation at key activation sites. In summary, ChK inhibits the proliferation, migration, and Akt activation of prostate carcinoma cells in vitro. Further mechanistic studies of ChK will substantiate its therapeutic potential in the treatment of prostate and other cancers.
Citation Format: Amna Ali, Silvia Caggia, Diane F. Matesic, Shafiq A. Khan. Chaetoglobosin K, an Akt pathway inhibitor, prevents proliferation and migration of prostate carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2669. doi:10.1158/1538-7445.AM2015-2669