bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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<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

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

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

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<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

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 (<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<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<0.05) and 0.7 fold (p<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<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

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

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

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
Abstract 2678: Targeting prostate cancer metastasis with novel small molecule agonists of EphA2
Authors: Wang Bingcheng , Petty Aaron
Published: August 2015

During tumor progression, EphA2 receptor can gain ligand-independent pro-oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement. The effects can be reversed by ligand stimulation, which triggers the intrinsic tumor suppressive signaling pathways of EphA2 including inhibition of PI3/Akt and Ras/ERK pathways. These observations argue for development of small molecule agonists for EphA2 as potential tumor intervention agents. Through virtual screening and cell-based assays, we report here the identification and characterization of doxazosin as a novel small molecule agonist for EphA2 and EphA4, but not for other Eph receptors tested. NMR studies revealed extensive contacts of doxazosin with EphA2/A4, recapitulating both hydrophobic and electrostatic interactions recently found in the EphA2/ephrin-A1 complex. Clinically used as an α1-adrenoreceptor antagonist (Cardura®) for treating hypertension and benign prostate hyperplasia, doxazosin activated EphA2 independent of α1-adrenoreceptor. Similar to ephrin-A1, doxazosin inhibited Akt and ERK kinase activities in an EphA2-dependent manner. Treatment with doxazosin triggered EphA2 receptor internalization, and suppressed haptotactic and chemotactic migration of prostate cancer, breast cancer, and glioma cells. Moreover, in an orthotopic xenograft model, doxazosin reduced distal metastasis of human prostate cancer cells and prolonged survival in recipient mice. More potent and selective derivatives of doxazosin have been developed with enhanced efficacy against prostate cancer and glioblastoma. To our knowledge, this is the first example of small molecule agonists of a receptor tyrosine kinase that is capable of inhibiting malignant behaviors in vitro and in vivo.

Citation Format: Bingcheng Wang, Aaron Petty. Targeting prostate cancer metastasis with novel small molecule agonists of EphA2. [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 2678. doi:10.1158/1538-7445.AM2015-2678
Abstract 2706: Inhibition of PFKFB3/glycolysis overcomes chemoresistance in ovarian cancers
Authors: Mondal Susmita , Roy Debarshi , Kalogera Eleftheria , Khurana Ashwani , Tapolsky Gilles H. , Telang Sucheta , Chesney Jason , Shridhar Viji
Published: August 2015

Metabolic alterations in cancer are increasingly being recognized as important novel targets. Among different regulators of altered metabolism, 6-PhosphoFructo-2-Kinase/Fructose-2,6-Bisphosphatases 3 (PFKFB3) a glycolytic enzyme required for tumorigenic growth, and produces fructose-2,6-bisphosphate (F2,6BP), is recognized as important regulator of glycolysis. We determined that the active form of PFKFB3ser471 was overexpressed in chemo-resistant ovarian cancer (OVCA) cell lines and resistant patient derived xenograft (PDX) models compared to their isogenic chemo-sensitive cell lines and sensitive PDX models. These results suggest that targeting PFKFB3 will have beneficial effects in patients with OVCA. PFK-158 is a potent and selective inhibitor of PFKFB3 that is currently being investigated in a Phase 1 study in patients with advanced solid malignancies. Here we report for the first time, PFK-158 dose-dependently inhibits cell proliferation and colony formation ability in both carboplatin and paclitaxel (PTX) resistant cell lines. PFK-158 markedly suppresses glycolysis by reducing glucose uptake, ATP production, lactate dehydrogenase activity and lactate secretion. Interestingly, both Chou-Talalay synergy analysis and apoptosis assay by annexin V-PI staining showed PFK-158 strongly synergies with both PTX and carboplatin in PTX and cisplatin resistant cell lines respectively. PFK-158 induced apoptosis through a significant increase in caspase-3/7 activation and PARP cleavage. Moreover, in a highly metastatic PTX-resistant in vivo model, combination of PFK-158 with carboplatin and PTX significantly reduced tumor weight, ascites and metastasis compared to untreated and PFK-158, carboplatin or PTX alone treated mice. Since the majority of OVCA patients recur with chemo-resistant disease, our results suggest that PFK-158 in combination with standard chemotherapy may have clinical utility in late stage ovarian cancer patients.

Citation Format: Susmita Mondal, Debarshi Roy, Eleftheria Kalogera, Ashwani Khurana, Gilles H. Tapolsky, Sucheta Telang, Jason Chesney, Viji Shridhar. Inhibition of PFKFB3/glycolysis overcomes chemoresistance in ovarian cancers. [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 2706. doi:10.1158/1538-7445.AM2015-2706
Abstract 2715: Hepatotoxicity and oxidative stress biomarker study of peg-coated and non-coated gold nanoparticles in Sprague-Dawley rats
Authors: Patlolla Anita K. , Fountain Myeisha , Tchounwou Paul
Published: August 2015

Nanoparticles (NPs) offer a great possibility for biomedical application, not only to deliver pharmaceutics, but also to be used as novel diagnostic and therapeutic approaches. Currently, there are no data available regarding to what extent the degree of the toxicity and the accumulation of gold nanoparticles (GNPs) are present in in vivo model. The aim of this study was to assess the effects, after oral administration, of poly-ethylene-glycol (PEG) coated and non-coated GNPs on various hepatotoxicity and oxidative stress markers such as alanine (ALT), aspartate aminotransferases and alkaline phosphatase, lipid hydro peroxide (LHP) in the mouse model. Sprague -Dawley rats were exposed to four different concentrations of PEG-coated and non-coated GNPs (12.5, 25, 50 and 100 mg/kg BW) and a control. Samples were collected 24 hours after the last treatment following standard protocols. Exposure to PEG-coated and non-coated GNPs enhanced the activities of serum amino-transferases (ALT/AST), alkaline phosphatases (ALP) and concentration of lipid hydro peroxide compared to control. However, PEG-coated GNPs demonstrated enhanced hepatotoxic effect than non-coated GNPs. The scientific findings reported here suggest that both GNPs have the potential to induce hepatotoxicity in Sprague-Dawley rats through activation of the mechanisms of oxidative stress at a higher level of exposure. However, more studies to clarify the role of encapsulation in the in vivo toxicity of GNPs, are required and parallel comparison is preferred.

Keywords: gold nanoparticle (GNP), poly-ethylene-glycol, lipid hydroperoxide, serum aminotransferases, alkaline phosphatases, Sprague-Dawley rats, hepatotoxicity.

Citation Format: Anita K. Patlolla, Myeisha Fountain, Paul Tchounwou. Hepatotoxicity and oxidative stress biomarker study of peg-coated and non-coated gold nanoparticles in Sprague-Dawley rats. [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 2715. doi:10.1158/1538-7445.AM2015-2715
Abstract 2726: Dysregulation of host cellular genes targeted by HPV integration contributes to HPV related cervical carcinogenesis
Authors: Zhang Ruiyang , Chen Xiangmei , Lu Fengmin
Published: August 2015

The integration of HPV viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports have indicated that this integration might cause functional dysregulation of the host cellular gene(s) involved, suggesting a possible role for such integration targeted cellular genes(ITGs) in cervical carcinogenesis. Therefore in this study, a comprehensive analysis of HPV integration events was undertaken using data collected from the scientific literature. 499 integration loci on human chromosomes were included. This systemic analysis first confirmed previous findings that the breakpointsof HPV genome are concentrated in E1, E2 and E2/E4 regions. The collected data revealed that HPV DNA preferred to integrate into intragenic regions, particularly gene-dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be transcriptionally active compared to similar collection of genes picked at random locations across the human genome. Furthermore, Analysis of the integration sites in the human genome revealed that all chromosomes were represented with several integration hotspots. In addition, the ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology (GO) and KEGG analysis. Besides, functional analysis of MPPED2, one of above ITGs, demonstrated a role in blocking G1/S transition and cell proliferation retardation. Overall the results of this comprehensive analysis has implicated for the first time dysregulation of ITGs caused by viral integration as having a possible etiological involvement in cervical carcinogenesis.

Citation Format: Ruiyang Zhang, Xiangmei Chen, Fengmin Lu. Dysregulation of host cellular genes targeted by HPV integration contributes to HPV related cervical carcinogenesis. [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 2726. doi:10.1158/1538-7445.AM2015-2726
Abstract 2731: Establishment and characterization of immortalized nasopharyngeal epithelial cells with stable infection of Epstein-Barr virus
Authors: Jia Lin , Tsang Chi Man , Yip Yim Ling , Law Wai Tak , Zhang Jun , Tsao George SW
Published: August 2015

Nasopharyngeal carcinoma (NPC), with a remarkably distinctive ethnic and geographic distribution, has the highest incidence among Southern Chinese. Unlike other types of head and neck cancers, a unique feature of NPC is its close association with Epstein-Barr virus (EBV). EBV infection represents an early event during the pathogenesis of NPC. Latent EBV infection is found in every cancer cell of virtually all cases of undifferentiated NPC in endemic regions. Genetic alterations in the premalignant epithelium may support the EBV latency. Although EBV-encoded proteins in its latent infection, including LMP1, LMP2A, etc., have been identified with crucial functions to initiate or promote oncogenesis, to date the exact role of EBV infection in the malignant transformation of nasopharyngeal epithelial (NPE) cells remains unclear. We have previously generated a panel of immortalized NPE cells by ectopic overexpression of hTert (catalytic unit of human telomerase). However, reliable in vitro models of stable EBV infection are also necessary for further elucidating the regulatory network supporting the persistent latency of EBV in NPE cells, and also the potential roles of EBV in the pathogenesis of NPC. In the present study, we established NP361hTert-EBV cells with stable EBV infection via co-culture with Akata B cells harboring EBV, followed by the effective enrichment of EBV-infected cells by FACS sorting. The loss of EBV episome in NPE cells was fast initially upon infection, and relatively stable maintenance of EBV could be achieved after enrichment of EBV-positive cells for three times. Results of western blotting analysis showed that the protein expression level of cyclin D1 was increased in NP361hTert-EBV cells, as compared to the non-infected NP361hTert cells. Meanwhile, we also observed increased expression of phosphorylated protein kinase Akt (Ser473) in NP361hTert-EBV cells, suggesting that the Akt signaling was activated, and such activation might contribute to the persistence of EBV in NP361hTert cells. The stable EBV-infected NPE cells will serve as a powerful in vitro model for further study in elucidating the functional role of EBV in the carcinogenesis of NPC.

This work was partly supported by General Research Fund (HKU 779713M, HKU780911M), and the AoE NPC grant (AoE/M-06/08) from Hong Kong Research Grant Council; and Small Project Funding (201309176242) from The University of Hong Kong.

Citation Format: Lin Jia, Chi Man Tsang, Yim Ling Yip, Wai Tak Law, Jun Zhang, George SW Tsao. Establishment and characterization of immortalized nasopharyngeal epithelial cells with stable infection of Epstein-Barr virus. [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 2731. doi:10.1158/1538-7445.AM2015-2731
Abstract 2732: The role of protein P in hepatocellular carcinoma
Authors: Fu Hongyong , Guo Lianying , HUANG Lin
Published: August 2015

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related death worldwide. Although treatment options have improved in the past 30 years, 5-year survival rate remains below 20%. To improve the therapeutics of HCC, great efforts are needed in understanding the mechanisms underlying HCC. Protein P, plays an important role in the development of cancer. To clarify the role of P in the development of HCC, we investigated the expression level of P in HCC tissue chips. The results showed that P level is much higher in carcinoma than adjacent tissue, and the overall 5-year survival is much better in P low expression patients than in P high expression patients. P expression was also found to be increased in HCC cell lines, compared with the normal liver cell line. Further, the proliferation of HCC cell lines was suppressed significantly by siRNA-mediated P knockdown in both anchorage dependent and independent growth assays. These data suggested that P is a crucial factor in the development of HCC, which might therefore represent a novel therapeutic target for HCC.

Citation Format: Hongyong Fu, Lianying Guo, Lin HUANG. The role of protein P in hepatocellular carcinoma. [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 2732. doi:10.1158/1538-7445.AM2015-2732
Abstract 2752: Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls
Authors: Cheung Mitchell , Talarchek Jacqueline , Howard Suzanne E. , Howard Timothy , Peng Hongzhuang , Hesdorffer Mary , Rauscher Frank J. , Ohar Jill A. , Testa Joseph
Published: August 2015

Malignant mesothelioma (MM) is an uncommon but aggressive cancer that has been linked with asbestos exposure. Contributing genetic factors appear to play a role because familial clustering of MM has been observed and that only a small percentage of asbestos-exposed individuals have been documented to develop MM. Germline mutation of BAP1 has been identified as one such predisposing factor. However, the frequency of germline BAP1 mutations in MM cases is debatable due to small sampling sizes of studies from previous publications. Therefore, we decided to determine the prevalence of germline BAP1 mutations in a large set of asbestos-exposed MM cases and controls, the biggest such population study to date. BAP1 mutation status was compared between 150 MM cases with a family history of cancer and 153 asbestos-exposed controls without indications of familial cancers. Although no alterations of BAP1 were discovered in the controls, BAP1 mutations were identified in 9 of the MM cases (6%). These alterations included 2 splice site changes, 4 insertion/deletions, and 3 missense mutations. In vitro enzymatic assays showed decreased deubiquitinase activity for each of the three BAP1 missense mutant proteins. We observed a statistically significant lower age of MM onset as well as a higher incidence of peritoneal MMs among the 9 BAP1 mutation cases compared to the non-mutated MM cases. The other tumors identified in family members of the 9 individuals included additional MMs, ocular and cutaneous melanomas, renal, breast, lung, and gastric carcinomas, and lymphomas. Interestingly, six of the nine MM cases with a germline BAP1 mutation had two or more primary cancers, suggesting a widespread targeting of tissues of multiple organs caused by the mutation. In summary, these findings suggest that patients presenting with MM and a family history of cancer should be considered for BAP1 mutation testing to identify those who might benefit from screening and regular monitoring of family members to enable early detection and intervention.

Citation Format: Mitchell Cheung, Jacqueline Talarchek, Suzanne E. Howard, Timothy Howard, Hongzhuang Peng, Mary Hesdorffer, Frank J. Rauscher, Jill A. Ohar, Joseph Testa. Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls. [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 2752. doi:10.1158/1538-7445.AM2015-2752
Abstract 2762: LFSpro: A risk assessment tool to estimate TP53 mutation status in families with Li-Fraumeni syndrome
Authors: Peng Gang , Bojadzieva Jasmina , Ballinger Mandy L. , Thomas David M. , Strong Louise , Wang Wenyi
Published: August 2015

Li-Fraumeni syndrome (LFS) is a rare disorder and characterized by autosomal dominant mutation inheritance with frequent occurrence of multiple cancer types including soft tissue/bone sarcoma, breast cancer, leukemia, brain tumors and many others. A majority of LFS is caused by germ-line mutations in p53 tumor suppressor gene. Given the diverse cancer spectrum and incidence in Li-Fraumeni syndrome (LFS) and limitations of the clinical criteria, accurate identification of candidates for prospective TP53 mutation testing has been difficult. A more efficient prediction tool is needed for TP53 mutation carrier identification, which, followed by appropriate management and screening, may ultimately decrease mortality. To this date, we developed LFSpro, which is built on a Mendelian model and estimates TP53 mutation probability through the Elston-Stewart algorithm. With independent validation data from 765 families (19,530 individuals), we demonstrated the accurate prediction of TP53 mutation status using LFSpro. Family history of cancer evolves, and LFSpro is sensitive to mutation carriers in families newly presenting in high-risk clinics and in families followed for years. It is more broadly applicable than the current clinical criteria and therefore may improve clinical management for families with LFS.

Citation Format: Gang Peng, Jasmina Bojadzieva, Mandy L. Ballinger, David M. Thomas, Louise Strong, Wenyi Wang. LFSpro: A risk assessment tool to estimate TP53 mutation status in families with Li-Fraumeni syndrome. [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 2762. doi:10.1158/1538-7445.AM2015-2762
Abstract 2765: Evaluation of family history of cancer in first-degree relatives and increased cancer risk: A multinational study
Authors: Modali Laxmi , Lehman Teresa A. , Modali Ramakrishna , Ratnasinghe Luke D.
Published: August 2015

Family history of cancer is a known risk factor for several of the more prevalent cancer types. However, familial aggregation of cancer may not follow the genetic linkage pattern seen with most inherited cancer syndromes. In these instances, clustering may be due to unknown hereditary genetic mutations or to an aggregation of environmental risk factors and such clustering may still confer a significant risk. We assessed the association between family history of cancer in first-degree relatives and cancer risk among 9,122 cancer cases and 76,537 controls in a multinational study. Analyses also included evaluation of breast, colon and prostate cancer risk associated with family history of these respective cancer types. Cases were verified by physician diagnosis and all study participants were administered an in-depth survey to ascertain various demographic and lifestyle factors as well as a complete family history of cancer among first-degree relatives. Multivariable logistic regression was used to assess the association between family history of cancer and cancer risk. Among all subjects, the odds ratio (OR) for individuals with a family history of cancer was 1.79 [95% confidence interval = 1.7-1.9] after adjusting for age, gender, BMI, smoking pack years and ethnicity. Additionally, a greater cancer risk was associated with increasing number of first-degree relatives with a history of cancer. Ethnic groups studied included Caucasian-Americans, African-Americans, Hispanic/Latinas and Caucasian-Polish. All ethnic groups showed a significant association between family history of cancer and cancer risk with the highest adjusted OR of 2.65 [95% confidence interval = 2.0-3.6] among the Hispanic/Latina group. Further analyses indicated that family history of colon, breast and prostate cancer was significantly associated with an increased risk of these respective cancer types across studied ethnic groups. In particular, the adjusted ORs for breast, colon and prostate cancer risk in the Caucasian-Polish group were at least double the overall adjusted ORs for each cancer type. Our study shows that family history of cancer is a significant predictor of cancer risk especially among certain ethnic groups. In addition, family history of cancer can represent both a genetic predisposition and/or environmental exposure and risk associated with familial clustering of cancer.

Citation Format: Laxmi Modali, Teresa A. Lehman, Ramakrishna Modali, Luke D. Ratnasinghe. Evaluation of family history of cancer in first-degree relatives and increased cancer risk: A multinational 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 2765. doi:10.1158/1538-7445.AM2015-2765
Abstract 2805: Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis
Authors: Shirakami Yohei , Sakai Hiroyasu , Kochi Takahiro , Ideta Takayasu , Miyazaki Tsuneyuki , Shimizu Masahito , Seishima Mitsuru
Published: August 2015

Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to have effects against colorectal cancer (CRC), since evidence has emerged that people who routinely use NSAIDs show a lower risk of CRC. Among NSAIDs, cyclooxygenase-2 (COX2) inhibitors are thought to exert its anti-cancer effect through blocking prostaglandin (PG) E2 whose actions are mediated by signaling via four receptors EP1, EP2, EP3, and EP4. Previous animal experiments have demonstrated that the development of colon tumor is suppressed by knocking down of either EP1 or EP4. In the present study, we investigate the effect of a novel small molecule EP4 antagonist on rat colon tumorigenesis. Employed animal is Kyoto Apc Delta (KAD) rat which has Apc mutation and is susceptible to chemically-induced CRC. Five-week-old KAD rats received injection of azoxymethane (20 mg/kg i.p.) and 2% dextran sodium sulfate in drinking water for two weeks, and then they were divided into two groups: no treatment (control) group and the group treated with an EP4 antagonist RQ-00015986 (RQ-15986) which was kindly provided by AskAt Inc. RQ-15986-treated 17-week-old KAD rats showed lower colon tumor incidence (37.5% vs 100% in control group, P < 0.05) and smaller multiplicity (1.33 ± 0.58 vs 2.86 ± 0.69 in control group, P < 0.05). The expression levels of inflammatory cytokines, including TNF-alpha and IL-6, in colonic mucosa were decreased in RQ-15986-treated group. By treatment with RQ-15986, the expression levels of monocyte chemo-attractant protein-1 (MCP-1) and indoleamine 2,3-dioxygenase (IDO) were also down-regulated in colon mucosa. Immunohistochemical analyses of colonic membrane revealed that PCNA-labeling index was lower and that F4/80 positive cells were fewer in RQ-15986-treated group. These findings suggest that RQ-15986 may suppress CRC development through mediating immune system and controlling chronic inflammation in the colon.

Citation Format: Yohei Shirakami, Hiroyasu Sakai, Takahiro Kochi, Takayasu Ideta, Tsuneyuki Miyazaki, Masahito Shimizu, Mitsuru Seishima. Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis. [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 2805. doi:10.1158/1538-7445.AM2015-2805
Abstract 2810: Identification of a natural compound as mammalian target of rapamycin kinase inhibitor
Authors: Jang Jeong-Hoon , Lee Cheol-Jung , Lee Mee-Hyun , Surh Young-Joon , Cho Yong-Yeon
Published: August 2015

The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, plays a critical role in the regulation of Akt signaling-mediated cell proliferation and transformation. Although several synthetic chemical compounds have developed to inhibit mTOR kinase activity, only few publications have been reported on the identification of natural compounds to target the mTOR kinase active pocket. In this study, we found that AME, a natural compound, inhibited cell proliferation by impairment of G1/S cell cycle transition when cells were co-treated with tumor promoters, such as epidermal growth factor. AME directly targeted the active pocket of mTOR kinase domain by competing with adenosine triphosphate (ATP), but not with PI3K and PDK1. We further confirmed that AME inhibited phosphorylation of Akt at Ser473, which is a target amino acid of mTOR complex 2 (mTORC2), and Akt-mediated GSK3β phosphorylation at Ser9, which resulted in activation of GSK3β. The activated GSK3β inhibited cell proliferation by c-Jun phosphorylation at Ser243, which facilitated destabilization and degradation of c-Jun through an ubiquitination-mediated proteasomal degradation pathway. Notably, decreased c-Jun stability by AME treatment suppressed EGF-induced neoplastic cell transformation in JB6 Cl41 mouse skin epidermal cells and HaCaT human skin keratinocytes in soft agar assay. Taken together, these results demonstrated that AME might be a natural chemopreventive agent targeting mTOR kinase active pocket.

Key words: Natural compound, ATP-competitive mTOR kinase inhibitor, mTORC2/Akt/GSK3 signaling, chemoprevention

Citation Format: Jeong-Hoon Jang, Cheol-Jung Lee, Mee-Hyun Lee, Young-Joon Surh, Yong-Yeon Cho. Identification of a natural compound as mammalian target of rapamycin kinase inhibitor. [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 2810. doi:10.1158/1538-7445.AM2015-2810