bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B104: Liposomal C6 Ceramide appears to potentiate chemotoxicity of paclitaxel, gemcitabine and cetuximab against aggressive pancreatic cancer.
Authors: Wanebo Harold J. , Cao Cong , Lu Shaun , Shrayer David , Wan Yinsheng , Bowen Wayne , Bowen Wayne
Published: August 2014

Introduction: Pancreatic adenocarcinoma a highly lethal malignancy (5 yr survival ∼ 5%) is poorly responsive to all chemotherapy, in part related to presence of chemo resistant pathways: prosurvival (AKT/PI3K/mTOR and mutant KRAS. We have previously demonstrated reversal of these resistant pathways by C6 Ceramide and now are pursuing optimum intracellular delivery using selected liposomal preparations ofC6Ceramide.

Methods: C6 Ceramide housed in 4 different liposomal vesicle formulations were tested against pancreatic cell lines L3.6, PANC1 and MIA, using combination therapy with chemotherapy agents Gemcitabine, Paclitaxel and Cetuximab with determination of the MTT anti tumor response. Liposomal preparations included : (#1)18:1 PC(1,2-dioleoyl-sn-glycero-3-phosphocholine; (#3),18:0 PC (1,2-distearoyl-sn-glycero-3-phosphocholine;(#5) DPGG (1,2-dipalmitoyl-sn-glycero-3-galloyl); and (#7) 18:0 PEG2 PE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethylene glycol)-2000. (#1)18:1 PC- has low transition temp and is fluid at bodyT*(# 3). 18:0 PC- has high transition Temperature(T*) is rigid at body T*;#5 DPGG- avoids RE System (is fluid at bodyT*, induces long circulations)#7. 18:0 PEG 2 PE - industry standard (also avoids RE system) Biologic effects of the 4 lipid formulations with/without C6 Ceramide were initially assessed invitro.

Results: Dose response MTT assay demonstrated no distinctive response of C6 combined liposomes vesicles # 1 & 3, but confirmed high activity in preparations #5 & 7.

Conclusion: Liposomal C6 preparations show high activity in potentiating chemo toxicity by Gemcitabine, Paclitaxel and Cetuximab against Pancreatic Cancer. Confirmatory in vivo studies are in process.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B104.

Citation Format: Harold J. Wanebo, Cong Cao, Shaun Lu, David Shrayer, Yinsheng Wan, Wayne Bowen, Wayne Bowen. Liposomal C6 Ceramide appears to potentiate chemotoxicity of paclitaxel, gemcitabine and cetuximab against aggressive pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B104.
Abstract B106: mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.
Authors: Elkabets Moshe , Vora Sadhna , Juric Dejan , Morse Natasha , Mino-Kenudson Mari , Muranen Taru , Tao Jessica , Bosch Campos Ana , Rodon Jordi , Ibrahim Yasir H. , Serra Violeta , Rodrik-Outmezguine Vanessa , Hazra Saswati , Singh Sharat , Kim Phillip , Quadt Cornelia , Manway Liu , Huang Alan , Rosen Neal , Engelman Jeffrey A. , Scaltriti Maurizio , Baselga José
Published: August 2014

Activating mutations of the PIK3CA gene occur frequently in breast cancer and inhibitors that are specific for PI3K p110α, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110α inhibition among PIK3CA-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORC1 signaling, although Akt phosphorylation was inhibited. Similarly in patients, pS6 (residues 240/4) expression (a marker of mTORC1 signaling) was associated with tumor response to BYL719, and mTORC1 was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3CA-mutant cancer cell lines with persistent mTORC1 signaling despite PI3K p110α blockade (that is, resistance), the addition of the allosteric mTORC1 inhibitor RAD001 to the cells along with BYL719 resulted in reversal of resistance in vitro and in vivo. Finally, we found that growth factors such as IGF1 and neuregulin1 can activate mTOR and mediate resistance to BYL719. Our findings suggest that simultaneous administration of mTORC1 inhibitors may enhance the clinical activity of p110α targeted drugs and delay the appearance of resistance.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B106.

Citation Format: Moshe Elkabets, Sadhna Vora, Dejan Juric, Natasha Morse, Mari Mino-Kenudson, Taru Muranen, Jessica Tao, Ana Bosch Campos, Jordi Rodon, Yasir H. Ibrahim, Violeta Serra, Vanessa Rodrik-Outmezguine, Saswati Hazra, Sharat Singh, Phillip Kim, Cornelia Quadt, Liu Manway, Alan Huang, Neal Rosen, Jeffrey A. Engelman, Maurizio Scaltriti, José Baselga. mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B106.
Abstract B110: Heterogeneous genetic alterations emerge during acquired resistance to anti-EGFR therapy in colorectal cancer.
Authors: Arena Sabrina , Misale Sandra , Lamba Simona , Siravegna Giulia , Lallo Alice , Hobor Sebastijan , Russo Mariangela , Buscarino Michela , Sartore-Bianchi Andrea , Bencardino Katia , Amatu Alessio , Siena Salvatore , Di Nicolantonio Federica , Bardelli Alberto
Published: August 2014

Occurence of acquired resistance constitutes one of the major limitations to tumor treatment. In colorectal cancer, the use of anti-EGFR antibodies such as cetuximab and panitumumab is effective in only 15-20% of patients, till secondary resistance to targeted treatment develops. Shedding light on the molecular basis of resistance represents then a mandatory effort in order to foster new lines of therapy. We recently showed that KRAS mutations are responsible for the emergence of secondary resistance to EGFR therapy in a subset of CRC patients (Misale et al., Nature 2012). Here we investigated the role of additional genetic alterations in the development of resistance to EGFR blockade in CRCs. We initially exploited the “liquid biopsy” approach to measure tumor derived DNA mutations in the blood of patients who initially responded and then became refractory to either cetuximab or panitumumab. We found that multiple KRAS and NRAS alleles often emerge during treatment. To better characterize the role of these genetic alterations in CRC, we generated preclinical models, by chronic treatment of several CRC cell lines with cetuximab or panitumumab until resistant derivatives emerged. The resistant populations were a mixture of clones bearing an heterogeneous panel of genetic alterations in KRAS, NRAS and BRAF at various frequencies. Biochemical pathway analyses revealed that, regardless of the genetic alterations, resistant derivatives consistently displayed MEK and ERK activation, which persisted on EGFR inhibition. Collectively, these results identify genetically distinct mechanisms that mediate secondary resistance to anti-EGFR therapies, all of which converge on the reactivation of ERK signaling. With this work, we provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with anti-EGFR drugs; we propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be considered for the treatment of CRC patients who become refractory to anti-EGFR therapies.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B110.

Citation Format: Sabrina Arena, Sandra Misale, Simona Lamba, Giulia Siravegna, Alice Lallo, Sebastijan Hobor, Mariangela Russo, Michela Buscarino, Andrea Sartore-Bianchi, Katia Bencardino, Alessio Amatu, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli. Heterogeneous genetic alterations emerge during acquired resistance to anti-EGFR therapy in colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B110.
Abstract B112: ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2.
Authors: Wang De-Shen , Patel Atish , Kumar Priyank , Xu Rui-Hua , Chen Zhe-Sheng
Published: August 2014

Background: ARRY-334543, an ATP-competitive, selective, reversible small molecule tyrosine kinases inhibitor of ErbB1 and ErbB2, has shown superior preclinical tumor inhibitory activity to that of lapatinib in a wide range of tumor cell lines and xenografts dependent on ErbB signaling pathway. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters, a major obstacle to successful cancer treatment.

Material and Methods: Lung cancer cell line NCI-H460 and its drug-selected derivative ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for this study.

Results: Our results found that ARRY-334543 at 1.0 µmol/l significantly reversed ABCG2-mediated multidrug resistance (MDR) through directly inhibiting the drug efflux function of ABCG2, therefore resulting in the elevated intracellular accumulation of chemotherapeutic drugs in both the drug-selected derivative ABCG2-overexpressing NCI-H460/MX20 and ABCG2-overexpressing transfected cell lines, as well as the NCI-H460, which intrinsically expressed low level of ABCG2, whereas ARRY-334543 at 1.0 µmol/l only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR. However, ARRY-334543 at reversal concentration did not affect the expression levels of ABCG2 protein. Moreover, ARRY-334543 did not regulate the re-localization of ABCG2 from cell membrane to the cytoplasm.

Conclusion: We concluded that ARRY-334543 (1.0 μmol/l) significantly reversed drug resistance mediated by ABCG2.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B112.

Citation Format: De-Shen Wang, Atish Patel, Priyank Kumar, Rui-Hua Xu, Zhe-Sheng Chen. ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B112.
Abstract B115: Use of a genome-wide loss-of-function screen to identify novel mechanisms of resistance to TRAIL induced apoptosis.
Authors: Dimberg Lina Y. , Cabrera Joshua , Menke Christina , Kim Jihye , Porter Christopher C. , Tan Aik-Choon , Behbakht Kian , Thorburn Andrew , Ford Heide L.
Published: August 2014

A biological approach to combat cancer is to define and specifically target signaling pathways involved in tumor progression and metastasis. One such target is the TNF-Related Apoptosis Inducing Ligand (TRAIL) signaling pathway. Importantly, TRAIL kills tumor cells selectively without inducing apoptosis in normal tissue. Recombinant TRAIL and agonistic antibodies against the receptors DR4 and DR5 are in early-phase clinical trials as an anti-cancer treatment in breast cancer. However, since cancer cells must evade tumor surveillance, it is not surprising that many tumors are TRAIL-resistant. We are interested in the molecular basis of acquired resistance to TRAIL induced apoptosis as a result of long-term exposure to the drug. Our goal is to gain an increased understanding of how cancer cells can become resistant to TRAIL and how this resistance can be predicted and circumvented, ultimately leading to more efficient TRAIL-based therapy. To this end, we utilized the Burkitt's lymphoma cell line BJAB-LexR that has been made naturally resistant to TRAIL through long-term culture in the presence of increasing concentrations of the drug Lexatumumab, an anti-DR5 antibody. We performed a genome wide loss-of-function screen using the GeneNet lentiviral shRNA library containing 200 000 shRNAs with sequencing tags, allowing for high throughput deep sequencing. After selection for a particular phenotype, in this case TRAIL resistance, the shRNAs that promote or prevent this phenotype can be deduced from the frequency in which the shRNA is present in the selected (TRAIL-treated) population versus the unselected population. Bioinformatic analysis yielded a list of putative resistance genes that were validated in the BJAB system and also in other cell lines that have been made resistant to TRAIL in a similar fashion. With this unbiased approach, we have identified novel genes associated with TRAIL resistance that may provide targets for combination therapy that could improve the response to TRAIL.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B115.

Citation Format: Lina Y. Dimberg, Joshua Cabrera, Christina Menke, Jihye Kim, Christopher C. Porter, Aik-Choon Tan, Kian Behbakht, Andrew Thorburn, Heide L. Ford. Use of a genome-wide loss-of-function screen to identify novel mechanisms of resistance to TRAIL induced apoptosis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B115.
Abstract B121: Ligand-independent AXL diversification of ErbB signaling and ErbB-targeted drug response mitigation in triple negative breast carcinoma cells.
Authors: Meyer Aaron S. , Gertler Frank B. , Lauffenburger Douglas A.
Published: August 2014

The relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Recently, activation of alternative RTKs as an important resistance process has been identified, although underlying mechanisms are not well understood. Amplification of the targeted signal can also confer resistance, particularly in vivo, where access to the tumor site by therapeutics may be limited. AXL is an RTK linked to secondary resistance in a variety of solid cancers, including those of the breast, lung, glioma, prostate, and colon. Though AXL-mediated resistance is well appreciated, the most effective means of targeting the receptor and basic mechanisms of activation have not been elucidated.

Using ligand-blocking antibodies, siRNA-mediated ligand knockdown, and ligand binding-incompetent mutants, we show ligand-independent activation of AXL is present in a subset of cell lines and that this form of activation is actively regulated by ectodomain interactions. With this in mind, we hypothesized ligand-independent mechanisms of activation may be predominant in particular contexts. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET, and PDGFR but not IGF1R or INSR. Activation of EGFR transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification amplified a subset of downstream signaling and was required for EGF-elicited motility responses in AXL-positive TNBC (triple-negative breast cancer) cells.

This alternative mechanism of receptor activation may limit the utility of ligand-blocking therapeutic approaches and indicate against therapy withdrawal after acquired resistance. Inhibiting ligand-independent activation, in contrast, may provide more specific efficacy on cancer cells. Moreover, sub-additive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR principally yields transactivation-mediated signaling.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B121.

Citation Format: Aaron S. Meyer, Frank B. Gertler, Douglas A. Lauffenburger. Ligand-independent AXL diversification of ErbB signaling and ErbB-targeted drug response mitigation in triple negative breast carcinoma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B121.
Abstract B13: Salmonella typhimurium A1-R targets human pancreatic cancer patient-derived orthotopic xenograft (PDOX) in nude mice.
Authors: Hiroshima Yukihiko , Zhao Ming , Maawy Ali , Zhang Yong , Katz Matthew H.G. , Fleming Jason B. , Uehara Fuminari , Miwa Shinji , Yano Shuya , Momiyama Masashi , Suetsugu Atsushi , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M.
Published: August 2014

The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R (A1-R) on pancreatic cancer patient-derived orthotopic xenografts (PDOX) in nude mice compared to standard chemotherapy. The pancreatic cancer PDOX was orthotopically implanted in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX acquire RFP-expressing stroma for the purposes of imaging the tumor in non-colored nude mice in order to non-invasively image tumor growth and drug response. The nude mice were treated with A1-R or standard chemotherapy including gemcitabine (GEM). Histopathological response to treatment was defined according to Evans's criteria. A1-R treatment significantly reduced tumor weight as well as tumor fluorescence area compared to untreated control (p=0.011), with comparable efficacy to GEM, CDDP and 5-FU. A1-R had the highest efficacy compared to any of the chemotherapy drugs tested based on Evan's histological response criteria. Salmonella typhimurium A1-R was effective on a human pancreatic PDOX and is a promising therapy for this disease in the clinic.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B13.

Citation Format: Yukihiko Hiroshima, Ming Zhao, Ali Maawy, Yong Zhang, Matthew H.G. Katz, Jason B. Fleming, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Atsushi Suetsugu, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Salmonella typhimurium A1-R targets human pancreatic cancer patient-derived orthotopic xenograft (PDOX) in nude mice. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B13.
Abstract B132: Next generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA).
Authors: Churi Chaitanya R. , Rashid Asif , Shroff Rachna , Mishra Lopa , Zuo Mingxin , Kaseb Ahmed , Janku Filip , Aloia Thomas A. , Vauthey Jean-Nicholas , Curley Steven , Ali Siraj , Palmer Gary , Javle Milind
Published: August 2014

Background: The incidence of CCA is rising and the clinical efficacy of systemic therapy is suboptimal. Next generation sequencing (NGS) technology offers potential for targeted therapeutics against genetically heterogenous solid tumors including cholangiocarcinoma (CCA).

Methods: DNA was extracted from biopsy specimens of 56 patients of CCA seen at MD Anderson Cancer Center Houston, TX. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform.Results: 162 genomic variations (GV) were identified from 56 patient samples with an average of 2.89 GVs/patient (range 0-10). GVs identified were mutations (72%), amplifications (17%), loss/deletions (7%) and others (4%). 6 (11%) tumors showed no GVs. Most frequent GVs were TP53 (35%), KRAS (31%), ARID1A (16%), PBRM1 (11%), BAP1 (9%), ERBB2 (9%), FBXW7 (9%), SMAD4 (9%) and IDH1 (7%). ERBB2 GVs included 4 mutations and 1 amplification. KRAS mutation was associated with a statistically significant reduction in overall survival (OS). Mean OS in patients with KRAS mutation was 32 weeks vs. 63 weeks in KRAS wt (t = -2.126, p = 0.039). Ingenuity Pathway Analysis indicated disruption in cell cycle, proliferation, development, death and DNA repair pathways. Targetable signaling pathways from this study are described in Table 1. Targetable GVs were noted in 59% of patients. These are potentially targetable by inhibitors to ERBB2, FGF, mTOR, MEK, BRAF and PARP-1.

Conclusion: These data are the single largest compilation of NGS analysis on CCA patients and demonstrate the range of GVs that are eligible for investigational targeted therapies. These results can be used as a basis to develop personalized treatments for CCA patients based on individual genetic profiles.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B132.

Citation Format: Chaitanya R. Churi, Asif Rashid, Rachna Shroff, Lopa Mishra, Mingxin Zuo, Ahmed Kaseb, Filip Janku, Thomas A. Aloia, Jean-Nicholas Vauthey, Steven Curley, Siraj Ali, Gary Palmer, Milind Javle. Next generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B132.
Abstract B141: Molecular imaging of DNA damage and repair in cancer.
Authors: Wang Yanming , Wu Chunying , Condie Allison , Zhu Junqing , Gerson Stanton
Published: August 2014

Objectives: To directly assess apurinic/apyrimidinic (AP) sites induced by DNA-targeted chemotherapeutic agents for in vivo studies of DNA damage and repair.

Background: Current cancer treatments rely heavily on chemotherapeutic agents to induce cytotoxic DNA damages and programmed cell death in ancer cells. However, the efficacy of DNA-targeted agents such as temozolomide are often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway results in formation of abasic or AP sites and inhibition of AP sites leads to significant reduction of drug resistance and enhancement of drug sensitivity. Thus, AP-site formation has been identified as an important biomarker in DNA-targeted chemotherapies.

Methods: Design, synthesis, and evaluation of small molecular probes used in combination with positron emission tomography (PET) that allows for quantification of AP sites in vivo.

Results: To date, we have design and synthesized a series of AP-binding agents for PET imaging studies. Following radiolabelling, microPET studies have been conducted to evaluate their pharmacokinetic profiles in melanoma and glioma xenograft tumor mouse models that are pre-treated with temozolomide to induce AP-site formation. Subsequent quantitative analysis showed that the radioactivity concentration were higher in tumor regions pre-treated with temozolomide relative to tumor regions without any treatment, indicating that AP-site formation was elevated following temozolomide treatment. In vivo blocking studies based on microPET also showed that the agents bound to AP sites with high specificity.

Conclusion: Our studies have proved the concept that PET imaging agents can be developed to monitor BER pathway and demonstrate the feasibility for future clinical applications in cancer research.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B141.

Citation Format: Yanming Wang, Chunying Wu, Allison Condie, Junqing Zhu, Stanton Gerson. Molecular imaging of DNA damage and repair in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B141.
Abstract B15: Increased clinical relevance of orthotopic glioma models through bioluminescence and MR imaging.
Authors: Lister Deanne , Meade Mary Anne , Woolliscroft Tracey , Balagurunathan Deepa , Trachet Erin , Leopold Wilbur , McConville Patrick
Published: August 2014

Glioblastoma multiforme (GBM) is the most common and most aggressive form of malignant primary brain tumors, affecting nearly 35,000 people in the United States. Most preclinical studies in glioma utilize survival as the primary endpoint to study, which provides limited information about disease progression, tumor burden response to treatment (a primary clinical end point). We have characterized two human glioma cell lines, Gli36 and LN827 that were modified to express luciferase in order to enable in vivo monitoring of disease progression and response to treatment using bioluminescence imaging (BLI). Anatomical magnetic resonance imaging (MRI) was also performed to directly correlate bioluminescence signal with tumor volume. Both models exhibited >90% tumor take-rate and responded to treatment with temozolomide, a clinical standard of care. Analysis of lifespan, tumor volume doubling times, and tumor growth delay all indicated that BLI is a reliable indicator of disease progression and response to treatment. BLI-based endpoints also showed good correlation with MR-based endpoints. These results support the use of in vivo imaging in these modified cell lines for longitudinal monitoring of tumor progression and response to therapy. Imaging was not only a reliable method for quantifying tumor burden, but enabled clinically relevant end points that could not be accessed through non-imaging means or lifespan determination alone. Further utility can be driven in these models through the use of other functional imaging end points.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B15.

Citation Format: Deanne Lister, Mary Anne Meade, Tracey Woolliscroft, Deepa Balagurunathan, Erin Trachet, Wilbur Leopold, Patrick McConville. Increased clinical relevance of orthotopic glioma models through bioluminescence and MR imaging. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B15.
Abstract B153: sVEGFR-1 functionalized nanoparticles for diagnosis of cancer using magnetic resonance imaging.
Authors: Ozgurtas Taner , Yesildal Fatih , Aydin Fevzi Nuri , Sardan Melis , Uzunalli Gozde , Kocaoglu Murat , Tekinay Ayse Begum , Guler Mustafa Ozgur , Genc Rukan , Deveci Salih
Published: August 2014

Cancer is considered to be an important public health problem throughout the world. Early diagnosis of cancer and recurrent tumors are extremely important for reducing mortality rates and also for following up the response to treatment. The increased need of oxygen leads to new vascular structures in and around the tumor. The most important components of this angiogenic process are vascular endothelial growth factor (VEGF) and its receptors which are overexpressed in tumor cells. The aim of this study is to develop soluble VEGF receptor-1 (sVEGFR-1) functionalized iron oxide nanoparticles for diagnosis of early stages of tumors or metastases by MRI. A single dose of N-nitroso-N-methylurea (NMU) at a concentration of 50 mg/kg was injected to inbred rats intraperitoneally on the 21st day of their birth to create breast cancer. In this study, in vivo characteristics of functionalized nanoparticles were studied by comparing rats with tumors and the healthy controls. Approximately 70 days later, tumor formed rats were administered with nanoparticles functionalized with sVEGFR-1, intravenously and scanned with MRI. MR images were taken before the treatment with nanoparticles (0 minute), and at 30th and 60th minutes after treatment. The evaluation of MRI data revealed that the images of metastases were hypointense at 30th minute with respect to the 0 minute and 60th minute images (p<0.05). Nanoparticles were observed to localize at the tumoral regions and there were significant contrast intensity differences in rats with tumor. These results showed that our sVEGFR-1 functionalized nanoparticles were localized at tumoral regions including metastasis. This method can be useful in diagnosis of early tumors, metastasis, and recurrencies. Further molecular and histological studies are necessary to explain the efficacy of these nanoparticles for tumor diagnosis.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B153.

Citation Format: Taner Ozgurtas, Fatih Yesildal, Fevzi Nuri Aydin, Melis Sardan, Gozde Uzunalli, Murat Kocaoglu, Ayse Begum Tekinay, Mustafa Ozgur Guler, Rukan Genc, Salih Deveci. sVEGFR-1 functionalized nanoparticles for diagnosis of cancer using magnetic resonance imaging. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B153.
Abstract B157: Understanding the role of transcription factor ETV1 in metabolic reprogramming of prostate cells as a route to novel therapeutics.
Authors: Baena Esther , Mamoor Shahan , Li Zhe , Orkin Stuart H.
Published: August 2014

ETV1 is the second most frequently rearranged ETS transcription factor gene in human prostate cancer. It is widely believed that ectopically expressed ETV1 (due to gene fusions) plays a similar role in prostate tumorigenesis to that of ERG. However, further analysis of clinical data revealed that high levels of ETV1 expression are often found in more advanced prostate cancers, whereas ERG overexpression is mainly associated with localized prostate cancer and elevated androgen receptor signaling. High expression of ETV1, rather than ERG, in the prostate has been associated with disease recurrence in some patients. Interestingly, many metabolic pathways often associated with cancer cells are enriched in the prostates of mice engineered to carry a Tmprss2-ETV1 knockin allele and ETV1-expressing human prostate cancer samples. To determine the dominant metabolic programs that accompany ETV1 expression, we have performed metabolic profiling, and integrated the data with human prostate cells and mouse transcriptome data. Our analyses have identified ETV1 as a regulator of lipid metabolism, glycolysis and glutamine metabolism. Of note, ETV1 expression reprograms the steroid biosynthesis pathway, leading to an increase in testosterone production at least in part through 17-β hydroxysteorid dehydrogenases activation. Indeed, one of the main causes of prostate cancer recurrence is local androgen production due to metabolic changes in prostate cancer cells. This novel finding may explain, at least in part, how ETV1 expression promotes castration-resistant disease, opening a new path to the development of novel therapies directed to progressive and lethal prostate cancer.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B157.

Citation Format: Esther Baena, Shahan Mamoor, Zhe Li, Stuart H. Orkin. Understanding the role of transcription factor ETV1 in metabolic reprogramming of prostate cells as a route to novel therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B157.
Abstract B158: Transcriptional profile of NAMPTi unveils modulation of Tankyrase and Wnt/B-catenin pathway.
Authors: Shomali Maysoun , McGlynn Patrick , Wiederchain Dmitri , August Paul , Adrian Francisco , Garcia-Echeverria Carlos , Theilhaber Joachim , Bouaboula Monsif
Published: August 2014

The coenzyme, NAD, is as an essential redox factor in cellular biochemical processes such as respiration and metabolism. NAD is also a substrate for cellular enzymes including sirtuins and poly (ADP ribose) polymerases. NAMPT, which catalyzes the rate limiting step of NAD biosynthesis, has been considered as promising cancer target for more than a decade. NAMPT inhibitors profoundly inhibit tumor cell growth; however, the mechanism that leads to the tumor cell growth inhibition is not understood.

In this work, we report the results of our exploration of the metabolic and transcriptional alterations post-NAMPT inhibition in HCT116 cell line. Our results show that NAMPTi induces a time-dependent modulation of tumor metabolism which in turn induces the reprogramming of tumor cell transcriptome concomitant with cell growth inhibition. The transcriptional profile revealed different metabolic and oncogenic signaling pathways are modulated by NAMPT inhibition. The wnt/b-catenin pathway was highlighted as one of the most modulated pathways by NAMPTi.

We indeed confirmed that the NAMPTi induces the inhibition of b-catenin/TCF reporter system transfected in HCT116 cells or in HEK293 cells constitutively expressing Wnt3A. NAMPT inhibition induces a strong decrease of cyclinD1 and c-myc expression in agreement with the modulation of Wnt/b-catenin pathways.

The NAMPTi impact on Wnt/b-catenin pathways can be seen in CRC cell lines bearing APC wt or APC mut and in cell lines with heterozygote but not homozygote b-catenin mutation suggesting that the effect of NAMPTi effect is upstream b-catenin. Our studies highlighted two potential mechanisms that contribute to wnt/b-catenin pathway modulation by NAMPTi. First, we observed an inhibition of disheveled activation and secondly, a decrease in the activity of tankyrase.

The results obtained from these studies highlight the key role of NAMPT in tumor metabolism and the wnt/b-catenin oncogenic pathway. This suggests that modulation of wnt /b-catenin contributes to the antitumor activity of NAMPTi.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B158.

Citation Format: Maysoun Shomali, Patrick McGlynn, Dmitri Wiederchain, Paul August, Francisco Adrian, Carlos Garcia-Echeverria, Joachim Theilhaber, Monsif Bouaboula. Transcriptional profile of NAMPTi unveils modulation of Tankyrase and Wnt/B-catenin pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B158.
Abstract B161: SLC1A5 inactivation induces apoptosis-mediated cells death in non-small cell lung cancer.
Authors: Hassanein Mohamed , Qian Jun , Hoeksema Megan , Jacobovitz Marie , Harris Fredrick T. , Harris Bradford , Massion Pierre P.
Published: August 2014

Introduction: We recently reported that solute carrier family A1 member 5 (SLC1A5) controls glutamine (GLN) uptake and modulates cell growth, oxidative stress and mTOR signalling pathway. SLC1A5 is a transmembrane, high affinity glutamine transporter that is overexpressed and located at the plasma membrane in non-small cell lung cancer (NSCLC). GLN deprivation has been shown to induce cell death in several types of cancers, however the exact mechanism by which SLC1A5 targeting affects NSCLC survival remains unknown. We hypothesize that inhibition of SLC1A5 deprives cells from GLN which induces autophagy which eventually leads to cell starvation and ultimately apoptotic cell death.

Methods: To test our hypothesis we targeted SLC1A5 by siRNA or by its specific inhibitor, GPNA, in a panel of 6 NSCLC lung cancer cell lines (express high level of SLC1A5). For comparison 2 human bronchial epithelial cell lines (HBEs) (express low level of SLC1A5) were used. The effects of targeting SLC1A5 on growth, GLN uptake, ATP level, autophagy, and cell death were examined. Markers of autophagy and cell death were analysed using western blot, nuclear staining and cell cycle analysis.

Results: SLC1A5 inactivation by GPNA or by siRNA resulted in a significant decrease in cellular GLN uptake in NSCLC cell lines, while HBE cell lines were unaffected. Decrease in GLN uptake was accompanied by an increase in autophagy as evident by decrease in cell size, increase of LC3-II and decrease if LC3-I markers of autophagy. In addition, we observed a significant drop in ATP levels by 2 folds with increasing doses of GPNA. Markers of internal apoptotic pathway that include decrease of mitochondrial potential and cleaved caspases-3 and 9 were detected in response to increasing doses of GPNA. No change was observed in external apoptotic markers, caspases 8 or 1. In addition a 2-10 fold increase (based on the cell line) of sub-G1 was observed in NSCLC cell lines but not in HBE cell lines.

Conclusion: Our results show that targeting SLC1A5 in NSCLC cells induces apoptotic cell death. Cells starve due to GLN deprivation and undergo autophagy which leads to a decrease in ATP level resulting in apoptotic cell death. These findings suggest that targeting SLC1A5 may have therapeutic implications in NSCLC.

Grant funding: Lung Cancer Research Foundation

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B161.

Citation Format: Mohamed Hassanein, Jun Qian, Megan Hoeksema, Marie Jacobovitz, Fredrick T. Harris, Bradford Harris, Pierre P. Massion. SLC1A5 inactivation induces apoptosis-mediated cells death in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B161.
Abstract B165: The antitumor efficacy of eribulin is mediated via suppression of invasion and profound induction of cell death in triple negative breast cancer.
Authors: Hu Jing , Horwitz Susan Band , McDaid Hayley M.
Published: August 2014

Eribulin, a microtubule-targeting antitumor drug, is FDA-approved for the treatment of certain patients with advanced or metastatic breast cancer. Some patients treated with this drug have evidence of reduced metastatic dissemination. Triple-negative breast cancer (TNBC), which accounts for approximately 15%-20% of all breast cancers, does not respond to hormone therapies so patients are dependent on chemotherapy. A subset of these patients are intrinsically resistant to chemotherapy, or subsequently relapse and develop metastatic disease, eventually leading to mortality. We explored the mechanistic basis for the antitumor efficacy of eribulin in a panel of triple negative breast cancer cell lines that histologically are classified as basal-like or claudin-low. Specifically, we determined the ability of eribulin to induce cell death versus senescence, and secondly to modulate cancer cell invasion and epithelial to mesenchymal transition (EMT) gene expression. Senescence is a clinically relevant cell fate following chemotherapy that can propel tumor progression and EMT. Eribulin was efficacious at inducing cell death in both subtypes of TNBC, and had a remarkably low propensity to induce senescence in TNBC compared to non-small cell lung cancer and colon cancer cells. A 24-hour treatment with eribulin partially prevented tumor cell invasion in the claudin-low subtype, as assayed by Boyden chamber analysis. Drug-tolerant claudin-low cells that survived high-dose eribulin treatment were also found to have a reduction in EMT markers. In summary, in vitro analysis of cell fate and metastasis indicate that eribulin has an ability to modulate invasiveness and EMT characteristics in preclinical models of TNBC.

This research was funded by Eisai Inc.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B165.

Citation Format: Jing Hu, Susan Band Horwitz, Hayley M. McDaid. The antitumor efficacy of eribulin is mediated via suppression of invasion and profound induction of cell death in triple negative breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B165.
Abstract B168: Investigating the role of SOX2- HEY1 signaling loop in Glioma Invasion.
Authors: Ramadoss Archana , Boulay Jean Louis , Tostado Cristobal , Ritz Marie-Francoisse , Mariani Luigi
Published: August 2014

Gliomas are the most frequent and the most aggressive tumors of CNS. Invasiveness and existence of glioma stem-like cells resistant to conventional therapy contribute to the aggressive phenotype of the tumor. Current treatment efforts (surgery and radiation therapy) fail to prevent the relapse of secondary gliomas.

Measurement of thickness of the infiltration zone surrounding the tumor mass, visualized by MRI, allows classification of patient glioma into Grade I (2-3 mm), Grade II (3-10 mm) and Grade III (>10 mm). Microarray data from classified biopsies indicate that SOX2 and HEY1 mRNAs expressions correlated with tumor invasion grade. This suggested a possible role for SOX2 and HEY1 in regulating genes involved in invasion. Lentiviruses expressing shRNAs against either SOX2 or HEY1 were used to knockdown human glioma cell lines U373 and LN319. Boyden chamber assays and wound healing assays were used as readouts for invasion and migration respectively.

Gene expression analysis on glioma cells depleted for SOX2 revealed 2-5 fold down-regulation of HEY1 mRNA. Interestingly, we observed that glioma cells depleted for HEY1 showed 1-1.5 fold up-regulation for SOX2. This suggested that these transcription factors could be regulating each other. We observed that invasion and migration was strongly enhanced in SOX2 depleted cells. Consistently, our microarray data on these cells showed that mRNA of genes related to epithelial-mesenchymal-transition (EMT) were 1-3.5 fold overexpressed. In contrast, glioma cells depleted for HEY1 showed significant reduction in invasion and migration and the mRNA of genes related to EMT were 2- 5-fold downregulated.

These results are consistent in supporting the hypothesis that a SOX2- HEY1 signaling loop participates in EMT and in glioma invasion. Confirmation of these observations is currently being carried out on a genetic mice model of glioma. Definition of the effectors of glioma invasion might ultimately contribute to identify targets for the development of customized therapies aimed at controlling glioma invasion.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B168.

Citation Format: Archana Ramadoss, Jean Louis Boulay, Cristobal Tostado, Marie-Francoisse Ritz, Luigi Mariani. Investigating the role of SOX2- HEY1 signaling loop in Glioma Invasion. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B168.
Abstract B17: Decreased expressions in autophagy-related proteins is associated with poor prognosis in patients with colorectal adenocarcinoma.
Authors: Lee Han Hong , Choi Ji Hye , Choi Young-Seok , Ko Yoon Ho
Published: August 2014

Background: Autophagy, a cellular degradation process, has paradoxical roles in tumorigenesis and progression of human cancers. The aim of this study was to investigate the expression of autophagy-related proteins in colorectal cancer (CRC), and to evaluate their prognostic significance.

Methods: We analyzed the expression of 3 autophagy-related proteins (LC3B, beclin-1, ATG5) in 263 resected colorectal cancer specimens by immunohistochemistry using tissue microarray.

Results: Of the 263 patients, autophagy-related protein expression frequencies were 71.3% (174/244) for beclin-1, 74.7% (186/249) for LC3B, and 65.1% (151/232) for Atg5. The correlation between the expressions of autophagy-related proteins was significant for all protein pairs. Kaplan-Meier analysis showed that low LC3B expression was positively linked to poor prognosis of the patients with CRC. Cox's proportional hazard model demonstrated that curative resection status, lymph node metastasis, LC3B expression, and the alteration of autophagy-related proteins were independent prognostic factor for CRC.

Conclusion: Alterations in the expression of autophagy-related proteins are closely associated with prognosis of CRC, suggesting that expression patterns may be used as a prognostic marker.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B17.

Citation Format: Han Hong Lee, Ji Hye Choi, Young-Seok Choi, Yoon Ho Ko. Decreased expressions in autophagy-related proteins is associated with poor prognosis in patients with colorectal adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B17.
Abstract B179: Targeted next generation sequencing for somatic mutations in human cancer.
Authors: Peterson Jason D. , de Abreu Francine , Gallagher Torrey L. , Burchard Paul R. , Amos Christopher I. , Wells Wendy A. , Pipas J. Marc , Ernstoff Marc S. , Fadul Camilo E. , Rigas James R. , Tsongalis Gregory J.
Published: August 2014

Objective: We have replaced single gene PCR-based methods for the detection of BRAF, KRAS and EGFR variants in routine clinical practice with next generation sequencing assays for the Ion Torrent AmpliSeq Cancer Hotspot Panel v2 (50 genes) and the Illumina TruSeq Amplicon Cancer panel (48 genes). Implementation of these panels requires constant optimization of technical and analytical procedures as reagents and software continue to be developed. In this study we describe somatic mutation findings from our clinical laboratory service.

Methods: DNA was extracted from 90 formalin fixed, paraffin embedded tissue specimens that included 50 lung cancer, 24 colon cancer and 16 other cancers. Barcoded libraries were prepared from up to 10ng of extracted DNA and multiplexed on single 318 chips. Data analysis was performed using Golden Helix SVS for the Ion Torrent panel and Variant Studio for the Illumina panel. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer (IGV).

Results: Of the 90 cancer cases sequenced, each panel returned on average 20 variants. Of these, there was 100% concordance between the two panels with respect to the clinically actionable mutations identified.

Conclusions: We have implemented next generation sequencing technologies for the detection of somatic mutations in human cancers. Two platforms, the Ion Torrent PGM and the Illumina MiSeq, have been used for the routine analysis of FFPE cancer tissues in a clinical setting with actionable and non-actionable variants reported and archived.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B179.

Citation Format: Jason D. Peterson, Francine de Abreu, Torrey L. Gallagher, Paul R. Burchard, Christopher I. Amos, Wendy A. Wells, J. Marc Pipas, Marc S. Ernstoff, Camilo E. Fadul, James R. Rigas, Gregory J. Tsongalis. Targeted next generation sequencing for somatic mutations in human cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B179.