bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A176: On the search for new tools to fight tumors and cancer pain with the aid of organic synthesis: Quicker access to pancratistatins and tetrodotoxins
Authors: Nieto-García Olaia , Cagide-Fagín Fernando , Alonso Ricardo 
Published: June 2012

Abstract
One of the biggest hurdles in the fight against cancer is the non-selective nature of most current treatments. On the other hand, opioids-refractive cancer pain is a most important unsolved problem. Consequently, the search and development of new drugs that are tumor-killing (while non-cytotoxic to normal cells) and/or potent analgesics are major goals in cancer research. In this context, pancratistatin and tetrodotoxin, the most prominent representatives of two different families of natural products, have been identified as highly promising leads for cancer treatment and cancer pain, respectively; in fact, they are currently at the focus of some initiatives for pharmaceutical development.
Interest in pancratistatin stems from its high level of in vitro and in vivo cell growth inhibitory activity on a wide variety of human cancer cell lines, but particularly from its mode of action that, while yet unknown, is very selective: pancratistatin does not affect normal cells in clear contrast with other agents clinically used at the moment such as paclitaxel (taxol®) or VP-16.
On the other hand, the exceptional potency and selectivity of tetrodotoxin in blocking voltage-gated sodium channels is responsible for its strong analgesic activity (3000 times more potent than morphine without the secondary side effects of opioids).
Unfortunately, the limited supply of pancratistatin, tetrodotoxin and their analogues from their natural sources is seriously precluding further progress in the area; thus stretching the need for practical chemical synthesis. We have now developed novel synthetic schemes to both families of compounds based on the expeditive gram-scale assemblage of an advanced common intermediate (a polyfunctionalized cyclohexanic core) in just three steps from commercially available compounds. In this way, we have just completed the shortest synthetic access to tetrodotoxin reported to date and two different routes to pancratistatins. We are currently preparing a number of derivatives pretended to be useful as biological probes. Details will be given at the Conference.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A176.
Abstract A178: Role of tumor and host-derived HGF in drug resistance to EGFR inhibitors in EGFR activating mutation-positive lung cancer
Authors: Kakiuchi Soji , Yano Seiji , Wang Wei , Li Qi , Yamada Tadaaki , Matsumoto Kunio , Hanibuchi Masaki , Mitsudomi Tetsuya , Yatabe Yasushi , Kuramoto Takuya , Otsuka Koji , Nishioka Yasuhiko , Sone Saburo 
Published: June 2012

Abstract
Background: Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However, 25–30% of patients with EGFRmu show intrinsic resistance, and the responders invariably acquire resistance to EGFR-TKIs. Here, we examined the role of hepatocyte growth factor (HGF), a specific ligand of MET, in gefitinib resistance of NSCLC with EGFRmu.
Methods: NSCLC cells, PC-9 and HCC827, with EGFRmu, but not T790M second mutation in EGFR or MET amplification, were used in this study. Sensitivity to gefitinib was determined by MTT assay. Phosphorylation of MET, EGFR, ERBB3, and the PI3K/Akt pathway were examined by Western blotting. HGF expression in 20 tumors from 16 NSCLC patients with EGFRmu who were treated with gefitinib was determined by immunohistochemistry.
Results: HGF induced resistance to gefitinib by restoring Akt phosphorylation independently of ErbB3. Specific down-regulation of MET, but not ErbB3, reversed gefitinib resistance and Akt phosphorylation induced by HGF. High levels of immunoreactivity for HGF were detected in cancer cells of 3 of 3 intrinsic resistant tumors and in one of 2 tumors with acquired resistance without T790M second mutation or MET amplification, suggesting HGF-induced resistance by autocrine mechanism. The lung cancer cells also became resistant to EGFR-TKIs when co-cultured in vitro with HGF-producing fibroblasts and co-injected into SCID mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4 successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo. Co-localization of fibroblasts and HGF was detected in both xenograft tumors in mouse model and lung cancer patient specimens, suggesting HGF-induced resistance by paracrine mechanism.
Conclusions: The findings indicate that HGF-mediated MET activation is a novel mechanism of intrinsic and acquired gefitinib-resistance in NSCLC with EGFRmu by both autocrine and paracrine mechanisms. Therefore, inhibition of HGF-MET signaling may be considerable strategy for more successful treatment with EGFR-TKIs.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A178.
Abstract A179: Synergistic interactions of Lapatinib and an AKT inhibitor in HER2 positive breast cancer cell lines depends on PI3K pathway status
Authors: Korkola James , Bayani Nora , Cooper Brian , Kuo Wen-Lin , Billig Jessica , Ziyad Saffiyah , Feiler Heidi , Spellman Paul , Wooster Richard , Gray Joe W. 
Published: June 2012

Abstract
Purpose: Lapatinib is a dual inhibitor of EGFR/HER2. Recent evidence suggests that resistance to HER2 inhibition by lapatinib may be in part due to re-activation of PI3K-AKT signaling mediated by HER3. The purpose of this study was to screen lapatinib in combination with a pan-AKT inhibitor in a panel of HER2 amplified breast cancer cell lines to determine if this dual inhibition had synergistic effects in preventing cell line growth.
Methods: Cell lines were treated in triplicate with nine two-fold serial dilutions of lapatinib, AKTi, or a combination of the two for 72 hours. Growth was measured using a cell titer glo assay (Promega) and growth inhibition (GI) was measured using standard techniques. Synergistic interactions were measured by the median effect method and reported as a combination index using the Synergy module in R.
Results: Of 11 HER2 positive cell lines tested, four showed strong evidence of synergy in more than half of the nine concentrations used. Five cell lines showed little or no synergy (and even some evidence of antagonism). The remaining two cell lines showed an intermediate response. Of the four lines with synergy, all were mutant for PIK3CA, while only one of the five lines that did not show strong synergy was mutant for PIK3CA. Interestingly, this line did show significant synergy at one dose combination, suggesting that it was likely to be more sensitive to lapatinib + AKTi than the other four lines. From microarray data, we identified two probe sets (representing one gene, SASH1) at a False Discover Rate of less than 5% that showed a significant association between expression and response. SASH1 has previously been implicated as a tumor suppressor gene in breast, although at this point, it is unclear whether it plays any functional role or is simply a marker for synergistic response to lapatinib and AKTi.
Conclusions: Our work demonstrates that a combination of lapatinib plus and AKT inhibitor may be beneficial in HER2 positive patients who also have PI3K pathway mutations. Care should be taken in screening patients prior to treatment, as the combination was found to be antagonistic in some cell lines that did not have PIK3CA mutations. SASH1 may be a useful screening tool in identifying such patients.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A179.
Abstract A180: Tumor heterogeneity in glioblastoma is actively maintained by a paracrine circuit driven by mutant EGFR
Authors: Inda Maria-del-Mar , Bonavia Rudy , Sah Dinah W.Y. , Hadwiger Peter , Tan Pamela , Cavenee Webster K. , Furnari Frank 
Published: June 2012

Abstract
Glioblastoma is typified by a heterogeneous composition of diverse cytological subtypes carrying a variety of gene alterations. An example of heterogeneity that is present in &gt;50% of cases is amplification of the epidermal growth factor receptor (EGFR) gene. This amplification is often accompanied by structural alterations leading to expression of a variant form of the gene, EGFR (also referred to as EGFRvIII, deltaEGFR, EGFR-de2-7 and EGFR*), which conveys enhanced tumor aggressiveness. This potent tumor-promoting function of EGFR would suggest that it should be the predominant amplified receptor in clinical samples, however, paradoxically, EGFR is usually present as minor and focal populations within tumors having more homogeneous wtEGFR amplification. This disconnect between tumorigenic potential and the frequencies and proportions of the amplified mutant EGFR and wtEGFR in GBM might arise if mutant EGFR occurs later in tumor progression where it not only enhances the tumorigenicity of cells which express it, but also potentiates, the proliferation of neighboring cells expressing amplified wtEGFR. If this were so, the potentiation loop might provide an attractive and novel therapeutic target. Here, we tested and validated the hypothesis that engraftment of a minor population of EGFR-expressing glioma cells can dramatically enhance the tumorigenicity of tumors cells expressing wtEGFR through paracrine stimulation. In support of this general notion, EGFR-driven pro-tumorigenic enhancement was lost upon siRNA-mediated knockdown of IL-6, and conversely, glioma cells engineered to over-express IL-6 enhanced the tumorigenicity of wtEGFR-expressing cells. These findings demonstrate that the molecular heterogeneity of GBM can be actively maintained, suggesting a coordinated strategy for therapeutic intervention.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A180.
Abstract A181: Dissecting the crosstalk between wt and mutant EGFR in glioblastoma multiforme
Authors: Bonavia Rudy , Inda Maria-del-Mar , Johns Terrance , Cavenee Webster , Furnari Frank 
Published: June 2012

Abstract
Glioblastoma Multiforme (GBM) exhibits intratumoral heterogeneity on the morphological and molecular levels, a hallmark feature which may contribute to its poor response to targeted therapy. A powerful oncogenic event in GBM is amplification and rearrangement of the epidermal growth factor receptor (EGFRvIII variant, deleted for exons 2–7, hereafter EGFR), yet notably, only a minority of primary tumor cells possess this signature lesion while the remainder maintain expression of the wildtype EGFR (wtEGFR). We observed that tumorigenicy of wtEGFR expressing cells can be significantly enhanced by the presence of EGFR-expressing cells within the tumor, suggesting that soluble factors produced by the latter cells might mediate this potent tumor enhancement. Here we show that in vitro treatment of U87 cells overexpressing wtEGFR (U87wt) with conditioned media from U87 cells overexpressing EGFR (U87) resulted in the activation of wtEGFR, STAT3, Akt, and Erk1/2. Surprisingly, U87 failed to demonstrate any increase in EGFR ligand production that could explain the enhanced wtEGFR phosphorylation. To identify the molecular mediators of this transactivation we analyzed the expression in U87 of cytokines of the IL-6 family, which are known potent activators of STAT3. We found a robust enhancement of the expression of IL-6 and LIF in U87 , compared to the parental cell line. Use of neutralizing antibodies allowed us to demonstrate that these candidate cytokines are responsible not only for the activation of STAT3, but also of the EGFR; results of which were confirmed by antibodies that block accessibility of their common gp130 receptor subunit. The analysis of other similar cellular systems suggested that, although not necessarily through the same cytokine(s), the more tumorigenic cells overexpressing EGFR generate signals to neighboring cells by engaging gp130, which is responsible for the activation of EGFR and STAT3. The importance of this circuitry in vivo was further demonstrated when, by knocking down gp130 expression in U87wt, we completely prevented the tumor growth enhancement usually observed in mixed composition tumors. These observations suggest gp130 as a potential new target for the treatment of gliomas.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A181.
Abstract A183: Ex vivo imaging of EGF receptor-mediated signal transduction for prediction of anti-EGFR treatment efficacy
Authors: Mishima Yuji , Matsusaka Satoshi , Terui Yasuhito , Mishima Yuko Matsumoto , Kuniyoshi Ryoko , Hatake Kiyohiko 
Published: June 2012

Abstract
Objectives: EGFR is a promising treatment target in solid tumors. Two major types of anti-EGFR agents have entered the clinical setting: antibodies and small-molecule EGFR TKIs. EGFR-TKI inhibits autophosphorylation of EGFR by binding to ATP binding site of tyrosine kinase domain of EGFR and interrupts the signal transduction. On the other hand, anti-EGER therapeutic antibodies interrupt EGFR signaling by blocking ligand binding. In addition, as for antibodies, the effects of the ADCC are also expected. In this study, we aimed at developing a method to estimate the effectiveness of anti-EGFR agents by analyzing these mechanisms using ex vivo imaging technique.
Methods: To establish a method that confirms the inhibition effect of the EGFR-signal transduction, we prepared fluorescent-labeled ligand and developed the imaging strategy to visualize membrane binding and subsequent internalization of labeled EGF. In addition, fluorescent-labeled NK-based effector cells that have been established by introducing fcgr3a gene into a NK leukemia cell line were used for characterization of ADCC susceptibility of individual tumor cells. In our strategy, a continuous confocal laser scanning microscopy was used for tracing fluorescent-labeled EGF or effector cells as well as tumor cell death.
Results: Fluorescent probe bearing EGF was highly specific and potent in the binding and activation of the EGF receptor, being rapidly internalized into endosomes. Pretreatment with therapeutic anti-EGFR antibody completely inhibited the ligand-binding and subsequent events. Meanwhile, EGFR TKIs partially prevented endocytotic step. K-ras mutation status did not significantly affect the ligand binding and internalization. The imaging analysis of the ADCC using primary colorectal cancer specimens revealed that cetuximab-coated tumor cells were gradually damaged by direct interaction of effector cells. ADCC susceptibility of individual tumor cells has varied to some extent.
Conclusion: We have established imaging methods of the early events of EGFR signaling pathway and ADCC reaction. This imaging method soffer the rapid reliable means that analyze the effect of the EGFR targeted agent to the individual tumor cells. By combining with already established prognostic factors such as K-ras mutation status or Fc receptor polymorphism, our imaging analysis will propose novel strategy to predict an individual treatment prognosis more precisely.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A183.
Abstract A185: Phase I clinical, pharmacokinetic, and pharmacodynamic study of SB939, an oral histone deacetylase inhibitor (HDACi), in patients with advanced solid tumors
Authors: Siu Lillian L. , Hotte Sebastien J. , Chen Eric X. , Hirte Hal W. , Powers Jean , Stayner Lee-Anne , Iacobucci Anne , Novotny-Diermayr Veronica , Zhu Joy , Eisenhauer Elizabeth A. 
Published: June 2012

Abstract
Background: SB939 is an orally available, potent, competitive HDACi selective for Class I, II and IV histone deacetylases. Preclinical evaluation of SB939 in a broad spectrum of xenograft mouse models revealed dose-dependent tumor growth inhibition. In the HCT116 colorectal cancer model, SB939 showed superior activity compared to other HDACi and prolonged histone H3 acetylation (acH3) in tumor tissues lasting ≥ 24 hours.
Methods: Patients (pts) with advanced solid malignancies were enrolled into 7 dose levels (DL). At DL1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other DLs. Detailed PK sampling was performed on cycle 1 days 1 and 5 (for DL1 on days 1 and 3). Peripheral blood mononuclear cells (PBMC) were collected on cycle 1 at various time points for determination of acH3 levels using a validated Western blot assay. MTD was defined as dose with ≥ 2/3–6 pt with DLT.
Results: To date, 28 pts have received a total of 72 cycles: median age 62 (range 48–88); F:M = 10:18; ECOG 0:1:2 = 7;17:4; tumor types = colorectal (15), neuroendocrine (3), gastric (2), lung (2) and others (6); prior chemotherapy regimens 0:1:2:3+ = 5:1:6:16. The most frequent non-hematologic adverse events (AE) of at least possible attribution to SB939 were (% of pts with all grade/gr 3+): fatigue (46%/7%), nausea (29%/0%), anorexia (21%/4%), vomiting (18%/4%) and diarrhea (11%/0%). Hematologic AE were all mild to moderate. DLT occurrence is described below, with the 90 mg DL declared MTD. PK analysis showed dose-proportional increases in AUC and Cmax. Elimination half-life is 6–9 hours. PBMC analysis for acH3 (lysine9/14) showed highest levels at 3 hours post-dose with return to baseline by 24 hours. The average relative acH3 levels at 70 mg dose level in this study are comparable to those obtained at 60 mg dose level in another phase I study of SB939, which evaluates a different schedule of thrice weekly (every other day) for 3 out of 4 weeks. Four pts (14%) received 4 or more 4-week cycles of SB939 (range 6–10).
Conclusions: SB939 is well tolerated at up to 70 mg on this schedule of 5 consecutive days every 2 weeks. The 70 mg DL is being expanded and will likely be the RP2D. Phase II trials in prostate cancer and sarcoma are planned.
Dose level Schedule Total no of cycles No of pts with DLT/Total no of pts DLT Other significant toxicity 10 3 days 6 0/3 - - Q2W 10 5 days 16 1/6^ - - Q2W 20 5 days 18 1/6 Gr 3 - Q2W myositis 30 5 days 19 0/4 - - Q2W 50 5 days 6 0/4 - - Q2W 70 5 days 5 0/3 - - Q2W 90 5 days 2 1/2* Gr 3 2 gr 2 N/V Q2W fatigue 1 gr 2 QTc ^ gr 3 bilirubin rise subsequently declared not drug related * neither pt completed a full cycle
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A185.
Abstract A187: HDAC inhibitor SNDX-275 enhances herceptin-mediated therapeutic effects on HER2-overexpressing breast cancer cells
Authors: Huang Xiaoping , Wang Shuiliang , Lee Choon-Kee , Ordentlich Peter , Liu Bolin 
Published: June 2012

Abstract
Numerous studies indicate that deregulation of histone acetylation and deacetylation plays an important role in aberrant gene expression in human cancers. The Histone deacetylases (HDAC) have become attractive therapeutic targets, and many inhibitors of HDAC are actively under investigation as potential anti-cancer agents. SNDX-275 is an oral, class I HDAC inhibitor currently in multiple phase II clinical trials. We have recently reported that SNDX-275 selectively induces apoptosis of HER2-overexpressing breast cancer cells. Herceptin®, a humanized monoclonal antibody against HER2 receptor, has been successfully used in breast cancer patients with HER2-overexpressing tumors. In the current studies, we have investigated the potential synergism of SNDX-275 and Herceptin on inducing growth inhibition and/or apoptosis in HER2-overexpressing breast cancer cells, focusing on their combinational effects on the expression of both HER2 and HER3, and inactivation of downstream signaling pathways.
The cell proliferation (MTS) assays showed that SNDX-275 significantly enhanced Herceptin-induced growth inhibition in HER2-overexpressing breast cancer cells as compared to the treatment with either agent alone. While SNDX-275 (0.5 µM) alone clearly decreased the levels of HER3 with little effect on HER2 levels, Herceptin (20 µg/ml) alone mainly lowered the expression levels of HER2 in the HER2-overexpressing SKBR3, BT474, and MDA-MB-453 cells. The combinations of SNDX-275 (0.5 µM) and Herceptin (20 g/ml) resulted in a dramatic reduction of both HER2 and HER3 levels, and subsequently led to inactivation of HER2 tyrosine kinase evidenced by western blot analysis showing reduced levels of both P-HER2 and P-HER3. On the downstream signaling pathways, neither the combination nor either agent alone had inhibitory effects on MAPK. In contrast, the combinations of SNDX-275 and Herceptin significantly decreased the levels of P-Akt in SKBR3, BT474, and MDA-MB-453 cells as compared to either agent alone. It appeared SNDX-275 induced expression of p21waf1, and Herceptin upregulated p27kip1, however, their combinations had no further inductions on either of these two CDK inhibitors. Moreover, apoptotic-ELISA and western blot analysis on PARP cleavage revealed that the combinations of SNDX-275 and Herceptin promoted more cells undergoing apoptosis as compared to SNDX-275 alone.
Taken together, our results indicated that SNDX-275 and Herceptin synergistically induced growth inhibition and apoptosis in HER2-overexpressing breast cancer cells through combined downregulation of HER2/HER3 levels, inhibition of HER2 tyrosine kinase, and inactivation of the PI-3K/Akt signaling. These data suggest that further evaluation of SNDX-275 in HER2 positive breast cancer may be warranted.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A187.
Abstract A195: Inhibition of angiogenesis and growth of HER2-overexpressing tumors by SV40 T/t-common polypeptide
Authors: Hsueh Shu-Ping , Hsu Wei-Bin , Wang Won-Bo 
Published: June 2012

Abstract
HER2 overexpression in various tumors results in increased angiogenesis, metastasis and reduced survival. Previously we reported that simian virus 40 T/t-common polypeptide can repress HER2 expression and specifically induce apoptosis in HER2-overexpressing cancer cells. In this study, we further explored the effect of T/t-common on tumor angiogenesis. HER2-overexpressing cancer cells were either infected with T/t-common-carrying adenovirus (rAd-T/t) or vector virus (rAd-V). The supernatant of infected cells were then used in the Tanswell migration, tube formation, and Matrigel plug assays to evaluate its ability to induce angiogenesis. Our data indicate that conditioned medium from rAd-T/t-infected cells had much lower ability to induce the migration and tube formation of endothelial cells and to induce blood vessel formation in Matrigel plugs than that from rAd-V-infected cells. T/t-common was found to be able to inhibit the expression of pro-angiogenic factor VEGF-A through inhibiting the HER2-ERK-HIF-1 signaling pathway. Moreover, T/t-common could induce the expression of anti-angiogenic factor TSP-1 through activating the HER2-p38 pathway. Finally we show that infection of HER2-overexpressing SK-OV-3 xenograft tumors by rAd-T/t virus could lead to inhibition of tumor growth and microvessel formation in NOD/SCID mice. Together, these data suggest that T/t-common is a potential gene therapeutic agent that can inhibit the growth and angiogenesis of HER2-overexpressing tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A195.