bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B12: The antitumor and antiangiogenic activity of brivanib, a dual inhibitor of VEGFR-2 and FGFR-1 kinases
Authors: Fargnoli Joseph , Lewin Anne , Henley Benjamin , Jeyaseelan Robert , Wautlet Barri , Hunt John T. 
Published: June 2012

Abstract
Angiogenesis plays a central supporting role in tumorigenesis in a wide variety of different cancer types. This complex and highly regulated process has been shown to be driven by various proangiogenic factors. The vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family of growth factors in conjunction with their associated tyrosine kinase receptors exert a major influence on tumor growth and dissemination, and potentially work synergistically to promote angiogenesis. Brivanib alaninate (BMS-582664) which is currently in phase III clinical trails is the orally active prodrug of brivanib (BMS-540215), a selective dual inhibitor of VEGF and FGF signaling. We demonstrate here that in vivo brivanib provides antitumor activity in a broad range of xenograft models over multiple dose levels, and that brivanib alaninate demonstrates dose-dependent efficacy equivalent to brivanib. Brivanib alaninate also reduces tumor cell proliferation as determined by a significant reduction in Ki-67 staining as well as a decrease in tumor vascular density as reflected by a reduction in CD34 staining, a cellsurface marker of endothelial cells. Additionally, using Matrigel™ plug assays in athymic mice we demonstrated that brivanib alaninate inhibits angiogenesis driven by VEGF or bFGF alone as well as when both of these cytokines are combined to drive angiogenesis in this model. Moreover, brivanib was more effective in inhibiting angiogenesis in this model system under all these conditions when compared to either bevacizumab, an antibody directed at the human VEGF cytokine or DC101, an antibody directed at the murine form of VEGF receptor-2. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, demonstrated a marked decrease in contrast agent uptake at an efficacious dose level, with a reduction in area under the plasma concentration-time curve from time 0 to 60 min (AUC60) at 24 h and 48 h of 54% and 64%, respectively. These results demonstrate that brivanib alaninate is an effective antitumor agent in preclinical tumor and angiogenesis models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B12.
Abstract B127: Single or combined in vivo therapies of cancer with h224G11, a humanized antibody targeting the c-Met receptor
Authors: Goetsch Liliane , Gonzalez Alexandra , Geronimi Fabien , Fabre-Lafay Stéphanie , Broussas Matthieu , Lepecquet Anne-Marie , Wurch Thierry , corvaia Nathalie , Bailly Christian 
Published: June 2012

Abstract
c-Met is the prototypic member of a sub-family of receptor tyrosine kinases (RTK) which also includes RON and SEA. The c-Met RTK family is structurally distinct from other RTK families and is the only known highaffinity receptor for the hepatocyte growth factor (HGF), also called scatter factor (SF). While the controlled regulation of c-Met and HGF is essential for in mammalian development, tissue maintenance and repair, their deregulation is implicated in the progression of cancers. Aberrant signalling of c-Met can arise by ligand-dependent and independent mechanisms such as over-expression of c-Met, paracrine or autocrine activations, or through gain-of-function mutations. However, an oligomerization of the c-Met receptor, either in the presence or absence of the ligand, is required to regulate the binding affinity and binding kinetics of the kinase toward ATP and tyrosine-containing peptide substrates. An inappropriate c-Met activation plays a crucial role in tumorigenesis and metastasis. We have generated, a humanized anti-c-Met IgG1 monoclonal antibody (h224G11) that display fully antagonist activities. The h224G11 Mab exhibits a high affinity for the receptor, blocks HGF binding, inhibits c-Met phosphorylation and c-Met dimerization. These effects are presumably responsible for the inhibition of the major functions of c-Met including cell proliferation, migration, invasion but also cell scattering and angiogenesis, observed in vitro with different cell lines. In addition to these in vitro properties, h224G11 dramatically inhibits in vivo growth of autocrine (U87-MG), partially autophosphorylated (NCI-H441) and c-Met amplified cell lines (MKN45, EBC1 and Hs746T). A dose effect experiment showed that a single i.v. injection of h224G11 resulted in a significant tumor inhibition with an in vivo EC50 about 9 mg/kg. Ex-vivo experiments on the Hs746T gastric tumor, demonstrated that h224G11 down-regulates c-Met, inhibits cell proliferation, induces a massive apoptosis of tumor cells and abrogates c-Met phosphorylation. In addition to this powerful effect as a mono-therapy, an almost complete inhibition of NCI-H441 (NSCLC) tumor growth was observed when mice were treated with the anti-c-Met antibody combined with the tubulin-binding vinca-alkaloid vinorelbine (Navelbine®). Likewise, our results showed that a combined h224G11/temozolomide bi-therapy significantly improved in vivo growth inhibition of U87-MG tumors compared to the corresponding mono therapies. Taken together the in vitro and in vivo data suggest that the h224G11 antibody targeting c-Met is a promising candidate for the treatment of ligand-dependent and ligand-independent tumors as a single or combined therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B127.
Abstract B141: Effects of AZD8055, a novel mTOR kinase inhibitor, in human cancer cells developing resistance to rapamycin
Authors: Serova Maria , Koumaravel Jacqueline , Bieche Ivan , Vidaud Michel , Guichard Sylvie , Raymond Eric , Faivre Sandrine 
Published: June 2012

Abstract
Background: Cancer cells are thought to adapt to rapamycin, an inhibitor of mTORC1, by activating AKT via mTORC2 and others mTORC1-independent survival pathways. In this study, we explored the effects of AZD8055, an ATP competitive inhibitor of mTOR, inhibiting both mTORC1 and mTORC2, in cancer cells with intrinsic and developing resistance to rapamycin.
Materials and Methods: Antiproliferative effects and cellular growth inhibition of AZD8055 and rapamycin were evaluated in a panel of 20 human cancer cell lines by MTT assay. Baseline and phosphorylated protein levels were assessed usingWestern blot. mRNA expression was studied by qRT-PCR.
Results: AZD8055 and rapamycin (48h exposures) displayed antiproliferative effects in our cell panel at IC50s ranging 0.005–&gt;3µM and 0.04–20µM, respectively. CAKI1 and SK-HEP1 cells expressed high mRNA levels of mesenchymal markers (vimentin, N-cadherin, ZEB1, SIP1, SLUG, ACTA2, and HMGA2) and low levels of E-cadherin associated with intrinsic resistance to several receptor tyrosine kinase inhibitors. AZD8055 induced antiproliferative effects in CAKI1 and SK-HEP1 cells at concentrations &lt;0.1µM. In CAKI1 and SK-HEP1 cells exposed to 0.1µM rapamycin for 5–24h, we observed the inhibition of p-S6 Ser235/236 but an activation of p-AKTser473. Consistent with its mechanism of action, exposure to 0.1µM AZD8055 led to the inhibition to p-S6, and p-4EBP1Ser65, without p-AKT ser473 activation. Downstream to mTORC2, PKC Ser657 was transiently activated by both rapamycin and AZD8055 in CAKI1 cells but not in SK-HEP1 cells. To study the acquired resistance to rapamycin, SK-HEP1 cells were grown with increased concentrations of rapamycin for &gt;6 months, making these cells tolerant to ≥4-fold IC50 concentrations. In SK-RAP cells, we observed the transcriptional activation of IGF1R, TGFB2, the anti-apoptotic factors BCL2 and CDKN1Ap21, and the multidrug resistance ABCB1mdr1. In SK-RAP cells, sustained exposure to rapamycin increased pAKTser473 and decreased p-S6 and p-PKC. Consistent with the inhibition of mTOR kinase activity, exposure to AZD8055 for 5h almost completely abrogated rapamycin-induced AKTser473 activation in SK-RAP cells. Furthermore, SK-RAP cells were more sensitive to AZD8055 than to the parental SK-HEP1 cells (IC50: 0.1 versus &gt;3µM, p=0.044), possibly due to the extended functions of AZD8055 against mTORC1 and inhibition of mTORC2.
Conclusions: AZD8055, by inhibiting mTOR kinase activity, decreases mTORC1 substrates pS6 and p-4EBP1Ser65 and mTORC2 substrate AKTser473. AZD8055 decreases cancer cell proliferation in cell lines expressing mesenchymal markers displaying intrinsic and developing resistance to rapamycin, abrogating the hyperactivation of AKT observed in these cells after rapamycin exposure.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B141.
Abstract B151: Epithelial-to-mesenchymal transition (EMT) in resistance to the antiproliferative effects of elisidepsin (Irvalec™), a novel marine-derived depsipeptide, in colon cancer cells
Authors: Serova Maria , Bieche Ivan , Emami Shahin , Gespach Christian , Berx Geert , Vivier Sabrina , Vidaud Michel , Aracil Miguel , Faivre Sandrine , Raymond Eric 
Published: June 2012

Abstract
Background: Elisidepsin (PM02734) belongs to Kahalalide F family and displays antiproliferative effects as single agent and in combinations with both cytotoxic and targeted therapies. This study aimed evaluating the role of EMT in resistance to elisidepsin.
Materials and Methods: Antiproliferative effects of elisidepsin were evaluated in a panel of colon (HT29, HCT116, COLO205, HCC2998), breast (MCF7, MDA-MB-435, SKBR3), ovarian (OVCAR3, IGROV1), lung (Hop62, Hop92), prostate (PC3, DU145), head&neck (SCC61, SQ20B, HEP2), and pancreatic (MiaPaCa2, CAPAN1) cancer cell lines after 72 hour exposure using MTT assay. Expression of several genes was evaluated using quantitative RT-PCR.
Results: Elisidepsin displayed antiproliferative effects against cancer cells with IC50s ranging 0.4’9 µM. As previously reported, cancer cells with high mRNA levels of Erb-B3 also displayed sensitivity to elisidepsin. Consistently, we found that cancer cells displaying an epithelial phenotype, characterized by high levels of mRNA expression of E-cadherin (CDH1), were more sensitive to elisidepsin than mesenchymal cancer cells showing high mRNA and protein levels of vimentin and N-cadherin (CDH2). To further evaluate the role of EMT in resistance to elisidepsin, we studied the antiproliferative effects of elisidepsin in the epithelial colon Colo205-S cells and its derived mesenchymal counterpart Colo205-R cells characterized by the overexpression of the transcription factors SIP1, ZEB1, SNAIL, SLUG, TWIST, and TGFβ. Interestingly, Colo205-S cells were at least 8-fold more sensitive to elisidepsin than Colo205-R cells, IC50s being 0.5 and 4.0µM, respectively. To confirm the role of EMT on resistance to elisidepsin, we used another colon cancer model with inducible SNAIL expression (DLD-1TR21-hSNAIL). In this model, SNAIL induction leads to a mesenchymal phenotype that coincides with loss of aggregation and induction of invasion (EMT). In this model, more than 100-fold SNAIL increase was associated with 12 and 6-fold decrease of E-cadherin and Erb-B3 expression, respectively. Consistent with our hypothesis, we found that the cytotoxicity of elisidepsin was at least 7-fold higher in parental epithelial cells than in SNAIL-induced cells in this model.
Conclusions: Sensitivity to elisidepsin correlates with high Erb-B3 and E-cadherin expressions in colon cancer cells. These data suggest that sensitivity to elisidepsin may be dependent of cancer cell differentiation, better results being observed in cancer cells retaining an epithelial phenotype.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B151.
Abstract B153: Small molecule modulators of tumor-stromal cell interactions, new natural compounds from fungi
Authors: Manabu Kawada , Arakawa Masayuki , Momose Isao , Someno Tetsuya , Ikeda Daishiro 
Published: June 2012

Abstract
Tumor microenvironment is now recognized as one of attractive strategies for cancer therapy. We have been studying molecular targets for tumor-stromal cell interactions and searching for small molecules that modulate the interactions. We have previously reported that angiogenin and IGF-I play critical roles in the development of prostate cancer. Because small molecules that interfere with these targets could suppress tumor growth through tumor-stromal cell interactions, we have designed assay systems and conducted random screening to find active small molecules. Here we report new natural compounds that can modulate the interactions. Terrein glucoside, a new terrein, was isolated from Aspergillus sp. PF1381 as a specific inhibitor of angiogenin secretion. Angiogenin is one of angiogenic factors that confer high tumorigenicity in human prostate cancer LNCaP cells. Terrein glucoside inhibited angiogenin secretion from a tumorigenic LNCaP subline without effect on VEGF secretion and also inhibited tube formation of HUVEC. On the other hand, NBRI23477 A and B, new atpenins, were isolated from Penicillium atramentosum PF1420 by another assay system. Human prostate stromal cells (PrSC) increased the growth of human prostate cancer DU-145 cells in the coculture of both cells through IGF-I secreted from PrSC. NBRI23477 A and B inhibited the growth of DU-145 cells in the coculture with PrSC more strongly than that of DU-145 cells cultured alone suggesting that these compounds indirectly suppress the tumor growth through modulation of tumor-stromal cell interactions. We are now continuing these screening programs to find more potent compounds.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B153.
Abstract B184: HSP90 inhibitor STA-9090 potently suppresses heterogeneous KIT kinase-domain mutations responsible for gastrointestinal stromal tumor progression during imatinib therapy
Authors: Fletcher Jonathan A. , Debiec-Rychter Maria , Swank Stephen , Morgan Jennifer , Liegl Bernadette , Rege Tanya A. , Heinrich Michael C. , Corless Christopher C. , Donsky Rachel , Fletcher Christopher D.M. , Raut Chandrajit P. , Ou Wenbin , Foley Kevin , Wang Yuexiang , Demetri George D. 
Published: June 2012

Abstract
Background: Most GISTs express mutant KIT or PDGFRA oncoproteins, which are targets of tyrosine kinase inhibitors (TKIs), such as front-line imatinib (IM) or second-line sunitinib (SU). GIST clinical resistance to IM or SU is commonly associated with the acquisition of heterogeneous secondary mutations in the KIT/PDGFRA ATP-binding pocket (ABP) or activation loop (AL), which maintain the constitutively activated state of these kinases. We therefore asked whether the heterogeneous IM-resistant KIT oncoproteins in GIST are uniformly HSP90 clients, and whether they can be inhibited by STA-9090, a synthetic small molecule HSP90 inhibitor that is structurally unrelated to the first-generation natural product-derived ansamycin HSP90 inhibitor 17-AAG.
Methods: KIT and PDGFRA were genotyped in up to 15 metastases from each of 10 patients whose metastatic GIST had progressed after IM therapy. Kinase mutants were biochemically profiled for IM and STA-9090 sensitivity in: 1. Ba/F3 cells transformed by mutant KIT constructs; 2. GIST cell lines (IM-sensitive and IM-resistant); and 3. a novel assay measuring inhibition of kinase phosphorylation after drug treatment in GIST48B (KIT-negative) GIST cells transfected with mutant KIT constructs. Drug effects on proliferation, apoptosis and cell cycle were evaluated in five GIST cell lines, including a KIT-dependent GIST subline (GIST882B) that is resistant to 17-AAG.
Results: As many as 8 different secondary KIT IM-resistance mutations (both ABP and AL) were detected in individual patients whose GISTs progressed after IM therapy. All mutations were sensitive to STA-9090. STA-9090 was 5-15 fold more potent than 17-AAG against these IM-resistant KIT secondary mutations, and was at least as effective against the primary + secondary (IM-resistant) mutations in combination, as compared to the primary IM-sensitive mutation alone (Table). STA-9090 also potently inhibited the 17-AAG resistant GIST882B cell line.
Conclusions: STA-9090 was more potent than 17-AAG against a panel of KIT mutations found in TKI-resistant GISTs. STA-9090 potency was undiminished against combination activating KIT mutations (including secondary kinase-domain resistance mutations), as typically occur in IM-resistant GIST clones. Based on these results, we hypothesize that STA-9090 might have broad clinical activity against IM-resistant GIST.
Table: IC50 (nM) for GIST viability: HSP90-inhibition vs. imatinib GIST Line STA-9090 17-AAG Imatinib GIST882: KIT Ex 13 40 200 300 GIST882B 35 &gt;1000 300 GIST430: KIT Ex 11 + V654A (ABP) 20 300 &gt;1000
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B184.
Abstract B188: Inhibition of Notch signaling for the treatment of cancer
Authors: Patel Bharvin K. R. , Bender Mark H. , Capen Andrew R. , Hanson Jeff C. , Credille Kelly M. , Heinz-Taheny Kathleen M. , Pomeroy Julie , Uhlik Mark T. , Perkins Everett J. , Reynolds Vincent L. , Audia James E. 
Published: June 2012

Abstract
The Notch pathway is a highly conserved signaling system that plays an important role in development and tissue homeostasis. While Notch mutations are well characterized and implicated in hematological malignancies such as T-cell acute lymphoblastic leukemia, in solid tumors ligand or receptor over-expression may lead to enhanced/sustained Notch function, triggering increased tumor cell proliferation/survival, angiogenesis and tumor formation. In order to delineate an oncogenic role of activated Notch in tumors of epithelial origin, we carried out a series of in-vitro and in-vivo studies. We demonstrated that the activated Notch1 receptor (a - secretase-dependent Notch1 E with the transmembrane domain and a-secretase-independent constitutively activated Notch1 intracellular fragment) can transform normal rat cells, RK3E. These transformed cells formed colonies in soft agar, confirming their anchorage-independent growth potential, and when implanted subcutaneously, formed tumors in athymic nude mice. Inhibition of Notch signaling through a small molecule inhibitor of -secretase, a key regulator of Notch processing, may provide an attractive targeted cancer therapeutic strategy. We have identified and characterized a novel small molecule that is an exquisitely potent inhibitor of Notch signaling in tumor cell lines and endothelial cells with an IC50 ranging from 0.005 nM to 20 nM. The Notch inhibitor meets all pharmacokinetic criteria in pre-clinical species. In a xenograft tumor model, the novel compound inhibited Notch cleavage in a dose-dependent manner at 6 hours after a single oral dose. This inhibition of Notch cleavage resulted in the induction of apoptosis (as measured by activated caspase-3 levels) that was statistically significant at 24 hours after a single oral dose of 3 mg/kg. Analysis of tumors from animals treated with the Notch inhibitor revealed inhibition of angiogenesis through formation of leaky vasculature which may also contribute to observed anti-tumor activity. Furthermore, Notch inhibition produced tumor regression in the Notch-dependent tumor models. Anti-tumor activity was also observed in several human xenograft tumors of epithelial origin. To mitigate mucoid gasteroentropathy due to Notch inhibition, PK/PD data were incorporated in devising dosing strategies that identified an optimal intermittent dosing schedule without negatively impacting efficacy. Furthermore, the mucoid gastroentropathy was also mitigated by the prophylactic administration of dexamethasone without negatively impacting Notch inhibitor mediated efficacy. In summary, we have characterized an orally bio-available small molecule Notch inhibitor that may provide therapeutic benefit to cancer patients.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B188.
Abstract B190: Efficacy of the specific ETA receptor antagonist zibotentan (ZD4054) in cancer cells and fibroblasts from colorectal cancer
Authors: Haque S. , Heetun M. , Farooqui N. , Loizidou M. , Dashwood M. , Shiwen X. , Abraham D. 
Published: June 2012

Abstract
Endothelin-1 (ET-1) contributes to growth and progression of solid cancers, mainly through endothelin receptor A (ETAR). Therefore endothelin receptor antagonism is emerging as a potential treatment for neoplasms. We evaluated the efficacy of the specific ETAR antagonist zibotentan (ZD4054) in blocking ET-driven cellular effects in colorectal cancer (CRC). CRC cell lines (HT29, SW620) and primary normal fibroblast strains isolated from human colorectal tissues (CF36, CF56, CF65, CF75) were incubated in ET-1 with/without BQ123, zibotentan (ETAR antagonists), BQ788 (ETBR antagonist). Resultant cell growth was measured by the colourimetric methylene blue assay; migration by a modified monolayer scratch assay; contraction in collagen gels; downstream effectors by western blotting. ET-1 driven growth (18%–45% above control) was significantly inhibited (p&lt;0.01) by ETAR (not ETBR) antagonism (BQ123=zibotentan CRC; fibroblasts). ET-1 driven fibroblast migration and contraction were blocked by ETAR and ETBR antagonism (zibotentan=BQ123). CRC cells did not migrate or contract. ET-1-stimulated expression of downstream effectors was driven by ETAR or ETBR, eg: (1) connective tissue growth factor (CTGF) was blocked by ETAR antagonism (zibotentan&gt;BQ123; CRC and fibroblasts); (2) collagen XI was blocked by ETAR&gt;ETBR antagonism (zibotentan&gt;BQ123; fibroblasts). The specific ETAR antagonist zibotentan is at least as efficacious as BQ123 in blocking ET-1 driven growth, migration and contraction both in CRC cells and colorectal fibroblasts, which form the supporting tumor stroma. Zibotentan is a strong candidate for adjuvant treatment in CRC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B190.
Abstract B207: Prostate specific membrane antigen is a diagnostic marker of response to allosteric androgen receptor inhibition
Authors: Evans Michael J. , Smith-Jones Peter , Wongvipat John , Larson Steven M. , Sawyers Charles L. 
Published: June 2012

Abstract
Molecular imaging in oncology aims to complement the growing repertoire of chemotherapies with noninvasive diagnostic tools to measure pharmacodynamics and improve predictions of disease response. In prostate cancer, several chemotherapeutic strategies have been developed to inhibit androgen receptor (AR) function, and currently show promise in treating advanced, castration resistant disease. Among these, competitive inhibitors of steroid agonist/receptor interactions have been effectively staged with fluorine-18-fluoro-5α-dihydrotestosterone, an AR agonist compatible with quantitative PET imaging. However, some allosteric inhibitors of AR do not impact agonist/receptor interaction (or AR stability) and currently cannot be evaluated with a quantitative imaging technology. We address this problem here by presenting evidence that prostate specific membrane antigen is a diagnostic marker of allosteric AR inhibition. In culture or in xenograft models of LNCaP, 22Rv1, LAPC4, and VCaP, PSMA is repressed by androgen treatment. Ablation of AR with siRNA inhibits the hormone-mediated suppression of PSMA, directly implicating AR in the mechanism. We further show that PSMA suppression is antagonized by several competitive and allosteric AR inhibitors. Finally, we conducted a pilot study with 22Rv1 xenografts to demonstrate that 64Cu-DOTA-J591, a monoclonal antibody designed for clinical PET imaging of PSMA, quantitatively detects hormone-mediated PSMA suppression. Collectively, these results promote the use of PSMA imaging reagents in the clinic to stage allosteric AR inhibitors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B207.