bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B130: Monoclonal antibody (mAb)-induced down-regulation of the RON receptor tyrosine kinase impairs malignant phenotypes of colon cancer cells
Authors: Li Zhuzhu , Guin Sunny , Padhyep Snehal , Yao Hangping , Wang Monghai 
Published: June 2012

Abstract
Targeting receptor tyrosine kinases (RTK) with specific mAbs disrupts oncogenic signals and diminishes tumorigenic activities. The RON receptor tyrosine kinase is a member of the MET proto-oncogene family and contributes to motile/invasive phenotypes of colon cancer cells. Here, we studied mAb-induced down-regulation of RON in modulating tumorigenic phenotypes of colon cancer cells. Three mAbs (Zt/g4, Zt/c9 and Zt/f2), recognizing different epitopes in the RON extracellular sequences, were used in various in vitro experiments. Colon cancer SW620 and other cells were used as the model. Treatment of SW620 cells individual mAbs results in transient RON phosphorylation within minutes. However, persistent treatment of cells with Zt/g4 or other mAb causes the down-regulation RON expression as evident by Western blot and cell surface fluorescent analyses. The effect of mAb was in both concentration and time-dependent manners. These activities were not related to antigenic epitopes recognized by individual mAb but highly specific to RON because MET or EGFR expression was not affected. Down regulation of RON impairs intracellular signaling events. Phosphorylation of Erk1/2 and AKT was dramatically reduced after Zt/g4 and other mAb treatment, indicating that the anti-RON mAb has the ability to disrupt downstream signal cascades. Functional studies showed that treatment of SW620 cells with anti-RON mAb affects tumor cell growth in soft agar. It also increases the sensitivity of colon cancer SW620 cells towards chemoagent gemcitabine. In this case, the cytotoxicity of SW620 cells treated with mAbs was significantly increased with reduced IC50 of gemcitabine. In conclusion, our results demonstrated that the persistent treatment of cancer cells with antibodies specific to the RON extracellular domains results in down-regulation of RON expression in colon cancer cells. The reduced RON expression is accompanied with the impaired signaling events and diminished tumorigenic activities. Thus, anti-RON mAb directed targeting could have therapeutic implication for controlling malignant phenotypes of cancer cells (*supported in part by NIH R01 grant Ca91980 and Amarillo Area Foundation of Texas)
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B130.
Abstract B131: Enhanced therapeutic effect of combined treatments with h7C10, a humanized antibody against insulin-like growth factor-1 receptor, and chemotherapeutic agents: In vitro results on MCF-7 cell line
Authors: Klinguer-Hamour Christine , Lokteff Maryline , Lepecquet Anne-Marie , Goetsch Liliane , Corvaia Nathalie 
Published: June 2012

Abstract
IGF-1 receptor (IGF-1R) plays a key role in the development of numerous tumors. Blockade of IGF-1R axis using monoclonal antibodies constitutes an interesting approach to inhibit tumor growth. We have previously described h7C10 (also named MK-0646), a humanized anti-IGF-1R Mab, that exhibits a potent anti-tumor activity both in vitro and in vivo. It blocks IGF-1 and IGF-2 induced signaling and blocks in vivo tumor growth of IGF-IR expressing tumors. In this report, we examined the in vitro effects of this selective IGF-1R Mab in combination with a panel of chemotherapeutic agents. The effect of drugs and h7C10 on the growth of human breast cancer cell line MCF-7 was determined by 3H-thymidine incorporation in DNA. The combined effect of drugs and h7C10 on MCF-7 cell line was evaluated by the combination index (CI) analysis method described by Chou and Talalay. We showed that the combination of h7C10 with a panel of drugs namely, paclitaxel, docetaxel, doxorubicin and gemcitabine induced synergistic inhibitory effects on MCF-7 breast cancer cell proliferation in vitro.
These findings demonstrated that h7C10 combined with established cancer therapeutics is highly effective against cancer cells that expressed IGF-1R and support clinical evaluation of h7C10 in combination with these drugs in the treatment of human cancers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B131.
Abstract B132: Enhanced therapeutic effect of combined treatments with h7C10, a humanized antibody against insulin-like growth factor-1 receptor, and chemotherapeutic agents in xenograft models
Authors: Beau-Larvor Charlotte , Akla Barbara , Lepecquet Anne-Marie , Corvaia Nathalie , Goetsch Liliane 
Published: June 2012

Abstract
IGF-1 receptor (IGF-1R) plays a key role in the development of numerous tumors. Blockade of IGF-1R axis using monoclonal antibodies constitutes an interesting approach to inhibit tumor growth. We have previously described h7C10, a humanized anti-IGF-1R Mab, that exhibits a potent anti-tumor activity both in vitro and in vivo. It blocks IGF-1 and IGF-2 induced signaling, inhibits cell proliferation and colony formation, induces cell cycle arrest and promotes IGF-1R degradation. In this report, a panel of combinations of h7C10 with chemotherapeutic drugs were tested in vivo in xenograft models based on preliminary studies performed in vitro using the method described by Chou and Talalay.
Our results confirmed a significant benefit of in vivo combinations of h7C10 with doxorubicin, docetaxel and paclitaxel. Data were less clear when h7C10 was combined to gemcitabine. An interesting combined effect was also noticed in mice treated by both h7C10 and 5-FU.
These findings demonstrate that h7C10 combined with established cancer therapeutics is highly effective in vivo against tumors expressing IGF-1R and support clinical evaluation of h7C10 in combination with these drugs for the treatment of human cancers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B132.
Abstract B14: The broad spectrum antitumor efficacy and tolerability of the RTK inhibitor, linifanib (ABT-869) alone and in combination with various cytotoxic therapies
Authors: Donawho Cherrie K. , Bukofzer Gail , Ellis Paul A. , Montgomery Debra A. , Rodriguez Luis E. , Wang Yi-Chun , Dai Yujia , Davidsen Steven K. , Frost David J. , Palma Joann P. 
Published: June 2012

Abstract
The RTKI, linifanib (ABT-869), is a potent inhibitor of vascular endothelial growth factor (VEGF) as well as platelet-derived growth factor (PDGF) receptors and is currently in Phase 1 – 2 clinical trials. It exhibits potent inhibition of mutant kinases, such as fms-like tyrosine kinase 3 (FLT3), c-kit (CD117) and colony stimulating factor-1 receptor (CSF1R). Hepatocellular carcinoma (HCC), renal cell carcinoma (RCC) and prostate carcinoma (PC) are known hypervascular/angiogenic tumor types. The role of the vascular process in HCC tumor progression, HIF-mediated induction of VEGF in many VHL-deleted RCCs, as well as PDGF expression in PC, highlight the potential of anti angiogenic therapy as an attractive therapeutic strategy. Previous studies have shown potent anti-tumor and anti-angiogenic activity against a spectrum of xenografts (HCC, RCC, PC, fibrosarcoma and NSCLC). Thus, the ability of linifanib to inhibit tumor growth in known hypervascular/angiogenic tumors suggests on-mechanism activity. Linifanib was well tolerated in the clinic and activity was observed in HCC, NSCLC, and renal carcinoma. The ability to be used as combination treatment regimen without excessive impact on tolerability is of great interest to increase clinical efficacy and positively impact patient outcomes. In this study, we sought to evaluate the activity of linifanib in a broad spectrum of xenograft models (breast, colon, HNSCC, liver, NSCLC, SCLC, ovarian and pancreatic), alone or in combination with various cytotoxic therapies (carbotaxol, irinotecan, radiation, 5-FU/leucovorin, gemcitabine and oxaliplatin). The doses used for ABT-869 were clinically relevant. For the cytotoxic therapies, doses were determined both by clinical schedules and tolerability as single agents in mice. In all studies, linifanib (25, 12.6, 6.25, p.o., b.i.d.x21) was well tolerated alone or in combination with cytotoxic therapy and demonstrated no exacerbation of cytotoxic agent toxicity as assessed by animal health observations. Significant anti-tumor efficacy (measured by percent tumor growth inhibition, % TGI) was observed with linifanib monotherapy and the combination with cytotoxic therapies showed significant efficacy over linifanib or cytotoxic therapies alone. Further, lower doses of linifanib in combination with cytotoxic agents achieved similar efficacy as higher doses of linifanib alone. These studies demonstrate the significant activity of linifanib or linifanib in combination with multiple cytotoxic therapies in a spectrum of models representing multiple histological types and provide a rationale for future clinical investigations.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B14.
Abstract B145: Highly selective pyrazolopyrimidine mTOR inhibitors with profound in vivo antitumor activity
Authors: Zask Arie , Kaplan Joshua , Curran Kevin , Verheijen Jeroen C. , Richard David J. , Brooijmans Natasja , Bennett Eric , Lucas Judy , Toral-Barza Lourdes , Hollander Irwin , Gibbons James J. , Abraham Robert T. , Ayral-Kaloustian Semiramis , Mansour Tarek S. , Yu Ker 
Published: June 2012

Abstract
The mammalian target of rapamycin (mTOR) is an important target for cancer chemotherapy due to the deregulation of its signaling pathway in a wide spectrum of human tumors. mTOR exists in at least two functional protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). While rapamycin and its analogs (rapalogs) inhibit only mTORC1, ATP-competitive inhibitors of mTOR target both mTORC1 and mTORC2 and therefore have the potential for improved anticancer efficacy. We have previously reported on the pyrazolopyrimidine series of ATP-competitive mTOR inhibitors (J. Med. Chem. 2009, 52, 5013 – 5016). We now report that derivatization of the morpholine ring in these inhibitors leads to greatly enhanced mTOR selectivity versus PI3K. Selective mTOR inhibitors have the potential to achieve a higher therapeutic index in the clinic due to better tolerability. Testing these inhibitors in tumor cells and evaluating the most potent analogs in human tumor xenograft models in the nude mouse led to the identification of WYE-125132, a candidate for clinical development. WYE-125132 is also selective versus a wide range of other kinases including the closely-related PIKKs. Detailed structure activity relationships in the pyrazolopyrimidine series will be presented. In conclusion, modification of the morpholine ring of a series of pyrazolopyrimidines leads to analogs with enhanced mTOR selectivity over PI3K and potent efficacy in human tumor xenograft models in the nude mouse.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B145.
Abstract B146: XL388: A novel, selective, orally bioavailable mTORC1 and mTORC2 inhibitor that demonstrates pharmacodynamic and antitumor activity in multiple human cancer xenograft models
Authors: Miller Nicole 
Published: June 2012

Abstract
Background: The mTOR kinase exists in at least two distinct kinase complexes, mTORC1 and mTORC2 which collectively regulate cell growth, proliferation, survival, autophagy, and angiogenesis. Derivatives of the macrolide antibiotic rapamycin have shown encouraging clinical activity as cancer therapeutics; however, these molecules only partially inhibit mTORC1 and mTORC2 activity. Here we provide the first pre-clinical description of XL388, a selective and orally bioavailable small-molecule ATP-competitive inhibitor of mTORC1 and mTORC2 that demonstrates pharmacodynamic and anti-tumor activity in multiple human cancer xenograft models.
Methods: The in vitro inhibition of mTORC1 and mTORC2 by XL388 was assayed using purified, recombinant mTOR/G L/raptor kinase and mTORC2 immunoprecipitated from cells, respectively. mTORC1 and mTORC2 substrate phosphorylation and pharmacodynamic activity were measured by phosphospecific immunoblot of lysates prepared from XL388-treated cancer cells or from xenograft tumor lysates prepared from XL388-treated animals. Cancer cell viability was determined by measuring cellular ATP concentrations or the disruption of cell membrane integrity. Synergy of XL388 with chemotherapeutics was measured by the combination index (CI) method as established by Chou and Talalay (1984). XL388 in vivo efficacy and pharmacodynamic studies were performed in nude mice bearing human tumor xenografts and dosed orally with XL388.
Results and Conclusions: XL388 inhibits mTORC1 and mTORC2 in vitro with IC50 values of 8 nM and 166 nM, respectively. In MCF-7 cells, XL388 blocks mTORC1 phosphorylation of p70S6K (T389) with an IC50 value of 94 nM and blocks mTORC2 phosphorylation of AKT (S473) with an IC50 value of 350 nM. In vitro, XL388 inhibits the viability of solid and hematopoietic tumor cell lines when assayed as a single agent. XL388 also synergizes with chemotherapeutics in cell-based assays to block cell viability. When dosed orally once daily in mice, XL388 shows robust anti-tumor activity in multiple xenograft models including &gt; 100% tumor growth inhibition in the MCF-7 xenograft model. Taken together, these data indicate that XL388 may have broad utility in cancer therapy both as a single agent and in combination with chemotherapeutics.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B146.
Abstract B149: Phase I, open-label, dose-escalating clinical and pharmacokinetic study of PM00104 administered weekly resting every fourth week, intravenously, over 1 hour to patients with advanced malignant solid tumors or lymphoma
Authors: Plummer Ruth , Coronado C. , Massard Christophe , Calvert AH , Margetts J. , Bahleda Rastilav , Prados R. , Kahatt C. , Soria Jean-Charles 
Published: June 2012

Abstract
Background: PM00104 (Zalypsis®) is a new synthetic alkaloid related to jorumycin. Preliminary data on mechanism of action suggested DNA-binding properties acting at minor groove and effects on the cell cycle (phase S). PM00104 shows a broad spectrum of activity against solid tumors both in vitro (bladder, gastric, kidney, melanoma, pancreas, prostate, sarcoma, thyroid, leukemia and lymphoma cell lines) and in vivo (xenografts of breast, gastric, prostate, and renal tumor).
Methods: Patients (n=49) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating clinical and pharmacokinetic study of PM00104 administered weekly resting every fourth week, intravenously, over 1 hour. The starting dose was 0.75 mg/m2 and the study followed an accelerated escalation design from 0.75 to 3.037 mg/m2 distributed in 9 dose levels
Results: Median age of patients (pts) was 58 (range, 22–76 y), 29 pts were males. The median ECOG was 1 (0–2). The most frequent cancer types were colorectal, gastric, esophageal and melanoma tumors (n=15/5/4/4). Most patients were heavily pretreated with a median of 3 (1–9) prior lines. A median of 2 cycles of Zalypsis (1–8) were given to each pt. Common mild (G1–2) toxicities were asthenia, anorexia, nausea/emesis, stomatitis, weight decreased, headache and hypotension. The highest dose achieved was 3.035 mg/m2, where 2 pts had DLTs: one had G4 asthenia and G3 nausea, and the other had G4 neutropenia and thrombopenia. At the next lowest level (2.5 mg/m2) 3 pts had DLTs (G3 asthenia and nausea in one pt; febrile neutropenia, G4 thrombopenia and G3 anemia in one pt, and G1 neutropenia and thrombopenia that resulted in two skipped doses in the third pt). Thus, this dose level was declared the MTD. The RD was 2 mg/m2, at which 24 pts were treated and only one pt had DLT (G4 asymptomatic lipase increase). Preliminary PK data showed a relatively prolonged half-life (up to 60 h, with a median value at the RD of 21 h), a wide distribution and high inter-patient variability. Efficacy data showed prolonged stabilization &gt; 3 months in 12 pts, mostly with gastrointestinal tumors (colon, pancreas, esophageal and gastroesophageal junction, n=1 each)
Conclusions: PM00104 shows acceptable safety and tolerability profile and prolonged stabilization (SD ≥3 months) in different tumor types. DLTs were manageable hematological and gastrointestinal toxicities. The RD for phase II studies is 2 mg/m2 weekly.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B149.
Abstract B165: Abl kinase myristate-site inhibitor, mechanism and application
Authors: Zhang Jianming , Gray Nathanael S. , Sim Taebo , Choi Yongmun , Deng Xianming , Adrián Francisco , Li Allen , Sun Frank , Liu Yi , Okram Barun , Warmuth Markus , Iacob Roxana , Engen John , Powers John , Azam Mohammad , Daley George , Jahnke Wolfgang , Cowan-Jacob Sandra , Manley Paul 
Published: June 2012

Abstract
We recently reported a new class of allosteric inhibitors, exemplified by GNF-2, that selectively inhibit the proliferation of Bcr-Abl dependent cells. Here we demonstrate, using selection for resistant Bcr-Abl clones, site-directed mutagenesis, affinity chromatography, and steady-state kinetics, that GNF-2 inhibits Bcr-Abl kinase activity by binding to the Abl myristate binding pocket and stabilizes the auto-inhibited conformation. We demonstrate that the 2-hydroxyethyl amide analog of GNF-2, GNF-5, in combination with ATP-competitive inhibitors such as nilotinib and dasatinib can overcome the T315I “gatekeeper” mutant of Bcr-Abl which is resistant to all clinically approved Bcr-Abl inhibitors. These studies demonstrate that targeting of the Abl myristate binding site can provide an important pharmacological means to overcome mutations that cause resistance to ATP-competitive inhibitors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B165.
Abstract B17: Fsn0503: A novel cathepsin S-specific antibody that blocks tumor invasion and angiogenesis
Authors: Ward Claire , Burden Roberta E. , Gormley Julie , Small Donna , Jacquin Thomas , Gazdoiu Mihaela , Bicknell Roy , Johnston James A. , Scott Christopher J. , Olwill Shane A. 
Published: June 2012

Abstract
Cathepsin S is a member of the papain family of cysteine proteases, which is normally localised in the lysosomes of antigen presenting cells. However cathepsin S has also been shown to be overexpressed and secreted in the tumor microenvironment of astrocytoma, breast, colorectal and prostate carcinomas. Upon secretion into the tumor microenvironment, it facilitates extracellular matrix remodelling, a process important for cancer cell invasion and angiogenesis. We have developed Fsn0503, a novel monoclonal antibody that targets and inhibits cathepsin S. We have demonstrated that Fsn0503 attenuates invasion of a range of invasive tumor cell lines, through inhibition of the hydrolysis of extracellular matrix components mediated by cathepsin S. Cathepsin S has also been implicated in promotion of endothelial cell movement during angiogenesis and in agreement with this we have shown that Fsn0503 significantly blocks HUVEC tube formation and rat aorta vessel outgrowth. Furthermore, these findings were replicated in vivo where administration of Fsn0503 impaired tumor growth and neovascularisaton in HCT116 xenografts. Our data indicates that Fsn0503 may yield significant clinical utility in the treatment of invasive and angiogenic tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B17.
Abstract B173: Synergistic interaction between CENP-E inhibitor GSK923295 and MEK inhibitor GSK1120212
Authors: Degenhardt Yan Y. , Zhang Xiping , Moy Christopher , Conway Theresa , Mcneil Liz , Jing Junping , Greshock Joel , Wegrzyn Ronald , Yin Holy , Mousses Spyro , Wooster Richard , Bachman Kurtis 
Published: June 2012

Abstract
Centromere protein-E (CENP-E) is a mitotic kinesin that is required during mitosis for metaphase chromosome alignment. GSK923295 (′295) is a potent and specific inhibitor of human CENP-E currently being developed as a next generation antimitotic drug for the treatment of cancer. It has shown a broad spectrum of anti-cancer activity in vitro and in vivo. A siRNA library screen targeting the ‘druggable genome’ identified multiple MAPK pathway genes as sensitizers to ′295, including BRAF and ERK1. Since the MEK protein plays an important role in the MAPK pathway, combination studies between GSK MEK inhibitor GSK1120212 (′212) and ′295 were performed in cancer cell lines from different tissue origins, and the combination effect was evaluated based on three different criteria: Excess over Single Highest Agent (EOHSA), Bliss, and Combination Index (CI).. Synergistic response was observed in 5/6 colon cancer cell lines, 5/15 lung cancer cell lines, and 6/8 pancreas cancer cell lines. Additionally, the combination of ′212 and ′295 treatment induced a much stronger apoptotic response than either drug alone in two colon cancer cell lines. These data suggest that combining MEK and CENP-E inhibitors might improve clinical efficacy over either as a single agent in selected tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B173.
Abstract B187: Role of aminopeptidase N in the activation of the alkylating prodrug J1
Authors: Wickström Malin , Viktorsson Kristina , Lundholm Lovisa , Aesoy Reidun , Nygren Helen , Sooman Linda , Fryknäs Mårten , Lewensohn Rolf , Larsson Rolf , Gullbo Joachim 
Published: June 2012

Abstract
Aminopeptidase N is a zinc-dependent metalloprotease which is involved in cancer invasion, metastasis and angiogenesis, and considered as a suitable target for anti-cancer drug design.
This in vitro study demonstrates a role of APN in the activation of J1, a prodrug of the alkylating agent melphalan, and subsequently, its cytotoxic activity. J1 (melphalanyl-L-p-fluorophenylalanyl ethyl ester) is currently in a phase I/II clinical trial. Previous studies have shown that J1-mediated cytotoxicity is dependent on hydrolytic activity of tumor cells. In this report we have analyzed potential peptidases and esterases of importance for release of free melphalan from J1. Exposure of tumor cell lines to J1 resulted in a significant increased level of free intracellular melphalan, at least ten-fold at Cmax, compared to exposure to melphalan at the same molar concentration. This efficient intracellular delivery could be inhibited in both magnitude and in time by bestatin, a broad spectrum inhibitor of the aminopeptidases, including the metalloproteinase aminopeptidase N (APN) and ebelactone A, an esterase inhibitor. These effects resulted, as expected, in decreased cytotoxic effects of J1. A specific role of APN in hydrolyzing J1 releasing free melphalan was demonstrated in vitro with pure APN enzyme. By using plasmid-based overexpression of APN or down regulation of endogenous APN with siRNA in different tumor cell lines we confirmed the involvement of APN in J1-mediated cytotoxic and apoptotic signaling. Given that APN is shown to be overexpressed in several solid tumors our data suggest that J1 may be activated in a tumor selective manner.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B187.