bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B272: The novel PIM kinase inhibitor SGI-1776 significantly enhances the preclinical activity of sunitinib in renal cell carcinoma
Authors: Mahalingam Devalingam , Medina Ernest , Swords Ronan T. , Kelly Kevin R. , Bearss David , Choy Gavin , Taverna Pietro , Carew Jennifer S. , Giles Francis J. , Nawrocki Steffan T. 
Published: June 2012

Abstract
The PIM kinases (PIM1, PIM2, and PIM3) are constitutively active serine/threonine kinases that promote tumorigenesis in mouse models and are associated with drug resistance. Upregulation of PIM kinase expression has been reported in many malignancies including renal cell carcinoma (RCC), suggesting that inhibition of PIM kinase activity may be an attractive therapeutic strategy. SGI-1776 is a novel orally available small molecule inhibitor of PIM kinase activity that is currently in Phase I clinical trials. We hypothesized that inhibition of PIM kinase activity would reduce the viability of RCC cells and enhance the activity of the multi-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib. Cell viability and apoptosis assays demonstrated that SGI-1776 possessed significant in vitro activity in a panel of RCC cell lines. One of the mechanisms by which the PIM kinases have been reported to inhibit apoptosis is by phosphorylating the BH3-only protein Bad to abrogate its pro-apoptotic function. Accordingly, SGI-1776-mediated apoptosis was associated with decreased levels of the phosphorylated form of Bad. Moreover, targeted knockdown of Bad expression significantly decreased sensitivity to SGI-1776 indicating that Bad is an important mediator of the anticancer activity of this agent. Treatment with SGI-1776 also led to a markedly decrease in phosphorylated and total c-Myc levels and enhanced the activity of sunitinib in RCC cells. The addition of sunitinib to SGI-1776 further reduced c-Myc expression. Silencing of the gene suggested that c-Myc plays a significant role in sensitivity to the SGI-1776/sunitinib combination. To further evaluate this drug combination, Caki-1 and 786-O RCC xenografts were established in nude mice and they were treated orally with SGI-1776, sunitinib, or the combination. The SGI-1776/sunitinib combination significantly reduced tumor burden in both xenograft models compared to single agent therapy and was very well tolerated. Analysis of the tumors revealed that the drug combination strongly decreased tumor proliferation and induced apoptosis as measured by PCNA and TUNEL immunohistochemistry, respectively. These data indicate that PIM kinase signaling has a significant role in the biology of RCC and warrants further investigation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B272.
Abstract B35: Validation of a multiplex method for detection of several oncosignaling proteins with potential utility for assessment of pharmacodynamic activity of hsp90 inhibitors
Authors: Hipolito Lori , Dakappagari Naveen , Stenzel Daniel , Pierce Laura , Timple Noelito , Ibanez Gerardo , Lundgren Karen , Harris Sarah , Tangri Shabnam 
Published: June 2012

Abstract
Biomarkers are increasingly being used in early phase clinical trials not only to determine pharmacodynamic activity but also as surrogate end points of clinical efficacy. BIIB021 is a synthetic small molecule that inhibits the activity of Hsp90, a molecular chaperone involved in the folding of multiple oncogenic signaling proteins. Treatment of tumor models and cancer patients with BIIB021 resulted in proteosomal degradation of key cancer survival proteins e.g., AKT, RAF, IGF-1R, ER and HER-2. BIIB021 is currently undergoing Phase I/II testing in GIST, Breast Cancer and Solid tumors. We are exploring robust methods for assessing multiple signaling markers with an objective of using them to confirm inhibition of Hsp90 activity and support dose/schedule finding studies. To that end, we have evaluated the utility of a sensitive multiplex assay on the Meso Scale Discovery (MSD) platform. This platform measures the levels of total and phosphorylated proteins of the MAPK and AKT signaling pathways. Peripheral blood mononuclear cells from healthy, breast and prostate cancer patients were treated ex vivo with BIIB021 and the levels of multiple signaling proteins were determined in the MSD assay. A significant decrease in the AKT family of signaling proteins was observed in all of the donors tested, while up to 75% of the subjects showed a marked reduction in the MAPK family of proteins over a period of 24hrs. The depletion of the similar oncosignaling proteins by BIIB021 was also confirmed in mouse models of human breast cancer and in vitro studies using the MSD platform1. Furthermore, to support the future development of BIIB021 in oncology, the multiplex assay will be validated for various clinical parameters (i.e., Quantitation range, reproducibility, accuracy, precision, linearity, longitudinal variability, and stability). We anticipate a rationally developed and rigorously validated multiplex assay measuring key signaling proteins involved in the survival of tumor cells would fully support the clinical development of BIIB021 and a wide range of anti-cancer agents affecting the AKT/MAPK pathways.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B35.
Abstract B42: ATM deficiency sensitizes gastric cancer cells to the PARP inhibitior olaparib
Authors: Guo Xiaoning , Shen Dihan , Cheng Wenxiang , Bai Yu , Ni Xing-Zhi , Shen Dan-ping , Zhang Shirong , Xie Liang , Knights Charlotte , Lau Alan , O'Connor Mark , Yin Xiaolu , Warford Anthony , Gu Yi 
Published: June 2012

Abstract
Ataxia telangiectasia mutated (ATM) is a protein kinase that regulates cell-cycle checkpoints, DNA repair and recombination (1). It has been shown that ATM interacts with and regulates NBS1 and BRCA complex which is essential for the homologous recombination (HR) repair in response to the DNA double-strand break (DSB) damage (2). These observations suggest that tumor cells with defective ATM expression or activity subsequently leading to HR deficiency are likely more sensitive to the targeted therapeutic/chemotherapeutic agents that cause the accumulation of DNA DSBs during replication. To test this, we studied the growth inhibitory effects of olaparib (AZD2281; KU-0059436) and SN-38 (the active metabolite of Irinotecan) on gastric cancer (GC) cells with reduced ATM expression. Olaparib is a potent oral inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), which has selective antitumor activity in cancers associated with BRCA1 and BRCA2 mutations (3). Our study here showed that 6 out of 7 GC cell lines with low or no expression of ATM are sensitive to olaparib inhibition with IC50s ≤ 1uM as measured by clonogenic survival assays. In contrast, the majority of other GC cell lines positive for ATM expression (11 out of 13) are less sensitive (1uM &lt; IC50 ≤ 1.5uM) or resistant (IC50 &gt; 1.5uM) to olaparib with only 2 of 13 lines sensitive. Similar correlation was also observed in these GC cell lines between reduced ATM expression and sensitivity to SN-38 treatment. In addition, combination of olaparib and SN-38 had a synergistic and selective inhibitory effect on cell growth of GC cells with low/no expression of ATM. These data suggest that loss of ATM in GC cell can sensitize their cellular response to olaparib or/and SN-38. Next, we asked whether this finding has clinical relevance in GC therapy. The tumor and tumor adjacent tissue specimens from more than 100 patients with gastric cancer were analyzed for ATM expression by immunohistochemistry. 22% (24/111) of the gastric tumor specimens were found stained ATM negative while the negative rate in the adjacent tissues was only 4% (1/26). These results suggested that loss of ATM expression is frequently associated with gastric tumorigenesis. Loss of ATM function may serve as an important tumor biomarker in GC and a PARP inhibitor as monotherapy or in combination with chemotherapy provides a promising therapeutic in this disease segment.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B42.
Abstract B53: Assessment of the effect of food on the oral bioavailability and assessment of diurnal variation in the pharmacokinetics of linifanib
Authors: Gupta Neeraj , Yan Zhiwu , LoRusso Patricia , Ricker Justin L. , Carlson Dawn M. , Pradhan Rajendra 
Published: June 2012

Abstract
Background: Linifanib (ABT-869) is a novel orally active and selective inhibitor of vascular endothelial growth factor and platelet derived growth factor families of receptor tyrosine kinases. Efficacy was observed at 0.25 mg/kg dose in 3 Phase II studies in patients with hepatocellular carcinoma, non-small cell lung cancer and renal cell carcinoma.
Methods: This is an ongoing Phase 1, single- and multiple-dose, openlabel, randomized, multicenter, crossover study. Patients (N=12) with advanced or metastatic solid tumors are randomly assigned to one of the two Groups (N=6 per group): Group I (oral administration of 0.25 mg/kg linifanib under fasting conditions on Day (D)1 followed by non-fasting conditions on D7 and alternating multiple doses in the AM or PM under fasting conditions), Group II (oral administration of 0.25 mg/kg linifanib under non-fasting conditions on D1 followed by fasting on D7 and alternating multiple doses in the PM or AM under fasting conditions). PK samples are collected at various time points after single dose on D1 and D7 for food effect and multiple doses on D21 and D31 for diurnal variation assessment. The samples were analyzed for plasma concentration using LCMS/MS. Maximum observed plasma concentration (Cmax), time to Cmax (Tmax) and total area under the concentration-time curve (AUC) or from 0 to 24h were determined by non-compartmental analysis using WinNonlin Professional V. 5.2.
Results: Based on preliminary data from 9 patients, there appears to be a negative effect of food on linifanib PK (a decrease of 43% in Cmax and 20% in AUC). AM dosing appears to result in higher exposures than PM dosing (an increase of 69% in Cmax and 58% in AUC) based on data from 5 patients. Terminal half-life of linifanib was estimated to be approximately 1 day.
Conclusion: Preliminary results show that linifanib exposures may be influenced by food and time of dosing.
Linifanib (single dose) for food effect assessment# Regimen Tmax (h) Dose-normalized Cmax (µg/mL/mg) Dose-normalized AUCinf (µg*hr/mL/mg) A: Fasting (N=9) 1.8±0.4 0.019±0.006 0.44±0.12 B: Non-fasting (N=9) 4.9±2.1 0.011±0.002 0.36±0.12 Ratio B/A (point estimate)* - 0.574 0.799 90% confidence interval for B/A - 0.505–0.653 0.725–0.880 Linifanib (multiple dose) for diurnal variation assessment Regimen Tmax (h) Dose-normalized Cmax (µg/mL/mg) Dose-normalized AUC24 (µg*hr/mL/mg) A: AM (N=5) 2.4±0.5 0.022±0.005 0.30±0.06 B: PM (N=6) 4.0±1.1 0.013±0.006 0.19±0.06 * Antilogarithm of the difference (B-A) of the least squares means for logarithms. # Mean±SD
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B53.
Abstract B7: TSU-68 suppresses the progression of malignant pleural mesothelioma cells in SCID mice by inhibiting angiogenesis
Authors: The Van Trung , Kuramoto Takuya , Goto Hisatsugu , Kakiuchi Soji , Taniguchi Tetsuo , Sekido Yoshitaka , Nishioka Yasuhiko , Sone Saburo 
Published: June 2012

Abstract
Background: Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm, for which the therapeutic options are limited. Pemetrexed combined with cisplatin, which has been approved, still has poor overall outcome. Molecular targeted therapies represent a promising strategy for overcoming limitation in therapy of malignant neoplasm including MPM. TSU-68 (SU6668), a tyrosine kinase inhibitor targeting VEGFR2, PDGFRβ and FGFR1 can inhibit the growth of various tumors. However, the efficacy of TSU-68 on MPM has not been investigated.
Purpose: Investigate the therapeutic efficacy of TSU-68 on the progression of human MPM cells in an orthotopical implantation model.
Method: Y-MESO-14 cells (expressing high level of VEGF and low level of bFGF) and MSTO-211H cells (expressing low level of VEGF and high level of bFGF) were orthotopically inoculated into thoracic cavities of SCID mice. From day 7 after inoculation, mice were treated with either TSU-68 (200mg/kg/day) or vehicle for two weeks. At the end of treatment, mice were sacrificed for analyzing the characteristics of thoracic tumors and pleural effusion.
Result: In both cells, TSU-68 inhibited the tumor size, pleural effusion volume and vessel density in the tumor compared to control group. Furthermore, TSU-68 inhibited the proliferation of endothelial cells stimulated by VEGF, bFGF, or supernatant of MPM cell culture media in vitro.
Conclusion: TSU-68 has anti-tumor activity for MPM progression. via inhibiting angiogenesis These findings suggest that TSU-68 may be clinically useful to improve the treatment outcome of MPM.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B7.
Abstract B71: Chemosensitization to bleomycin conferred by a constitutive activation of IKK pathway in viral FLIP expressing cells
Authors: Noguchi Kohji , Masuda Yuri , Katayama Kazuhiro , Mitsuhashi Junko , Sugimoto Yoshikazu 
Published: June 2012

Abstract
Chemosensitivity to anticancer drugs is influenced by various gene expressions in a variety of cancer cell types. Identification of gene affecting chemotherapeutic efficacy should contribute to design of optimized therapeutic strategy for cancer. IkappaB kinase (IKK) complex activates NF-kappaB pathway, and NF-kappaB activation causes complicated effects on cell proliferation, survival, apoptosis and chemosensitivity through induction of various gene expressions such as antiapoptotic genes. To address an effect of IKK complex activation on cancer cell chemosensitivity, viral FLIP (vFLIP/K13/ORF71) encoded by Kaposi sarcoma-associated virus/Human herpes virus-8 (KSHV/HHV-8) was stably expressed in HEK293 cells. Viral FLIP activates IKK complex by a direct binding with IKKgamma, and the sensitivity of these vFLIP-expressing cells was examined by MTT assay with various anticancer drugs. The results indicated that vFLIP expression induced selective sensitization to bleomycin and another bleomycin-related reagents peplomycin. Regarding bleomycin sensitivity, bleomycin hydrolase inactivates bleomycin and decreases sensitivity to it. Interestingly, we found that vFLIP expression disturbed subcellular localization of bleomycin hydrolase although bleomycin hydrolase expression level was not affected. These observations suggest for the first time that an activation of IKK-pathway is a novel modulator of bleomycin chemosensitivity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B71.
Abstract B8: A phase I pharmacokinetic (PK) study of TSU-68 plus S-1 and oxaliplatin (SOX) in patients with metastatic colorectal cancer (mCRC) treated with prior chemotherapy
Authors: Shin Sang Joon , Ahn Joong Bae , Jeung Hei-Cheul , Rha Sun Young , Roh Jae Kyung , Ahn Jung Ryun , Kim Chan , Chung Hyun Cheol 
Published: June 2012

Abstract
Background: TSU-68 is a novel oral multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. Since TSU-68 inhibit angiogenesis pathway which is important to tumor growth and metastasis in human colorectal cancer, we conducted a phase I study to evaluate the safety, tolerability and PK of TSU-68 plus S-1 and oxaliplatin (SOX) in patients with metastatic colorectal cancer (mCRC) treated with prior chemotherapy. Methods and Materials: ECOG PS 0 or 1 patients with mCRC were treated with TSU-68 400 mg/day (Level 1) or 800 mg/day (Level 2) on Days 1–21, S-1 70 mg/m2 on Days 1–14 with one week rest and oxaliplatin 130 mg/m2 IV on Day 1 repeated every 3 week. The dose escalation of TSU-68 was not done more than Level 2 based on the results of phase I studies of TSU-68 alone in Japan.
Results: Eleven patients were enrolled in the study. Of 11 patients, 2 patients were excluded from DLT assessment because both patients withdrew the written informed consent (IC) without a DLT during cycle 1. Of 9 evaluable patients, initial 3 patients in Level 1 experienced no DLT. Of 3 patients in Level 2, two patients experienced a DLT (one patient: grade 3 hiccup and grade 3 rash, another one: grade 2 neutropenia which prevented the initiation of the next cycle within 14 days). According to the protocol, additional 3 evaluable patients were enrolled in Level 1, and experienced no DLT. The MTD and RD of TSU-68 in combination with SOX was 400mg. Common adverse drug reactions (ADRs) in cycle 1 included peripheral sensory neuropathy (91%), nausea (82%), anorexia (82%), fatigue (46%), vomiting (36%) and diarrhoea (36%). No patient exhibited grade 4 ADR and treatment related death. Partial response was observed in 2 patients treated with prior chemotherapy. Median PFS was 218 days. TSU-68 plasma concentrations, Cmax and AUC0-t in Level 1 were higher than those in Level 2. There was no appreciable effect of administered TSU-68 on the PK of S-1 components (FT, CDHP and Oxo) and oxaliplatin-derived platinum.
Conclusions: Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 400mg. A multi-institutional phase II study of TSU-68 at 400mg/day in combination with SOX is planned.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B8.
Abstract B80: HSP90 inhibitor SNX-2112 and prodrug SNX-5422 (PF-04929113) inhibit key signal pathways Akt, Src and STAT3 and reactivate tumor suppressor p53 in head and neck cancer
Authors: Friedman Jay A. , Hu Michael , Arun Pattatheyil , Skillings Jamey , Chen Zhong , Van Waes Carter 
Published: June 2012

Abstract
Purpose: Heat shock 90 (Hsp90) is a molecular chaperone that interacts with and stabilizes many client substrates involved in modulating cell proliferation, survival, and apoptosis. Natural product Hsp90 inhibitors, such as benzoquinone ansamycins and their derivatives (i.e. geldanamycin, 17AAG), degrade oncogene and signal protein clients of Hsp90 and possess anti-tumor activity. Due to the limited solubility and hepatotoxicity caused by these agents, other Hsp90 inhibitors with a more favorable profile have been intensely sought after. In this study we investigated the biological activity of a synthetic small molecule inhibitor of Hsp90, SNX-2112, or the orally available prodrug SNX-5422 (PF-04929113), in human head and neck squamous cell carcinomas (HNSCC).
Experimental Design: The effects of SNX-2112 on cellular proliferation and Hsp90 client signal molecules, p53, and p53-targets were examined in human HNSCC cell lines from the University of Michigan Squamous Cell Carcinoma (UMSCC) series. The effect of SNX-5422 administered by oral gavage on tumor growth was examined in the UMSCC-11A murine xenograft model. Protein expression of Hsp90 client signal molecules were measured in tumor specimens harvested at three time points by immunohistochemistry (IHC) during SNX-5422 treatment, to identify the molecules mediating drug effects on proliferation, apoptosis and angiogenesis.
Results: SNX-2112 exhibited potent growth inhibition in the UMSCC cell lines, with an IC50 range of 25 - 75 nmol/L, and inhibited pro-survival signal kinase phospho-Akt at 24, 48, and 72 hours following exposure to SNX-2112 in UMSCC-11A. We also observed increased expression of pro-apoptotic transcription factor p53, and target gene PUMA, at 24, 48, and 72 hours following SNX-2112 exposure. Pro-drug SNX-5422 (PF-04929113) administered 20 mg/kg 5 days/wk or 50 mg/kg 3 days/wk for 3 wks significantly decreased tumor growth. By IHC, tumor specimens showed increased staining for p53 and apoptosis (TUNEL), and decreased staining for signal molecules Src, p-STAT3, and p-Akt together with markers of proliferation (Ki67) and vessel density (CD31). No apparent toxicity was observed in mice with SNX-5422 administered 20 mg/kg 5 days/wk for three weeks.
Conclusion: Synthetic Hsp90 inhibitor SNX-2112 is effective at degrading Hsp90 clients that play a significant role in proliferation, cell survival, and angiogenesis in HNSCC in vitro. In addition, SNX-5422 inhibits tumor growth by promoting apoptosis through modulation of several key signaling pathways. SNX-5422 warrants investigation as a clinical agent for treatment of head and neck cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B80.
Abstract B94: The roles of ERK1/2 and ERK5 in age-related breast cancer proliferation
Authors: Monlish Darlene A. , Cavanaugh Jane E. 
Published: June 2012

Abstract
The purpose of the current study is to examine the relative roles of the extracellular signal-regulated kinases 1, 2, and 5 (ERK1/2 and ERK5) and novel benzimidazole inhibitor compounds in cellular proliferation in breast tumors with aging. Breast cancer risk progressively increases with age, in part due to an accumulation of genetic mutations that occur during cellular division and/or exposure to environmental toxins. It has been estimated that over the next thirty years the number of Americans older than 65 years of age will double. With this increase in the aged population, the incidence of breast cancer will rise; therefore, it is important to examine the underlying mechanisms involved in breast tumor proliferation with aging. It has been well established that activation of the mitogen-activated protein kinase (MAPK) ERK1/2 leads to increased cellular proliferation and differentiation in cancer cells. Many of these studies rely on pharmacological inhibitors that were thought to be specific for the ERK1/2 pathways. Interestingly, recent studies demonstrate that these inhibitors also block the activation of a novel MAPK, ERK5. Indeed, an increase in ERK5 activity has been observed in mammary tumors in aged patients. However, the roles of ERK1/2 and ERK5 in breast cancer cell proliferation with aging have not been fully explored. In our studies, the transgenic MMTV-neu mouse model was utilized to examine ERK1/2 and ERK5 activity with age. MMTV-neu mice develop spontaneous mammary tumors which make them an appropriate model for the studies of human breast cancer. Tumors were extracted from young (3 mo), middle (9 mo), and old (15 mo) mice. Higher levels of ERK5 expression and activity were observed in middle- and old-aged animals as compared to their younger counterpart. Similarly, ERK1/2 expression and activation were increased with age. To further study the role of the ERK pathways on cell proliferation with aging, the BT-474 human breast cancer cell line and the MMTV-neu cell line (MMC) were utilized. Cell lysates were collected at passages 2, 12, 24 and 36 to mimic aging. At early passages ERK5 was constitutively active under basal conditions. At later passages, an age-dependent increase in ERK5 was observed. Breast cancer cell proliferation may be regulated by ERK5 exclusively or in conjunction with ERK1/2. We next investigated how novel benzimidazole compounds can act as specific inhibitors of ERK5 signaling in MMC and BT-474 cells. Overall, these studies will provide novel information about the cellular mechanisms involved in cancer cell proliferation and progression with aging. A better understanding of the ERK1/2 and ERK5 pathways in age-related mammary cell proliferation may lead to the development of preventative therapeutics or treatment possessing enhanced specificity for aging patients.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B94.