bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C200: Effects of indirubin derivatives on the FLT3 activity and growth of acute myeloid leukemia cell lines
Authors: Choi Sang-Un , Ahn Jin Hee , Kim Min-Jin , Yoo Miyoun , Kim Eunbin , Kim Young-Kyoon , Ryu Shi Yong , Han Sun-Young 
Published: June 2012

Abstract
Indirubin is an active constituent of traditional Chinese recipe used for the treatment of chronic myelocytic leukemia. In this study, inhibitory activity of indirubin and its derivatives toward Fms-like tyrosine kinase 3 (FLT3) was examined. Indirubin-3′-oxime(IO) and 6-bromoindirubin-3′-oxime(BIO) showed potent inhibitory activity against FLT3 with 50% inhibitory concentration (IC50) of 79 nM and 254 nM, respectively. Meanwhile, indirubin and 6-bromoindirubin exhibited negligible effect on FLT3 inhibitory activity up to 10 µM. We also tested the cytotoxicity of those compounds against acute myeloid leukemia cell lines; MV4;11 cells harboring constitutively activated form of FLT3 and RS4;11 cells with wild type FLT3. IO and BIO potently inhibited the growth of MV4;11 cells with IC50 of 30 nM and 61 nM, respectively. On the other hand, RS4;11 cells were far less sensitive to those compounds with IC50 values of 3600 nM and 820 nM, respectively. In the cell cycle assay, IO arrested the cell cycle of MV4;11 cells at G1 phase, and increased dead cell population at sub-G1 phase about 25 and 50% at 0.1 and 1.0 µM after 48 hours, respectively. These results strongly suggest that the derivatives of IO have potentials to be developed for novel anti-leukemic agents.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C200.
Abstract C204: Inhibition of c-Met signaling in combination with cisplatin and 5-fluorouracil significantly enhances antitumor effects in gastric cancer models
Authors: Efferson Clay , Lee Linda , Tammam Jennifer , Ware Chris , Deshmukh Sujal , Harrington Elizabeth , Pan Bo-Sheng , Reilly John F. , Majumder Pradip K. , Marshall Christopher Gary 
Published: June 2012

Abstract
Gastric cancer is currently the second most frequent cancer-related cause of death with an incidence rate of approximately one million cases annually. The present worldwide standard of care treatment regimen for gastric cancer is the combination of 5-fluorouracil (5-FU) and platinum analog (cisplatin). Many receptor tyrosine kinases are deregulated in gastric cancer including erbB2, c-Met, and EGFR. The purpose of our study was to dissect the role of c-Met signaling in gastric cancer and test the effects of our c-Met inhibitor (MK-8033) alone and in combination with the standard of care agents 5-FU and cisplatin. As a monotherapy, MK-8033 potently inhibited proliferation in a panel of gastric cancer cell lines in vitro. When administered simultaneously with cisplatin and 5-FU, the effects of the combination were diverse, ranging from additive to antagonistic. Altering the treatment schedule by the addition of 5-FU and cisplatin prior to MK-8033 resulted in an overall combination benefit across the panel. In a gastric cancer xenograft model, while MK-8033 alone significantly inhibited tumor growth progression, the co-administration of 5-FU and cisplatin with MK-8033 showed greater benefit than either the monotherapy or the standard regimen. In vitro cell cycle and survival analysis support the observed in vivo data, and provides a mechanistic rationale for the observed combination benefit. Our data suggest the combination of c-Met inhibitors with standard of care agents 5-FU and cisplatin may be beneficial in gastric cancer patients with activated c-Met signaling.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C204.
Abstract C210: LIM kinase small molecule inhibitors block tumor cell invasion
Authors: Crighton Diane , Charles Mark , Trivier Elizabeth , Hooper Steven , Scott Rebecca , Riddick Michelle , Brookfield Joanna , Ekwuru Tennyson , Stockley Martin , Foxton Caroline , Williams Juliet , Raynham Tony , Sahai Erik , Olson Michael , Hammonds Tim 
Published: June 2012

Abstract
The invasive potential of carcinomas greatly contributes to their ability to metastasize, a process which is estimated to cause 90% of all human cancer deaths. The LIM kinase (LIMK) family of Ser/Thr kinases sit at a hub of signaling pathways downstream of the Rho family of GTPases. Functionally, LIMK is directly involved in regulating the activity of cofilin, a family of proteins which modulate cell movement through reorganization of the actin cytoskeleton network. LIMK is up-regulated in a number of invasive cancer cell lines and metastatic breast and prostate tumors, whilst an increase in LIMK activity has been shown to cause increased cellular invasion in multiple model systems.
We demonstrate that LIMK inhibition by siRNA reduces the invasive capacity of MDA-MB-231-Luc breast cancer cells in an in vitro matrigel invasion assay and reduces fibroblast lead collective invasion in a co-culture organotypic model. Potent, selective, small molecule LIMK inhibitors have been identified that inhibit LIMK in vitro with sub-nanomolar activity in biochemical assays and low micromolar activity in cells as measured by cofilin phosphorylation. Treatment of MDA-MB-231-Luc cells or tumor associated fibroblasts with these small molecule inhibitors decreased cell invasion in vitro with minimal cellular toxicity. Collectively, these data further validate LIMK as an anti-invasive therapeutic target in tumor cells and demonstrate the potential utility of LIMK inhibitors in metastatic disease.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C210.
Abstract C241: Fine needle aspiration biopsy as a new method for monitoring of tumor microenvironment after treatment with polymeric drugs
Authors: Betka Jaroslav 
Published: June 2012

Abstract
Introduction: Cancer therapy seems to be, according to the latest findings, a combination of direct tumor cytotoxicity and the reaction of host immune system, which should become activated to successfully treat neoplastic disease. Monitoring time-dependent changes in composition of tumor infiltrating population of immunocompetent cells during the treatment could help to optimize therapeutic protocols and dosage.
Water soluble polymeric conjugates based on N-(2-hydroxypropyl)-methacrylamide (HPMA) bearing anticancer drug doxorubicin bound through amide (DOX-HPMA-AM)) or hydrazone bond (DOX-HPMA-HYD) minimize unwanted side effects of conventional chemotherapy and thus enables much more aggressive treatment with very promising results. To analyze changes in tumor microenvironment during the treatment with such polymeric conjugates, we have used fine needle aspiration biopsy (FNAB). This is a commonly used clinical method to acquire samples from the body with minimal influence to tissues. It seems to be an ideal tool for gaining cell material repeatedly from one experimental animal during the treatment with simultaneous possibility to evaluate tumor growth and efficacy of used therapeutic protocol.
Materials and Methods: C57BL/6 mice bearing EL4 T-lymphoma stably expressing Enhanced Green Fluorescent Protein (EL4-EGFP+) were treated with DOX-HPMA-AM, DOX-HPMA-HYD or free doxorubicin. FNAB was applied to isolate samples from EL4-EGFP+ tumors from mice treated with different drugs. All samples were stained with specific fluorescently labeled antibodies (CD3, CD4, CD8, CD45), analyzed by flow cytometry, and verified with the samples obtained from the tumor by excision. Also the tumor progression and survival of mice after FNAB were observed regular time distances.
Results: The data obtained by FNAB or standard excision are comparable. Moreover, cell populations gained by FNAB method are more properly separated and contaminated with less debris. FNAB influences neither the tumor progression nor survival of experimental animals.
Our data show that the number of tumor-infiltrating CD4 and CD8 lymphocytes increasing rapidly on third day after treatment with DOX-HPMA-AM and DOX-HPMA-HYD, while this treatment leads to complete recovery of neoplasma in all experimental animals. Contrary to this, free doxorubicin has no influence on composition of immunocompetent cells in tumor microenvironment and also no animal was able to recover from neoplastic disease. This fact suggests that both cytotoxic and immunomobilizing effect participate on tumor regression after treatment with HPMA conjugates.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C241.
Abstract C253: Effective inhibition of Hedgehog signaling pathway with small molecule Smoothened inhibitor GDC-0449 in a bone producing prostate cancer xenograft
Authors: Karlou Maria , Tzelepi Vassiliki , Maity Sankar , Navone Nora M. , Yang Jun , Lu Jing-Fang , Hoang Anh , Logothetis Christopher J. , Efstathiou Eleni 
Published: June 2012

Abstract
Background: The tumor microenvironment is involved in prostate cancer progression. Several stromal-epithelial-interacting pathways associated with prostate cancer (PCa) progression in the bone, are also considered candidates of resistance to current therapeutic strategies applied. Hedgehog (Hh) signaling has been associated with PCa aggressiveness. Therefore Hh pathway could be a novel diagnostic and therapeutic target, also contributing to therapy against prostate carcinoma metastasis in bone. Experimental work on specific chemical inhibitors of Hh signaling suggests that they may represent an entirely new class of therapeutic agents. In this study we tested the efficacy of Hh pathway inhibition with Smoothened inhibitor GDC-0449 in 118b prostate cancer xenograft model.
Experimental Design: We employed the xenograft MDA PCa 118b, derived from the bone metastasis of a patient with castrate-resistant prostatic adenocarcinoma. This is characterized by unique bone producing feature when injected subcutaneously in SCID mice. Bone is the most common site for metastasis of prostate carcinoma, therefore a model with the new bone formation distinctive characteristic is really informative. Following MDA PCa 118b sc injection, animals were treated with Smoothened inhibitor GDC-0449 (oral administration, for 21 days). Hh pathway components expression was measured both in the tumor cells and stromal compartment using species specific primers for real-time PCR, western blot analysis and immunohistochemistry.
Results: Paracrine Hedgehog signaling was confirmed in the tumor xenograft microenvironment. Baseline Shh expression was present in human tumor cells and significantly higher compared to stromal compartment, while nuclear Gli1 (a hallmark of pathway activation) and Ptch1 expression in the stromal compartment were present and significantly higher compared to human tumor cells. Smoothened inhibition resulted in attenuation of stromal expression of Gli1 and Ptch1, in the treated group compared to the control thus confirming the pharmacodynamic effect of the agent. A trend for slower tumor growth at the treated group was observed, while a decline in proliferation rate was noted when Hh pathway was suppressed in the stromal compartment.
Conclusion: Hh signaling pathway demonstrates paracrine activation in the 118b prostate cancer bone producing xenograft model. GDC-0449 is effective in blocking Hh signaling in PCa. Future directions: A combination of Hedgehog signaling inhibition and cytotoxic therapies, such as androgen ablation would likely increase efficacy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C253.
Abstract C39: Phase I clinical trial of CX-4945: A first-in-class orally administered small molecule inhibitor of protein kinase CK2
Authors: Marschke Robert F. , Andreopoulou Eleni , Von Hoff Daniel D. , Lim John K.C. , Padgett Claire S. , Northfelt Donald W. 
Published: June 2012

Abstract
Introduction: CX-4945 is a novel, orally administered small molecule designed to potently and selectively inhibit protein kinase CK2, a previously unexploited molecular target with well documented roles in many cancers. In vitro, CX-4945 selectively kills cancer cells by modulating key survival pathways, resulting in inhibition of proliferation, promotion of apoptosis and cell cycle arrest. Pre-clinically, CX-4945 has demonstrated single-agent potency in suppressing xenograft tumor growth with a wide therapeutic window. The objectives of this phase I study are to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), to characterize the pharmacokinetics (PKs), and to study the pharmacodynamic effects of CX-4945.
Procedures: Eligible patients with advanced solid tumors, Castleman's disease or multiple myeloma with progressive disease, or for whom there are no available standard therapies, receive CX-4945 in successive dose cohorts at: 90, 160, 300, 460, 700 and 1000 mg per dose. Oral doses are administered twice daily for twenty-one consecutive days of a four week cycle. Therapy is continued in consenting patients until signs of intolerance to CX-4945 are observed, or there is evidence of advancing disease. Response by RECIST is determined after every 2 cycles. Serial blood and plasma samples are collected on the first and final dosing days of Cycle 1 (i.e., Day 1 and Day 21) for pharmacokinetic analysis and for pharmacodynamic biomarker evaluations (specifically, total and phosphorylated forms of p21 and Akt.)
Results: Thirteen patients with solid tumors (3–4 patients per cohort, from four separate dose cohorts) have received oral doses of CX-4945. These doses have been well tolerated, with no reported adverse events of grade 3 or higher. CX-4945 has demonstrated general linearity in PK parameters between the dose cohorts, with a terminal half life of approximately 25 hours at steady state.
Conclusions: To date, CX-4945 has shown no drug related toxicity and has dose proportional PKs. No DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Further enrollment to the planned dose escalation cohorts is ongoing.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C39.
Abstract C45: Preventive effect of Iressa in the hydroxybutyl(butyl) nitrosamine (OH-BBN) induced model of bladder cancer: Dose dependency, treatment timing, and alterations in biomarkers
Authors: Lubet Ronald , Bode Ann , Townsend Reid , Grubbs Clinton 
Published: June 2012

Abstract
The preventive efficacy of the EGFr inhibitor Iressa was examined on the induction by OH-BBN of urinary bladder cancers in female Fischer-344 rats. The OH-BBN induced model yields invasive bladder tumors with most having the histopathological appearance of transitional cell carcinomas (TCC). The resulting tumors show various protein changes; e.g., increased expression of survivin, GSTPi, and various S100 calcium binding proteins that are routinely observed in human bladder cancers. More recent array data have also implied many similarities. Recently we examined the effects of daily treatment of rats with Iressa (6 mg/kg BW/day, i.g.) beginning either 2 weeks after the last dose of OH-BBN (24 weeks of treatment) or at 12 weeks after the last dose of OH-BBN when microscopic TCCs already existed (14- weeks of treatment). Both regimens decreased the incidence of large palpable bladder cancers by 90%. This demonstrated that Iressa was highly effective even when administered late in tumor progression. In contrast, treatment with Iressa beginning 2 weeks after the last OH-BBN and followed for only 14 weeks caused a 60% decrease in the incidence of microscopic bladder cancers. Additional data examining various dose levels and the combination of suboptimal doses of Iressa with NSAIDs will be presented. In addition, we examined biomarker modulation in OH-BBN bladder cancers treated short term (5 days) with Iressa. When using a candidate marker approach, it was found that Iressa decreased levels of EGFrP as expected, but caused striking decreases in levels of phosphorylated AKT as well. A more generalized approach to modulation of biomarkers was also taken to examine altered expression of peptides in Iressa treated and control bladder tumors employing 2D gel analysis. When certain of the identified peptides were examined by pathway analysis, it was found that certain proteins associated with the VEGF pathway [ANP32A and HNPRL] were both decreased in Iressa treated tumors. Supported by NCI Contract HHSN261200433001C.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C45.
Abstract C66: Development of mechanistic assays to differentiate PI3K and mTOR inhibitors
Authors: Trinh Lan , Yen Ivana , Lesnick John , Malek Shiva 
Published: June 2012

Abstract
The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a key role in the regulation of cellular growth, survival, and proliferation. Inappropriate activation of the pathway as a result of mutations and amplifications has been implicated in a variety of human cancers. Pathway dysregulation drives tumorigenesis through phosphorylation of proteins that directly regulate protein synthesis, cell cycle, and metabolism. The complexity of the mTOR and PI3K pathways, which include two functionally distinct mTOR complexes, feedback loops, and parallel regulatory pathways, clearly invokes a need for functional assays that can clarify the mechanism of action for drugs targeting mTOR and PI3K either as single agents or in combination. In this work, we used three different types of cell based assays to investigate the effects of PI3K versus mTORc1 inhibition on signaling pathways, cell cycle, and autophagy. The first set of assays differentiates an inhibitor of the mTorc1 complex versus the mTorc2 complex by utilizing two different cell lines and stimulation with either nutrient or growth factors. We show that the mTorc1 inhibitor, rapamycin, has potent activity in the nutrient stimulated mTorc1 assay, while PI3K inhibitors have very weak activity in such an assay. In the second type of assay, we used high content image analysis to produce cell cycle distribution profiles in PC3 cells, clearly showing G1 arrest for both mTOR and PI3K compounds as both single agents and in combination. However, the profiles showed no apoptotic population for either class of compounds in the cell lines tested. Therefore, as a means to investigate an alternative route of cell death to apoptosis, we also developed an autophagy assay using high content image analysis. Our results show that treatment of cells with a PI3K inhibitor or rapamycin as single agents or in combination can have different effects on autophagy and may potentially help differentiate the mechanism of action between the two classes of inhibitors. Taken together, we have generated a panel of mechanistic cellular assays which can help differentiate and characterize the effects of mTor and PI3K inhibition as both single agents and in combination.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C66.
Abstract C85: Novel molecular targets for genistein in prostate cancer cells
Authors: Merchant Kendra T. , Rathinavelu Appu , Kumi-Diaka James , Esiobu Nwadiuto , Zoeller Robert , Hartmann James , Johnson Michelle 
Published: June 2012

Abstract
Background: Prostate cancer is the most common form of non-skin cancer and the second leading cause of cancer deaths within the United States. The five year survival rate has increased from 69% to 99% over the last 25 years for the local and regional disease, but has remained fairly low (approximately 34%) for the advanced disease. Current research is aimed at finding complementary or alternative treatments that will specifically target components of signal transduction, cell-cycle and apoptosis pathways to induce cell death, with little or no toxic-side effects to the patient. In this study we investigated the effect of genistein on expression levels of genes involved in these pathways. Genistein (4, 5, 7-trihydroxy-isoflavone) is a major isoflavone micronutrient constituent of soy that has been shown to inhibit growth proliferation and induce apoptosis in cancer cells.
Methods: The mechanism of genistein-induced cell death and potential molecular targets for genistein in LNCaP prostate cancer cells were investigated using several techniques. The chemosensitivity of genistein towards prostate cancer cells was investigated using the ATP and MTS assays and apoptosis induction was determined using apoptosis indicator assays and caspase assays. Expression levels of several molecular targets were also determined using cDNA microarray and RT-PCR analysis.
Results: Our results revealed that genistein induces cell death in a time and dose-dependent manner and regulates expression levels of several genes involved in carcinogenesis and immunogenicity. Several cell cycle genes were down-regulated including the mitotic kinesins, cyclins and cyclin dependent kinases, indicating that genistein is able to halt cell cycle progression through the regulation of genes involved in this process. Several members of the Bcl-2 family which are involved in apoptosis were also affected and a number of genes involved in immunogenicity were upregulated including DefB1 and HLA membrane receptors.
Conclusion: The results of this study provide evidence of genistein's ability to inhibit cancer cell proliferation and induce apoptosis which indicates its potential as an adjuvant in chemotherapy and immunotherapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C85.
Abstract C94: Deubiquitylases as novel anticancer targets: Discovery and development of novel USP7 inhibitors
Authors: Kumar KG Suresh , Cao Ping , Goldenberg Seth J. , Leach Craig A. , McDermott Jeffrey L. , Kodrasov Matthew P. , Chauhan Dharminder , Tian Ze , Anderson Kenneth C. , Mattern Michael R. , Nicholson Benjamin 
Published: June 2012

Abstract
The ubiquitin-proteasome pathway is a complex system consisting of enzymes that conjugate or deconjugate ubiquitin to/from target proteins upstream of the 26S proteasome. In particular, ubiquitin deconjugation is performed by families of proteases known as deubiquitylating enzymes (DUBs). The therapeutic validation of the ubiquitin-proteasome system was provided by the marketing approval of bortezomib (PS-341) for the treatment of multiple myeloma (MM). In our search for alternative approaches for the treatment of MM, we investigated the therapeutic potential of inhibiting another component of the ubiquitin-proteasome pathway, the DUB USP7. Our rationale for targeting USP7 is as follows: 1) Blockade of USP7 using siRNA or homologous recombination results in elevated levels of the tumor suppressor p53 and cell cycle arrest in cancer cells. In contrast to the situation in the majority of human tumors, mutations or deletions of p53 in MM are relatively rare and thus the activation of p53 is likely to offer a therapeutic benefit in MM. 2) Knockdown of USP7 destabilizes the adaptor protein Claspin, inhibiting activation of Chk1, an effector kinase in the DNA damage response, abrogating the G2M cell cycle checkpoint and providing a mechanism for inducing tumor cell death in a p53 independent manner. Thus inhibition of USP7 would be predicted to activate pro-apoptotic and inactivate pro-survival pathways in multiple myeloma, resulting in tumor suppression.
Recently, using its proprietary screening technology, Progenra discovered and characterized a small molecule inhibitor of USP7, P5091. Specifically, P5091 selectively inhibits USP7 relative to other proteases and exhibits cytotoxic activity against both p53 wild type and p53 mutant tumor cell lines. Furthermore, P5091 destabilizes the pharmacodynamic markers HDM2 and Claspin in tumor cells and induces cell death synergistically in combination with genotoxic agents. Medicinal chemistry has identified a series of potent and selective novel chemical entities. Initial preclinical studies at the Dana-Farber Cancer Institute demonstrate that P5091 induces apoptosis and is cytotoxic against human MM cells but not normal plasma cells.
In conclusion, these data demonstrate that 1) USP7 is a viable target for the treatment of MM and other cancers; and 2) P5091 is an efficacious inhibitor of USP7. Preclinical development of the P5091 series continues, augmented by a comprehensive medicinal chemistry program designed to identify a clinical candidate from this series in 2010.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C94.