bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A217: Comparison of long-term pharmacodynamic actions of the synthetic small molecule HSP90 inhibitor AT13387 in multiple xenograft models
Authors: Lyons John , Curry Jayne , Smyth Tomoko , Harada Isobel , Fazal Lynsey , Reule Matthias , Graham Brent , Thompson Neil 
Published: June 2012

Abstract
AT13387 is a novel small molecule inhibitor of HSP90. a member of a family of molecular chaperones. Previously we highlighted an association between the high affinity binding of AT13387 to the N-terminal ATPase domain of HSP90 and the duration of target inhibition in tumor cell lines in vitro. Further, AT13387 was shown to inhibit HSP90 and deplete client proteins in tumor xenografts longer than other, lower affinity inhibitors in the class. Here we have expanded the investigation to a wider number of tumor cell lines and to in vivo xenograft models and demonstrate that AT13387 has an extended pharmacodynamic action in tumors compared to other HSP90 inhibitors. We reason that the cumulative effects of these properties allow for less frequent dosing thus maximising efficacy whilst minimising systemic exposure and the potential for side effects.
This study reports extended inhibition of HSP90 by AT13387 in a wider range of tumor cell lines in vitro. A 24hr exposure of A375 (melanoma) cells to AT13387 suppressed the expression of client proteins for 72 hrs or more. However in other cell lines such as NCI-H1975 (lung) and BT474 (breast), the suppression of client proteins by AT13387 was found to last in excess of 7 days.
The pharmacodynamic action of AT13387 in vivo has been compared with that of 17-AAG and SNX-5422 in A375 and NCI-H1975 xenografts in nude mice. Following a single dose of each agent, we have investigated and compared the time course of the suppression of levels of several client proteins (e.g. AKT, CDK4) and the phosphorylation of key growth/survival signalling components (e.g. pERK, pS6, pAKT). These effects were rapidly induced in tumors following treatment with AT13387 and levels remained suppressed for up to 96 hrs. The durability of the AT13387 effects was significantly greater than for the other competitor compounds. Investigation of tumor growth in these models demonstrated that the longer pharmacodynamic action of AT13387 ensured that efficacy could be maintained on a once weekly schedule, whereas such a schedule for the other agents resulted in a significant loss of their anti-tumor effects. These data provide further support for the potential benefit of long acting HSP90 inhibitors as a way of maintaining anti-tumor effects whilst minimising potential for undesirable effects associated with systemic exposure.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A217.
Abstract A221: Results of preclinical and clinical phase I/II open-label dose-ranging trial with HE3235, a synthetic adrenal hormone, in castrate-resistant prostate cancer
Authors: Montgomery Bruce , Morris Michael , Ryan Charles , Corey Eva , Stickney Dwight , Frincke James , Reading Chris , Scher Howard 
Published: June 2012

Abstract
Background: HE3235 (17α-ethynyl-5α-androstane-3α, 17β-diol) is an androstenediol analog, which shows activity in preclinical CRPC and breast cancer models. HE3235 decreased AR expression in LNCaP cells in vitro, in the CRPC LuCaP 35V xenograft, and suppressed ER-a expression in MNU-induced breast tumors in rats. HE3235 also decreased intra-tumoral androgen synthesis (both T and DHT) in the LuCaP 35V tumors. In toxicology studies, it decreased steroidogenesis (DHEA and T in male dogs and sex steroids in female rats). HE3235 did not inhibit CYP17 in H295R adrenal tumor cells, but inhibited the conversion of d-cholesterol to d-pregnenolone. We are therefore conducting a Phase I/II clinical study in CRPC patients to determine safety, tolerance, pharmacokinetics, maximum tolerated dose and activity of this compound.
Methods: Men with CRPC and an ECOG PS of &lt;2 who progressed either radiographically or biochemically through at least one taxane-containing chemotherapy regimen are eligible. HE3235 is given orally, twice daily in cohorts of 3–6 pts. Cohorts were defined by doses of 10 mg, 20 mg, 30 mg, 50 mg or higher until MTD is observed. Cohorts may be expanded based on dose limiting toxicity, activity or pharmacokinetics demonstrating adequate blood concentrations of drug to deliver a therapeutic effect. Subjects were treated on 28-day cycles until toxicity or disease progression. Scans were obtained every 2 cycles. The Prostate Cancer Consortium Clinical Trials consortium sites were supported by a grant form the Department of Defense.
Results: 22 subjects have been treated to date at doses of 10 mg/day (n=7), 20 mg/day (n=9) and 30 mg/day (n=6). Dose escalation continues to determine the MTD. Pharmacokinetics was dose proportional with a drug half-life of 11–14 hours. HE3235 was well tolerated. Nine of 22 subjects experienced a drop in PSA during treatment with 6 of 22 equal to or greater than 20%. No patient had a 50% decline in PSA. Eight of 17 (47%) subjects who were evaluable for response had stable disease. Median time to progression was 56 days (IQR 55, 224) for 10 mg/day, 112 days (IQR 56, 168) for 20 mg/days, 112 days (IQR 56, &gt;122) for 30 mg/day and 112 days (IQR 56, 168) for all 22 subjects.
Conclusion: HE3235 is a novel, small orally delivered compound with preclinical activity for CRPC. It is well tolerated through a dose of 30 mg, and has a T1/2 linear to dose in cohorts tested to date. The trial continues to accrue, and a cohort of patients with chemotherapy-naïve CRPC will be enrolled into the ongoing Phase I/II Study.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A221.
Abstract A229: Novel in vivo imaging of chemotherapy-induced gonadotoxicity
Authors: Bar-Joseph Hadas , Ben-Aharon Irit , Tzarfaty Galia , Tzabari Moran , Stemmer Salomon M. , Shalgi Ruth 
Published: June 2012

Abstract
Introduction: Advances in cancer therapy have improved the long-term survival of cancer patients who may then face infertility and premature gonadal failure due to chemotherapy. It has been demonstrated that the chemotherapeutic agent doxorubicin (DXR) induces apoptosis in germ cells, though its role in inflicting potential gonadal failure remains obscure. We had previously shown ovarian damage in mice following DXR treatment, manifested by reduced ovarian size and weight and by apoptosis. We aimed at establishing a real-time in vivo molecular imaging platform in mice designated to evaluate chemotherapy-induced toxicity and to assess potential vascular insult in both ovaries and testes.
Methods: The volume of both ovaries and testes was measured in vivo by ultrasound biomicroscopy (Vevo2100) and by high resolution MRI, over a period of one month after adminstration of 10mg/kg intraperitoneal DXR. Ovaries were imaged by ultrasound using microbubbles as a contrast agent for evaluating the effect of DXR on ovarian blood flow.
Results: We have established a platform of visualizing the gonads by innovative high resolution ultrasound biomicroscopy and MRI that enabled in vivo detection of chemotherapy-induced effects in the same individuals over time. We observed a constant, significant reduction in gonadal volume, evident by both MRI and ultrasound. The ovary volume was reduced to 52% (N=10, p&lt;0.05) of baseline values over one month. A similar trend was observed in the testes (reduced to 38% of baseline values over one month; N=6 p&lt;0.05)). The use of bubbles as contrast media depicted a 30% reduction in ovarian blood flow already 15 min after DXR administration.
Conclusions: Using high resolution, state of the art imaging modules enabled us to trace chemotherapy-induce gonadotoxicity by in vivo imaging of the same individuals throughout an extended period of time. The acute reduction of ovarian blood flow following chemotherapy treatment may suggest a role for vascular injury in inflicting ovarian damage.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A229.
Abstract A23: A collection of patient-derived pancreatic adenocarcinoma xenograft models: Chemosensitivity in vitro and in vivo and molecular characterization
Authors: Beckers Thomas , Maier Armin , Schüler Julia , Hofmann Michael , Giesemann Torsten , Hopt Ulrich , Keck Tobias , Fiebig Heinz-Herbert , Küsters Simon 
Published: June 2012

Abstract
Pancreatic cancer is a devasting disease with an incidence of 0.1% and - in most cases - only palliative treatment options. The standard 1st line chemotherapy in inoperable, locally advanced (stage II and III) and metastatic (stage V) pancreas adenocarcinoma is Gemcitabine as a single agent with a median survival of about 6 month. In addition, Gemcitabine is indicated as adjuvant chemotherapy after surgery. Although the antimetabolite 5-Flourouracil (5-FU) and the EGF-R inhibitor Tarceva (Erlotinib) have been approved for 2nd line treatment, new and more efficacious treatments are urgently needed. In the present study, more than 60 primary pancreatic carcinoma samples from patients were transplanted subcutaneously (s.c.) into NMRI nude mice. In most cases, tumor material from chemonaive patients with defined histology and staging was used for implantation. Up to now, 14 pancreatic carcinoma models named PAXF and passaged in nude mice have been established and characterized comprehensively. Tumor bearing animals were treated in-vivo with 5-FU (100 or 75mg/kg, q7dx3, i.p.), Gemcitabine (240mg/kg, q7dx3, i.v.) and Tarceva (25 and 50mg/kg, qdx21, p.o.). In most studies, tumor growth was inhibited with best T/C values &gt; 50%, highlighting the general chemoresistance of pancreatic cancer. Only for PAXF1872 and PAXF1998, a high sensitivity towards Gemcitabine was evident with best T/C values of 8% and 3.8%, respectively. In general, there was no correlation of response to Tarceva with EGFR expression status and best T/C values ranging from 89.6% (PAXF1876) to 38.5% (PAXF1982). A more broad chemosensitivity profile was established with Gemcitabine, 5-FU, Tarceva, Taxol, Cisplatin, Rapamycin, Sorafenib and Sunitinib in the ex-vivo clonogenic assay. Interestingly, 2 out of 12 pancreatic cancer models responded with high sensitivity towards treatment with Rapamycin (IC50 &lt;= 10nM) with a mean IC50 = 0.18 µM over all models. Finally, the established tumor models were characterized by using Affymetrix HG U133 plus2.0 gene expression arrays, exon sequencing (Ki-ras, B-raf, p53) and the Sequenom MassARRAY® System - OncoCarta(TM) panel. In all tumors analysed so far, an activating Ki-ras (H-ras, B-raf) mutation was identified. Mutational analysis of p53 (exons 4 to 10) revealed only 4 out of 13 models as p53 wild-type. For the PAXF1998 tumor model with animals cured by Gemcitabine therapy, mutations in Ki-ras (G12V, heterozygous) and p53 (V274A, homozygous) have been identified.
In summary, a unique collection of patient-derived xenograft models of high clinical relevance has been established. These pancreatic carcinoma models are available for translational research studies including in-vivo efficacy testing of new investigational drugs.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A23.
Abstract A232: Optical imaging of tumors using a near-infrared probe for cell death
Authors: Smith Bryan A. , Akers Walter J. , Leevy W. Matthew , Lampkins Andrew J. , Xiao Shuzhang , Wolter William , Suckow Mark A. , Achilefu Samuel , Smith Bradley D. 
Published: June 2012

Abstract
Imaging probes that can determine, non-invasively, the amount of cell death in a specific tumor may have utility in clinical prognosis, as there is evidence that some highly malignant tumors have high rates of cell death, and in measuring anti-cancer treatment efficacy.i,ii Annexin V, a protein that binds exposed phosphatidylserine (PS) during cell death, is commonly used to determine drug efficacy and cell viability in vitro, and has been investigated for use in vivo. It is often challenging to optimize the formulation and pharmaceutical properties of proteins; therefore, we have developed a fluorescent small molecule mimic of Annexin V. Our near-infrared probe contains a carbocyanine dye conjugated to a zinc (II)-2,2-dipicolylamine (Zn(II)-DPA) coordination complex, which binds to anionic phospholipids on apoptotic and necrotic cells. Using tumor-bearing mouse and rat models, the probe (PSS794) was easily visualized at the site of the tumor. Ex vivo analysis revealed heterogeneity of probe localization in the tumor, with most of the probe concentrated in the necrotic core. Small molecules that can selectively target tumor anionic membrane surfaces and distinguish them from the near-neutral membrane surfaces of normal human cells have promising potential as imaging probes,iii drug delivery agents,iv and targeted molecular therapeutics.v
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A232.
Abstract A252: KRAS mutant lung cancer cells are differentially responsive to MEK inhibition due to AKT or STAT3 activation: Implication for combinatorial approach
Authors: Yoon Young-Kwang , Kim Hwang-Phill , Han Sae-Won , Im Seock-Ah , Oh Do Youn , Bang Yung-Jue , Kim Tae-You 
Published: June 2012

Abstract
KRAS is frequently mutated in non-small cell lung cancer (NSCLC), resulting in the activation of the MEK/ERK pathway. High-throughput mutation profile has shown that lung cancer frequently harbors co-mutation of cancer related genes. Therefore, given that cancer cells have multiple genetic alterations, combinatorial therapeutic strategy is demanded for effective cancer therapy. To address this, we first characterized MEK dependence in four NSCLC cells. Two cells (H358, A549) carried KRAS mutation only, and the other two (H23, H157) harbored co-mutation of KRAS/PTEN. H358 cells with KRAS mutation only were sensitive to MEK inhibition. However, the other KRAS mutant A549 cells were resistant to MEK inhibition. Previously, we have shown that dual inhibition of EGFR and MEK signaling shows a synergistic effect on KRAS mutant gastric cancer cells by suppressing compensatory activation of AKT. Here we also observed that this combination was effective in KRAS mutant A549 cells. However, the combination was ineffective in H23 and 157 cells with co-mutation of KRAS/PTEN. Compared to KRAS mutant/PTEN wild-type cells, STAT3 was significantly activated following MEK inhibition in KRAS/PTEN co-mutant cells. Combined STAT3 inhibition by a JAK2 inhibitor or gene knockdown with MEK inhibition blocked STAT3 activation, synergistically suppressed cell growth, and induced apoptosis in co-mutant cells. Taken together, our study provides molecular insights that help explain the heterogeneous response to MEK inhibition in KRAS mutant lung cancers, and presents a rationale for the clinical investigation of combination of MEK and EGFR inhibitor or MEK and STAT3 inhibitor depending on PTEN status.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A252.
Abstract A39: Development and validation of an integrated genomic classifier to predict sensitivity to the IGF-1R/IR tyrosine kinase inhibitor, OSI-906, in colorectal cancer
Authors: Pitts Todd M. , Tan Aik Choon , Kulikowski Gillian N. , Tentler John J. , Flanigan Sara A. , Leong Stephen , Brown Amy , Coldren Chris D. , Varella-Garcia Marileila , Hirsch Fred R. , Eckhardt S. Gail 
Published: June 2012

Abstract
Background: The role of the IGF-1 receptor (IGF-1R) pathway in mediating proliferative, invasive and pro-survival responses in cancer has led to a plethora of agents targeting this pathway, including antibodies and small molecule tyrosine kinase inhibitors. In order to maximize the clinical utility of such agents, it is imperative that patient selection strategies be applied. The goal of this study was to develop and characterize predictive biomarkers for the small molecule IGF-1R/IR tyrosine kinase inhibitor, OSI-906, in colorectal cancer (CRC).
Methods and Results: Twenty-seven human CRC cell lines were exposed in vitro to OSI-906 and classified according to the IC50 value as sensitive (&lt; 1.5 mol/L) or resistant (&gt; 1.5 mol/L). Immunoblotting and immuno-histochemistry for effector proteins was performed on all CRC cell lines as well as fluorescent in-situ hybridization (FISH) to assess IGF-1R gene amplification and KRAS/BRAF/PI3K mutation sequencing. Baseline expression levels of effector proteins were not predictive of OSI-906 sensitivity. Although IGF-IR FISH did not reveal amplification, the OSI-906 sensitive CRC cell lines displayed an “unbalanced gain” of IGF-IR based upon ploidy. Likewise, there was a trend toward KRAS wildtype status and sensitivity to OSI-906. Next, the baseline gene expression of selected in vitro and in vivo sensitive or resistant cell lines was analyzed using Affymetrix U133 Plus 2.0 gene arrays. These transcriptional profiling data led to the development of a k-Top Scoring Pair (k-TSP) classifier which identified three gene pairs as the final classifier: (PROM1&gt;MT1E), (LY75&gt; OXCT1) and (HSD17B2&gt;CALD1). Pathway analysis at baseline indicated IGF-IR signaling and insulin pathways were among the top 20 up regulated BioCarta pathways whereas in the resistant cells, the ErbB, MAPK, VEGF, and multiple cell adhesion/motility signaling pathways were prominently represented. From these data an integrated genomic classifier of FISH, KRAS status, and the k-TSP was developed and tested against 5 human CRC explants in vivo. The classifier was able to predict with 100% accuracy the responsiveness of these explants to OSI-906.
Conclusions: These results indicate that an integrated approach to the development of individualized therapy is feasible and should be applied early in the development of this and other novel classes of anticancer agents. Additionally, such data may be used to develop rationale combination partners, such as VEGF or MEK inhibitors, to enhance responsiveness to OSI-906.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A39.
Abstract A41: The preanalytic impact of simulated ischemia on PI3K biomarkers
Authors: Ostrom Lance , Mosher Rebecca , Loda Massisimo 
Published: June 2012

Abstract
Introduction: Pharmacodynamic (PD) measurements in patient tissues following administration of cancer drugs may be used to determine a drug's activity and calculate dosing schedules. Biomarker selection for these tests must evaluate the most pertinent proteins in the pathway, but must also take into account biomarker stability in the tissue being tested. Constitutive expression of the PI3K pathway occurs with a high frequency in a variety of human malignancies. We sought to determine whether improper handling of tumor tissue can lead to inaccurate analysis of PI3K-AKT pathway activation when using immunohistochemistry (IHC).
Methods: 23 human cancer xenograft tumors were grown in nude mice (n=3/line) and allowed to stay at room temperature for fixed lengths of time to simulate handling of human specimens following surgery. Uniform sized tissue fragments (600–1000 mg) were kept in PBS for 0, 15, 30 and 120 minutes following resection prior to fixation in formalin and paraffin embedding. Four of these tumor lines were also frozen and analyzed by Western blot. IHC was preformed utilizing two pAKT antibodies and one pP70S6K (pS6) antibody. Following IHC, staining intensity was quantified using the Aperio image analysis system.
Results: Significant decrease in signal (p&lt;.05) was seen as soon as fifteen minutes of ischemia with both pS6 and pAKT antibodies by IHC in some samples. In nearly all of the samples that had detectable levels of pAKT or pS6 at time zero, this was gone by 120 minutes. There was also considerable discordance between pS6 and pAKT staining in the control samples bringing into question pS6 as a relevant pAKT surrogate biomarker.
Conclusion: Significant care should be taken in the interpretation of phospho-specific antibodies since results are strongly dependent on the time of ischemia. Broader analysis of pre-analytic biomarkers not dependent on tissue ischemia may be utilized as surrogate for pathway activation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A41.
Abstract A55: A first-in-human, phase I study of an oral hedgehog pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors
Authors: Siu Lillian L. , Papadopoulos Kyriakos P. , Alberts Steven R. , Taylor Sara , Patnaik Amita , Chen Eric X. , Tolcher Anthony , Vakkalaguada Blisse , Lang Lixin , Ahlers Christoph , Bennett Kelly L. , Van Tornout Jan M. 
Published: June 2012

Abstract
Background: The hedgehog pathway is dysregulated in basal cell carcinoma, medulloblastoma, pancreatic, lung, gastric, and a variety of other cancers. BMS-833923 is a potent, oral, small molecule antagonist of hedgehog signaling.
Methods: Subjects with advanced or metastatic solid tumors were enrolled into a multiple ascending dose study to identify a maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-833923. All subjects receive a single dose one week prior to continuous daily dosing. The single dose window allows for single dose PK collection for one week. To identify the pharmacologically active dose range surrogate tissue was collected prior to Day 1 and again on Day 22 of the first cycle.
Results: As of August 14, 2009 sixteen subjects have been treated at four dose levels: 30 mg (n=5), 60 mg (n=3), 120 mg (n=3), and 240 mg (n=5); with mean patient age of 56 (range 21–78) and ECOG performance 0–1. No subjects in the first three dose cohorts experienced drug-related CTCAE AEs greater than Grade 2. One subject with medulloblastoma in the 30 mg dose cohort continues on study for more than 10 months with stable disease. Treatment of patients in the fourth cohort at 240 mg continuous daily dosing is still on-going. In this cohort one subject experienced drug-related CTCAE Grade 2 lipase elevation and pancreatitis that quickly resolved when drug was withheld. This subject has a diagnosis of Gorlin Syndrome, which is caused by germline mutations in the hedgehog pathway genes Patched or Smoothened. This subject experienced a partial response (PR) that is still ongoing. BMS-833923 PK properties showed dose proportionality between the 30, 60, and 120 mg dose cohorts with a Cmax of 30 ng/ml, 56 ng/ml and 102 ng/ml respectively. The terminal half-life was greater than 7 days and drug accumulations were observed.
Conclusion: BMS-833923 is generally well tolerated at daily doses of 30, 60, 120 mg.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A55.