bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B185: Bench to bedside experience with TH-302: A tumor-selective hypoxia-activated prodrug as a promising treatment for prostate cancer
Authors: Hart Charles P. , Armstrong Andrew J. , Chiorean Elena G. , Sun Jessica D. , Langmuir Virginia K. , Meng Fanying , Eng Clarence , Kroll Stewart , Matteucci Mark D. , Curd John G. 
Published: June 2012

Abstract
Hypoxia is a defining feature of solid tumors, including prostate cancer. Metastases also exhibit subregional hypoxia and micrometastases may be severely hypoxic. Hypoxic cells are known to be resistant to standard chemotherapies and thus play a role in treatment failure and disease relapse. TH-302, a tumor-selective hypoxia-activated prodrug of the cytotoxic warhead bromo-isophosphoramide mustard (Br-IPM), is currently in clinical development for the treatment of advanced solid tumors. We explored the preclinical efficacy of TH-302 in both in vitro and in vivo models of prostate cancer. Based on these translational results, we identified prostate cancer as an indication for further clinical investigations.
Preclinically, TH-302 demonstrated hypoxia-selective cytotoxicity in the human prostate cancer cell lines PC-3, LNCaP, and DU-145. We explored in vivo prostate cancer efficacy in PC-3 xenograft models that included (1) an ectopic subcutaneous model, (2) an orthotopic model, and (3) a model of bone and soft tissue prostate cancer metastases. TH-302 demonstrated efficacy both as monotherapy and in combinations with taxanes in all three settings. The combination of TH-302 and docetaxel in the disseminated prostate cancer metastases model demonstrated 100% complete responses in the 8 of 10 animals surviving to the end of the study at approximately 8 weeks.
The TH-302 Phase 1 dose escalation clinical trial established the monotherapy maximum tolerated dose (MTD) of TH-302 dosed weekly for 3 weeks of a 4 week cycle at 575 mg/m2. Mucosal and skin toxicity were dose limiting, while hematologic toxicity was minimal. Evidence of anti-tumor activity was observed including four RECIST responses in patients with small cell lung cancer and metastatic melanoma. In the ongoing Phase 1/2 combination therapy clinical trials of TH-302, the MTD of TH-302 was established at 340 mg/m2 when dosed at days 1 and 8 with docetaxel 75 mg/m2 on day 1 every 3 weeks. Neutropenia was dose-limiting. In the first two patients with metastatic castration-resistant prostate cancer (CRPC) treated with the combination of TH-302 and docetaxel, PSA responses (a &gt; 50% reduction from baseline) have been observed along with a marked reduction in cancer-related pain in one of the patients. An additional 12 CRPC patients will be enrolled.
These translational studies and early clinical findings indicate that the addition of TH-302 to docetaxel may be a promising new treatment option for prostate cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B185.
Abstract B189: The Nedd8-activating enzyme inhibitor MLN4924 combined with rituximab induces additive/synergistic anti-tumor activity in preclinical non-Hodgkin's lymphoma models
Authors: Tou Derek Liqiang , Traore Tary , Pickard Michael , Pulukuri Sai , Manfredi Mark , Petruzzelli Lilli , Berger Allison , Smith Peter G. 
Published: June 2012

Abstract
MLN4924 is a novel, small molecule inhibitor of Nedd8-activating enzyme (NAE) that is currently in Phase I clinical trials in hematologic malignancies. We have previously described the pre-clinical anti-tumor activity of MLN4924 in human xenograft models of hematological and solid tumors. Rituximab is an anti-CD20 monoclonal antibody that has been established as part of the standard of care for the treatment of non-Hodgkin's lymphoma (NHL). In the present study, we investigated whether a combination of MLN4924 and Rituximab may act in a complementary manner in pre-clinical models of NHL. We utilized models of ABC-like Diffuse Large B-cell Lymphoma (ABC-like DLBCL, OCI-Ly10 cells) dependent on NF- B signaling for survival and Germinal Center B-cell like DLBCL (GCB-like DLBCL, OCI-Ly19 cells) that are not dependent on NF-κB signaling for survival. In vivo administration of MLN4924 to mice bearing xenograft tumors of OCI-Ly10 and OCI-Ly19 resulted in a pharmacodynamic response of NAE pathway inhibition. In both models, a single dose of MLN4924 resulted in a dose-dependent inhibition of NAE and stabilization of Cullin Dependent Ligase substrates including Nrf-2 and pI Bα.
MLN4924 induced antitumor activity that was dose-dependent in both models. In the OCI-Ly10 model co-administration of MLN4924 (10 or 3 mg/kg) and Rituximab (0.3 or 1 mg/kg) induced either synergistic or additive anti-tumor activity (P&gt;0.05). The combination of 10 mg/kg MLN4924 and 1 mg/kg Rituximab resulted in 3 partial and 7 complete responses. In the OCI-Ly19-luc disseminated lymphoma model combining MLN4924 (10–30 mg/kg) with Rituximab resulted in additive tumor growth inhibition. The mean survival endpoint was significantly longer (p=&lt;0.01) in the combination group when compared to the single agent group. Importantly, all animals in the MLN4924 (60 mg/kg) and Rituximab (10 mg/kg) combination group were still alive 100 days after treatment ended. All doses and regimens were well tolerated.
The results of these studies demonstrate that combination treatment with MLN4924 and Rituximab resulted in additive and/or synergistic reduction in tumor burden in the OCI-Ly10 and OCI-Ly19 models. In addition, these data provide the rationale for future clinical evaluation of MLN4924 in combination with Rituximab in lymphoma.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B189.
Abstract B208: Phase I study of angiotensin-(1–7), an endogenous antiangiogenic hormone: Clinical, pharmacokinetic, and biomarker findings
Authors: Petty William Jeffrey , Miller Antonius A. , McCoy Thomas P. , Gallagher Patricia E. , Tallant E. Ann , Torti Frank M. 
Published: June 2012

Abstract
Background: Angiotensin-(1–7) [Ang-(1–7)] is an endogenous peptide hormone of the renin-angiotensin system with anti-proliferative and anti-angiogenic properties. The primary objective of this study was to establish the recommended phase II dose of Ang-(1–7) for treating patients with advanced cancer. Secondary objectives were to assess toxicities, pharmacology, clinical responses, and potential biomarkers of anti-angiogenic effects.
Methods: Patients with advanced solid tumors refractory to standard therapy were eligible. Patients were treated with escalating doses of Ang-(1–7) in cohorts of three patients. Ang-(1–7) was administered by subcutaneous injection once daily for five consecutive days on a three week cycle. Tumor measurements were performed every two cycles and treatment was continued until disease progression or unacceptable toxicity. Blood samples were obtained for pharmacokinetic and plasma biomarker analyses.
Results: Eighteen patients were enrolled. Serious adverse events possibly related to treatment included stroke, reversible cranial neuropathy, and deep vein thrombosis. Other toxicities were mild. One patient developed a 19% reduction in tumor measurements. Three additional patients demonstrated clinical benefit with stabilization of disease lasting more than three months. One patient with stable disease also demonstrated cystic tumor changes, and one patient with stable disease also demonstrated minor PSA reductions after each cycle. In patients with clinical benefit, Ang-(1–7) administration resulted in a dose-dependent decrease in plasma placental growth factor (PlGF) (P = .04) on day 1. No change in plasma PlGF occurred in patients without clinical benefit on day 1 (P = .25). On day 5, PlGF levels remained lower in patients with clinical benefit compared to patients without clinical benefit (P = .04).
Conclusions: Ang-(1–7) is a first-in-class anti-angiogenic drug targeting the mas receptor. Clinical benefit is associated with a reduction in plasma PlGF levels following Ang-(1–7) treatment. The recommended phase II dose is 400 mcg/kg for this administration schedule.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B208.
Abstract B213: Pharmacokinetics (PK) and efficacy of axitinib in patients (pts) with sorafenib-refractory metastatic renal cell carcinoma (mRCC)
Authors: Dutcher Janice , Garrett May , Wilding George , Stadler Walter M. , Pithavala Yazdi , Kim Sinil , Tarazi Jamal , Rixe Olivier , Rini Brian I. 
Published: June 2012

Abstract
Background: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, 3. The objectives of this analysis were to assess the impact of food, gender, race, weight, age, and disease status on axitinib PK and to explore the relationship between PK, diastolic blood pressure (dBP), and clinical efficacy in sorafenib-refractory mRCC pts. A relationship has been previously reported in refractory mRCC pts.
Methods: Pooled PK data were analyzed using nonlinear mixed-effects modeling to estimate population PK parameters (mean and inter-individual variability; Rixe et al. ASCO Annual Meeting 2009; abstract 5045). Efficacy data from sorafenib-refractory mRCC pts (n=59) were included in the PK/pharmacodynamic analysis. Mean steady-state area under the plasma concentration-time curve (AUC) at the end of cycle 1 and dBP during axitinib therapy were utilized as predictors of clinical efficacy in the mRCC pts using logistic regression and Kaplan-Meier survival analyses.
Results: Median overall survival (OS) for sorafenib-refractory mRCC pts with an AUC below the median (662 ng·hr/mL; n=29) was 42 weeks vs 84 weeks (P&lt;0.05) for pts with an AUC above the median (n=30). Median OS for sorafenib-refractory mRCC pts with at least 1 dBP measurement ≥90 mmHg (n=29) during axitinib therapy was 88 weeks vs 42 weeks for pts without any dBP ≥90 mmHg (n=30; P&lt;0.05). Furthermore, logistic regression showed that for every 100 ng·hr/mL increase in axitinib AUC, there was a 1.24-fold increase in the odds of a partial response (PR). BP was the stronger predictor vs PK, with a 2.41-fold increase in the odds of a PR with every 10 mmHg increase in dBP.
Conclusions: Increased exposure to axitinib and dBP ≥90 mmHg during axitinib therapy are associated with greater probability of a PR and longer median OS in sorafenib-refractory mRCC pts. These data support an ongoing, pivotal, phase III trial in previously-treated mRCC that incorporates a dosetitration scheme based on patient tolerance and BP.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B213.
Abstract B214: Use of a pharmacokinetic model derived from early clinical studies to assess the relevance of covariates on cilengitide pharmacokinetics
Authors: Zuehlsdorf Michael , Bhattaram Venkatesh Atul , Kroesser Sonja , Derendorf Hartmut , Kovar Andreas 
Published: June 2012

Abstract
Background: Cilengitide is a selective competitive inhibitor of αvβ3 and αvβ5 integrins. It demonstrates anti-angiogenic, direct anti-tumor and anti-migratory properties and is under investigation for use in treating glioblastoma, cancer of the head and neck, NSCLC and other indications. The primary objective of this analysis was to characterize the population pharmacokinetic behavior of cilengitide from data obtained from three studies in patients with advanced solid cancer, NSCLC or advanced unresectable pancreatic cancer using a nonlinear mixed effects modeling technique.
Methods: A stepwise approach was used on the data (992 concentration time points from 136 patients) beginning with exploratory analysis to verify the database for the three studies and target covariate relationships. A two compartment pharmacokinetic structural model was developed in NONMEM® to describe the concentration-time profile of cilengitide using initial parameter estimates determined from preliminary analysis using KINETICA®. Main individual covariates were tested to estimate their impact on PK parameters using two procedures: i) a stepwise selection procedure in NONMEM and ii) generalized additive modeling with XPOSE® software. The model was validated by testing the stability of the base and final model via a bootstrap procedure (1000 replicate data sets generated from the original data set).
Results: A pharmacokinetic model was developed and validated for cilengitide from data obtained from three different studies. Study was not a significant covariate for the model. Estimated pharmacokinetic parameters for the structural model were 2.79 L/h/m2 for CL (clearance from central compartment), 6.75 L/m2, for V1 (volume of distribution for central compartment), 1.3 L/h/m2 for Q (intercompartmental clearance) and 3.85 L/m2 for V2 (volume of distribution for peripheral compartment). The half-life was estimated as 0.9 h and 3.8 h for and -phase. The model PK parameters are consistent with individual study derived PK parameters (2 to 4 L/h/m2 for mean systemic clearance (CL), 0.84 to 3.36 for renal clearance and 3 to 5 hours for terminal half-life).
From the covariates analyzed (age, weight, BSA, albumin, bilirubin, serum creatinine, aspartate amino transferase, alanine amino transferase, alkaline phosphatase, hepatic status, gender and study) only weight and body surface area were highly correlated (r=0.95, p&lt;0.01). Although the albumin and bilirubin covariates were statistically significant for the final model, their inclusion is not clinically relevant based on the information obtained from the studies.
Information generated by using the model to predict cilengitide profiles in different patient populations can speed identification of optimized dosing regimens.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B214.
Abstract B250: Clinical benefit of lapatinib-based therapy in patients with HER2-positive breast tumors expressing p95HER2
Authors: Scaltriti Maurizio , Chandarlapaty Sarat , Prudkin Ludmila , Aura Claudia , Jimenez Jose , Angelini Pierdavide , Ellis Cathrine , Gagnon Robert , Rosen Neil , Baselga Jose 
Published: June 2012

Abstract
Purpose: A subgroup of HER2 overexpressing tumors also express p95HER2, a truncated fragment of the HER2 receptor that lacks the extracellular domain, retains kinase activity and correlates with intrinsic trastuzumab resistance. We tested the hypothesis that the small molecule lapatinib, an EGFR/HER2 dual tyrosine kinase inhibitor, would be active in these tumors. We studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinic [lapatinib monotherapy (Study EGF20009) or lapatinib in combination with capecitabine (Study EGF100151)].
Patients and Methods: Expression of p95HER2 in primary tumors was evaluated by immunofluorescence and correlated with clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) and progression-free survival using logistic regression and Cox-proportional hazard models.
Results: Lapatinib was efficacious in inhibiting tumor growth and HER2 downstream signaling of p95HER2 expressing tumors in two different animal models. In human samples, expression of p95HER2 was evaluable in 76% (105/138) and 56% (223/399) of patients from EGF20009 and EGF100151 studies, respectively. The percentage of p95HER2 positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In neither study there was a statistically significant difference in progression-free survival between p95HER2-positive and p95HER2-negative patients. Similarly, in both studies the clinical benefit rate was not significantly associated with p95HER2 expression.
Conclusions: Lapatinib as a monotherapy or in combination with capecitabine is equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B250.
Abstract B252: Identification of a new class of highly potent and selective c-Met kinase inhibitors
Authors: Blaukat Andree , Bladt Friedhelm , Dorsch Dieter , Fittschen Claus , Friese-Hamim Manja , Graedler Ulrich , Meyring Michael , Rautenberg Wilfried , Schadt Oliver , Stieber Frank 
Published: June 2012

Abstract
The role of the receptor tyrosin kinase c-Met in tumor progression and metastasis has been shown in preclinical studies and in early clinical settings. Several c-Met inhibitors with different selectivity profiles are currently in preclinical/clinical investigation and might provide effective cancer therapeutics in the future.
A biochemical HTS run using the recombinant kinase domain of c-Met enabled us to identify N-(3-(3,6-Dihydro-5-(3,4-dimethoxyphenyl)-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl)-phenyl)-carbaminic acid-(3-(N,N-diethylamino)-propylester) representing as new chemical class of kinase inhibitors. This HTS hit inhibited c-Met in vitro kinase activity and HGF-induced c-Met phosphorylation in A459 lung cancer cells with IC50 values well below 1 µM. The analysis of co-crystal structures defined the molecular requirements for potency and selectivity and guided the subsequent chemical optimization. As a result of the lead optimization process, two candidate compounds with distinct pharmacological properties were synthesized, EMD 1214063 and EMD 1204831. Both compounds are highly potent and efficient inhibitors of c-Met in vitro kinase activity and c-Met auto-phosphorylation induced in vitro by HGF stimulation or by c-Met overexpression. Both compounds displayed an exquisite selectivity profile when tested in vitro against a panel of more than 250 potential off-targets, including kinases, GPCRs, ion channels, transporters and various enzymes.
EMD 1214063 and EMD 1204831 exhibited excellent anti-tumor activity in vivo in a variety of xenograft models, including U87-MG glioblastoma cells (autocrine HGF production), TPR-Met-transformed mouse fibroblasts (oncogenic Met fusion protein) or Hs746T gastric and EBC-1 lung cancer cells (c-Met gene amplification and HGF-independent activation).
In c-Met-driven models complete regressions were observed with doses as low as 6 mg/kg/d administered per os. PK/PD analysis revealed efficient, dose- and time-dependent inhibition of c-Met phosphorylation, reduction of IL-8 and cyclin D1 expression as well as an induction of the cell cycle inhibitor p27. The pharmacodynamic effects of EMD 1214063 were longlasting and allowed various schedule variations without compromising its anti-tumor activity, while c-Met inhibition by EMD 1204831 was rather transient, allowing optimal anti-tumor activity when the compound was applied once or twice daily.
The profile of EMD 1214063 and EMD 1204831 including synthesis, structure activity relationships, X-ray structures and a comprehensive pharmacological in vitro and in vivo characterization will be presented. Furthermore, potential pharmacodynamic and predictive biomarkers will be discussed.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B252.
Abstract B255: Discovery and validation of a novel class of small molecule inhibitors of the CDC7 kinase: Modulation of tumor cell growth in vitro and in vivo
Authors: Frattini Mark G. , Shum David , O'Dwyer Kristen , Brentjens Renier , Maslak Peter , Heaney Mark , Jurcic Joseph , Djaballah Hakim , Kelly Thomas 
Published: June 2012

Abstract
High throughput screening of compounds comprising the Memorial Sloan Kettering chemical library resulted in several confirmed hits against the recombinant Cdc7:Dbf4 heterodimeric kinase, a key regulator in the initiation of DNA replication and the G1 to S phase transition. Chemoinformatic analysis of the hits revealed an enrichment in one chemical cluster made up of several naturally occurring compounds, of which the most potent compound, CKI-7, was selected for further investigation. First, CKI-7 was found to be a non competitive inhibitor for ATP and prompted us to prolife it against a panel of 200 known kinases in order to assess its selectivity profile. The results were as predicted and very few kinases were specifically affected. Second, CKI-7 cytotoxic activity was assessed against a panel of well established cancer cell lines representing both hematopoietic and solid tumor malignancies as well as against a panel of primary hematopoietic cells derived from leukemia patients (both chemotherapy naive and relapsed/refractory samples) and was found to be a very effective agent with potencies in the low nanomolar range. Subsequent studies using an isogenic pair of cell lines with one over expressing the Bcl_xL anti-apoptotic protein further confirmed the induction of the intrinsic apoptotic pathway via caspase-3 activation in the absence and attenuation of the activity in the presence of Bcl_xL. This was further demonstrated through standard cell cycle synchronization studies revealing that exposure to the Cdc7 inhibitor results in an S phase arrest, cell cycle dependent caspase-3 activation, and apoptotic cell death. This cell death is the direct result of Cdc7 kinase inhibition by CKI-7 as demonstrated using a Cdc7 substrate biomarker assay. Third, the physicochemical properties of this class of naturally occurring compounds also prompted us to investigate their effect on several multidrug resistence (MDR) over-expressing cell lines. We found that CKI-7 was not a substrate for the efflux pumps demonstrating that this novel compound can overcome a major mechanism of chemotherapy resistence in human tumor cells. Based of the above observations, in vivo dose-dependent anti-tumor activity of CKI-7 was subsequently demonstrated in a SCID-Beige mouse systemic tumor model utilizing a recently isolated Philadelphia chromosome positive acute lymphoblastic leukemia cell line (PhALL3.1) in addition to melanoma and non small cell lung cancer xenograft models. Taken together, our data confirm that Cdc7 is a new promising target for cancer therapy, and that the newly discovered inhibitor CKI-7, a naturally occurring selective small molecule inhibitor of this enzyme, is an equally promising novel cancer therapeutic agent.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B255.