bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B198: The pattern of in vivo biological activity of Zalypsis® is different from that of trabectedin
Authors: Frapolli Roberta , Bello E. , Galmarini Carlos , Cuevas Carmen , Aviles Pablo M. , Guillen Maria José , D'Incalci Maurizio 
Published: June 2012

Abstract
Trabectedin is a tetrahydroisoquinoline molecule that was originally derived from the Caribbean marine tunicate Ectenaiscidia turbinata and is now produced by chemical synthesis. The compound is approved in the European Union and a number of other countries for use in patients with advanced soft tissue sarcomas. Zalypsis® (PM00104) is a novel synthetic tetrahydroisoquinoline structurally related to jorumycin. Both compounds have a similar A and B ring structures that bind DNA but differ in their C ring which protrudes out of DNA and is possibly relevant for the interaction with DNA binding proteins, including DNA repair proteins and transcription factors. In the present study, we characterized the in vivo antitumor activity compared to trabectedin. The antitumor activity of Zalypsis® was investigated in two murine models, M5076 reticulosarcoma and MNMCA1 fibrosarcoma, respectively metastasizing liver and lung. Zalypsis® (0.9 mg/kg) and trabectedin (0.15 mg/kg) were administered intravenously every week for three times (q7dx3). In both models Zalypsis® was very effective in inhibiting the primary tumors (T/C 18% and 20% respectively). In the case of MNMCA1, it was also effective against metastasis whereas it was inactive against liver metastasis of M5076 sarcoma. In the two experiments, trabectedin was very effective against metastasis although against M5076 sarcoma it was only marginally able to inhibit primary tumor growth (T/C 52%). In Cen3 tel sarcoma, of human origin, Zalypsis® was very effective with a T/C of 19% whereas trabectedin was essentially inactive (T/C 78%). In contrast Zalypsis® was less effective than trabectedin against HOC22 ovarian carcinoma. In summary it appears that Zalypsis® is biologically different from trabectedin when tested on in vivo tumor models, therefore its clinical development should not necessarily addressed to the same tumors that have shown sensitivity to trabectedin.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B198.
Abstract B2: Results of a phase 1b study of PTC299, a novel oral inhibitor of tumor VEGF expression, in patients with advanced cancer
Authors: Schwartz Gary , Miao Harry , Dickson Mark , Rodrigues Leslie , Llorente Mary , Cao Yen , Dials Heather , Darby Charles H. , Elfring Gary , Miller Langdon L. 
Published: June 2012

Abstract
Background: PTC299 is a novel, orally bioavailable, small molecule designed to inhibit the expression of tumor-derived VEGF and other angiogenic cytokines. In multiple xenograft models of human cancers, single-agent PTC299 decreases tumor and plasma VEGF levels and induces significant tumor regression or growth delay.
Methods: A Phase 1b study has been initiated with 3 stages, each using a classic 3+3 design. In Stages 1 and 2, patients received PTC299 monotherapy in repeated 6-week cycles (Stage 1: 4 weeks on and 2 weeks off therapy with body-weight-adjusted BID dosing; Stage 2: continuous therapy with unit BID or TID dosing). In Stage 3, unit dosing PTC299 is administered with docetaxel. In all stages, treatment was given until disease progression or unacceptable toxicity. Safety, PK, PD activity, and antitumor activity have been assessed.
Results: The study has enrolled 18 subjects (6 males, 12 females) with median [range] age 61 [31–81] years, ECOG performance status of 0 (n=10) or 1 (n=8), 9 different tumor types, and median [range] of prior therapies of 3 [0–8] to receive PTC299 in Stage 1 (n=12) and Stage 2 (n=6). Median [range] of time on treatment has been 2 [1–7] cycles. No maximum tolerated dose (MTD) has been established through the highest dose levels tested: Stage 1, 1.2 mg/kg/dose BID and Stage 2, 100 mg/dose TID. Adverse events have been infrequent, usually Grade 1, and have not generally been considered PTC299-related. No hypertension has been observed. PTC299 pharmacokinetics is generally dose proportional, with rapid appearance of drug in plasma, Tmax of ∼4 hours, and an effective t1/2 of ∼12 hours. From Day 1 to Day 28 in Stage 1 (Day 42 in Stage 2), there has been an increase in plasma concentrations at all dose levels, indicating accumulation (∼2 fold) when PTC299 is dosed continuously. PTC299 trough plasma concentrations have exceeded values of 0.5–1.0 g/mL associated with maximal activity in mouse xenograft models. PTC299 treatment has been associated with reductions in circulating angiogenic/inflammatory cytokines. Five of eighteen (28%) patients with thyroid cancer, melanoma, basal cell carcinoma, and chondrosarcoma (2) have remained on study with stable disease for 11+, 4.5, 5, 6+, and 4.5+ months respectively. A patient with papillary thyroid cancer has had a sustained tumor marker decrease of &gt;50% lasting for &gt;7 months.
Discussion: Single-agent PTC299 has been well tolerated, has achieved target plasma concentrations, and has shown evidence of pharmacodynamic and clinical activity. Accrual to Stage 3 with docetaxel has been initiated.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B2.
Abstract B201: Selective peptides for targeting EphA2 in cancer cells
Authors: Mitra Sayantan , Duggineni Srinivas , Koolpe Mitchell , Dail Monique , Zhu Xuejun , Huang Ziwei , Pasquale Elena B. 
Published: June 2012

Abstract
EphA2 receptor tyrosine kinase is highly overexpressed in tumors and is rapidly emerging as a promising new therapeutic target in cancer. Agents that target EphA2 have been shown to deliver cytotoxins/drugs selectively to cells expressing EphA2 and to decrease tumor growth and metastasis in animal models. We have recently isolated two peptides (YSA and SWL) by phage display that selectively target EphA2, and show the ability to deliver quantum dots and phage particles to cancer cells overexpressing EphA2. Furthermore, we elucidated the structure-activity relationship of one of the EphA2 agonistic peptides (YSA) by alanine scanning mutagenesis, characterized the SWL peptide and a series of related peptides, all of which retain their selectivity for EphA2. The selectivity of the peptides was determined by measuring the ability of the Eph receptors to bind immobilized peptide, and their potency was measured using an ELISA assay that monitors the inhibition of ephrin-A1 binding to EphA2. Our analysis revealed that only 4 of the 12 amino acids are critical for binding of YSA, and a 5-mer peptide derived from YSA retains selectivity for EphA2. All these peptides are reasonably stable in conditioned cell culture medium and rat liver microsomal preparations. In addition, at least some of these peptides show the ability to activate the EphA2 receptor inducing its phosphorylation and inhibit serum-induced phosphorylation of Akt and Erk1/Erk2 MAP kinases, which are key mediators in major oncogenic pathways. Therefore, our results indicate that in addition to selectively targeting cancer cells, these peptides can also lead to inhibition of oncogenic pathways.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B201.
Abstract B209: A self-emulsifying lipid suspension formulation enhances oral bioavailability of MP-470 in a randomized two-way crossover study in healthy male subjects
Authors: Joshi-Hangal Rajashree , Tang Chunlin , Roger Inloes , Shi Chongtie , Geddes Denice , Collier J. , Rodriguez Sara , Angelique Mittan , McLaughlin Heather , Fine Gil , Sanjeev Redkar , Choy Gavin 
Published: June 2012

Abstract
Background: MP-470 is an orally bioavailable multi-targeted tyrosine kinase inhibitor specifically designed to be a potent inhibitor of mutant c-Kit and PDGFR. MP-470 is also active as an inhibitor of DNA repair following chemotherapy. MP-470 has shown significant synergistic activity with DNA damaging chemotherapy in several xenograft models and in a phase I combination study. Oral bioavailability of this agent is limited by its solubility but not permeability. An in vitro/in vivo iterative approach was utilized preclinically for formulation selection. In the Beagle dog model, the oral bioavailability of MP-470 is enhanced to a maximum of 4–5-fold by formulating it in tocopherols and lipidic surfactants with self-emulsification ability (5%, dry powder vs. 20%, lipid suspension). Results presented herein are from a randomized two-way crossover pharmacokinetic (PK) study evaluating two formulations in healthy human subjects.
Methods: Twelve healthy male subjects 18–45 years with a body mass index of 18–35 kg/m2 were randomized in a 1:1 ratio to receive either a 100 mg dry powder capsule or 90 mg (3 × 30 mg) lipid suspension capsules in a fasted condition with 240 mL of water. Subjects receiving MP-470 90 mg lipid suspension capsules ingested all three capsules within one minute. The alternate formulation was administered after a 14 day washout. Plasma for PK assessments was collected and evaluated at pre-dose through hour 48 post MP-470 administration.
Results: Comparative PK results from twelve subjects are summarized below. Additional information will be summarized in the final presentation.
Conclusions: Solubility of the drug in the formulation vehicle alone plays a limited role in bioavailability enhancement; rather the ability of the formulation to keep the drug in solution after dilution in the GI tract seems critical. It is also possible that physiological mechanisms such as active transport or metabolism contribute to the enhanced absorption of MP-470 in the tocopherol-based vehicles. Consistent with preclinical Beagle dog data, the lipid suspension formulation offers an enhanced oral bioavailability over the dry powder formulation in healthy human subjects. The lipid suspension formulation will be utilized in future MP-470 clinical studies.
Pharmacokinetic summary - Dry Powder vs. Lipid Suspension Capsules Parameters 100 mg MP-470 Dry Powder Average (CV, n=12) 90 mg MP-470 Lipid Suspension Average (CV, n=12) Average % Increase* (95% CI) Cmax (ng/mL) 23.2 (71%) 132.6 (55%) 635% (420%, 851%) Tmax (h) 4.1 (44%) 1.7 (54%) - AUClast (ng·h/mL) 253 (54%) 488 (40%) 131% (85%, 177%)
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B209.
Abstract B210: Shed MET (sMET), VEGFA, and sVEGFR2 are markers of foretinib treatment in metastatic gastric cancer patients
Authors: Cecchi Fabiola , Liu Yuan , Gagnon Robert C. , Kallender Howard , Rabe Daniel C. , Shah Manish A. , Martin Anne-Marie , Bottaro Donald P. 
Published: June 2012

Abstract
Foretinib (formerly GSK1363089) is a small molecule multikinase inhibitor which includes inhibition of MET and VEGFR2. The ongoing phase II study, MET111643, is evaluating the safety and efficacy of 2 dosing schedules (continuous daily dosing and intermittent 5 days on/9 days off dosing) of foretinib as a single agent in pts with metastatic GC. An additional component of the study is to collect patient plasma samples before and during treatment with foretinib, to explore the potential pharmacodynamic effect and/or the modulation by foretinib of MET and VEGFR2.
Plasma samples were collected from 42 pts on the intermittent 5 days on/9 off foretinib schedule at baseline and prior to dosing on days 5, 15, 29, and 47. The plasma levels of sMET, HGF, sVEGFR2, and VEGFA were measured using the Meso Scale Discovery platform (MSD). These marker changes from baseline were analyzed at each time point using analysis of variance and their relationships with plasma concentrations of foretinib (PK) and clinical outcome (progression free survival [PFS] and RECIST response) were also examined.
Statistically significant increases from baseline of sMET at days 5, 15, 29, and 47 (p&lt;.0001, p =.0344, p=.0353, p&lt;.0001 respectively), VEGFA at days 5 (p&lt;.0001) and 47 (p&lt;.0001), and HGF at day 47 (p&lt;.0001) were observed. Statistically significant decreases of sVEGFR2 at days 5, 15, 29, and 47 (all p&lt;.0001) were also observed. Plasma VEGFA levels at day 5, 15, 29 are weakly correlated with PK (p=.033, p=.0138, p=.0165, respectively). Plasma sMET levels and changes from baseline at day 47 showed significant correlation with baseline tumor SLD (sum of longest diameter, R=0.54, p=0.0042; R=0.40, p=0.0443 respectively). Plasma VEGFA levels and changes from baseline at day 47 showed significant correlation with baseline tumor SLD (R=0.55, 0.44, respectively, p&lt;0.01) and SLD at 8 weeks (R=0.64, 0.61, respectively, p&lt;0.01). No correlation was observed between these four markers and PFS/RECIST response.
Changes in sMET, VEGFA, and sVEGFR2 levels were observed for both intermittent and daily dosing schedules in the gastric cancer study. Although SLD at 8 weeks did not change significantly from baseline in the GC study, plasma levels of sMET and VEGFA correlated positively with the week 8 magnitude of SLD. Hence plasma levels of sMET and VEGFA may reflect biological changes following foretinib treatment.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B210.
Abstract B211: Pralatrexate pharmacokinetics with intravenous administration to oncology patients
Authors: Venitz J. , Brar S.S. , Pronk G. J. , Huntington M. , Wilroy S. , O'Connor O.A. , Azzoli C.G. 
Published: June 2012

Abstract
Pralatrexate is a rationally designed antifolate with high affinity for reduced folate carrier-1 (RFC-1) and folyl poly-glutamyl synthetase (FPGS), resulting in efficient uptake and retention in cancer cells. Pralatrexate is being developed for various indications, including peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma, non-small cell lung cancer (NSCLC), and bladder cancer. Pralatrexate is a 1:1 racemic mixture of R- and S- diastereomers. Here we summarize the pharmacokinetics (PK) of pralatrexate from 3 Phase 1–2 studies. Pralatrexate was administered weekly or bi-weekly by IV push over 3–5 minutes (n=44) or as a 60-minute infusion (n=10) at doses ranging from 30–325 mg/m2. Serial plasma and urine samples, collected for up to 72 hours after dosing, were analyzed using a validated chiral LC-MS/MS method (lower limit of quantitation: 0.5 ng/ml). PK parameters were estimated by noncompartmental PK analysis. Clinical covariates were captured at screening to explore relationships with pralatrexate PK. The final PK results were based on 54 patients; 10 with relapsed/refractory PTCL (PDX-008), 38 with advanced NSCLC (PDX-007), and 6 with advanced solid tumors and concurrent docetaxel administration (PDX-99-083). The PK population was predominantlyWhite (81%) and balanced by gender (52% female). Age ranged from 24 to 77 (mean 60) years, body weight from 43–127 (77) kg, and estimated creatinine clearance from 53 to 130 (89) mL/min. Patients had adequate hepatic and hematologic function. Both pralatrexate diastereomers showed a similar multiphasic decline in plasma concentrations with a slow terminal phase (t½term = 12∓18h, PDX-008), likely reflecting the return from deep intracellular compartments. There was no evidence of PK nonlinearities in the dose range of 30–325 mg/m2. On a weekly or biweekly administration schedule, there was no significant drug accumulation in plasma over the first 2–6 doses. Other than expected changes in Cmax and Tmax, there were no apparent differences in PK between IV administration over 3–5 minutes and 60-minute infusion. Mean (COV) values (n=41−54) for total body clearance, renal clearance and volume of distribution at steady-state were 495 mL/min (57%), 125 mL/min (71%) and 106 L (121%) for the S-diastereomer and 218 mL/min (44%), 74 mL/min (60%) and 36 L (78%) for the R-diastereomer, respectively. These results suggest net renal tubular secretion, low hepatic extraction, and limited tissue distribution for both diastereomers. Consistent with approximately 30% contribution of renal excretion to overall drug elimination, creatinine clearance and age accounted for only 10% of the observed variability in total body clearance. In conclusion, this analysis suggests that pralatrexate PK is linear and dose-proportional across the dose range tested, with no accumulation with repeated dosing.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B211.
Abstract B215: Ascending single-dose study of safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy subjects
Authors: Abbas Richat , Hug Bruce A. , Leister Cathie , Burns Jaime , Sonnichsen Daryl 
Published: June 2012

Abstract
Introduction: Bosutinib (SKI-606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of patients with chronic myelogenous leukemia. An oral dose of 500 mg daily shows evidence of clinical efficacy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Cortes et al. Blood 112:1098, 2008). To support the clinical pharmacology assessment of bosutinib, a single-ascending-dose safety and pharmacokinetic (PK) evaluation was performed in healthy subjects.
Methods: This was a randomized, double-blind, placebo-controlled, single-ascending dose, sequential-group study of oral bosutinib in healthy subjects. Subjects were originally to receive doses of 200, 400, 600, 800, 1000 and 1200 mg of bosutinib in the fasting state. However, subjects who received 400 mg bosutinib had multiple adverse events and then 200 mg, 400 mg, 600 mg, and 800 mg bosutinib was administered with food. Each cohort included 6 subjects who received one dose of bosutinib and 2 who received placebo. Plasma samples, collected through 96 h post-dose, were analyzed by using a liquid chromatography/tandem mass spectrometry assay for bosutinib concentrations. PK analyses were performed using a noncompartmental method and dose linearity was assessed using a power model.
Results: A total of 55 subjects (41 bosutinib, 14 placebo) were enrolled (47 males, 8 females, median age [range] 28 [18–50] y, 87%White). Thirty-three (81%) subjects had adverse events (AEs) after receiving bosutinib. The most common AEs for all subjects receiving bosutinib included diarrhea (39% subjects), nausea (29%), headache (22%), postural dizziness (22%) catheter site-related reaction and fatigue (10% each). The frequency and severity of gastrointestinal AEs appeared to be dose related. Doses up to 600 (fed) were well tolerated. After administration of single ascending doses of 200–800 mg bosutinib with food, absorption of bosutinib was relatively slow with a median tmax of 6 h, and both Cmax and AUC increased with increasing dose in a linear fashion. The apparent volume of distribution (Vz/F) was large (131–214 L/kg), mean clearance (CL/F) was 2.25–3.81 L/h/kg, and mean half-life was 32–39 h. Food increased bosutinib exposure (Cmax and AUC) by ∼2-fold and 1.5-fold after administration of the 200-mg and 400-mg doses, respectively.
Conclusions: Bosutinib was generally safe and well tolerated in healthy subjects after administration of single oral doses up to 600 mg (fed). The PK of bosutinib was linear when given with food, and the half-life supports a once-daily dosing regimen.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B215.
Abstract B216: Exposure-response (E-R) relationship of ABT-263-induced thrombocytopenia in cancer patients in phase 1 studies
Authors: Xiong Hao , Noertersheuser Peter A. , Pradhan Rajendra S. , Krivoshik Andrew P. , Humerickhouse Rod , Awni Walid 
Published: June 2012

Abstract
Background: ABT-263 is a novel small molecule Bcl-2 family protein inhibitor that binds with high affinity to multiple antiapoptotic Bcl-2 family proteins. The pharmacokinetics, safety and preliminary efficacy of ABT-263 in patients with relapsed or refractory lymphoid malignancies, CLL/SLL, SCLC and other non-hematological malignancies are being studied in three Phase 1/2a studies. Both a 14/21-day dosing schedule and a continuous dosing preceded with a 7-day lead-in period are being evaluated in these studies. Grade 4 thrombocytopenia has been the most prominent, mechanism-related, dose-limiting toxicity in patients in these studies. E-R relationship in this drug-induced thrombocytopenia may inform the selection of the dose and dosing schedule for a Phase 3 study in CLL patients.
Methods: ABT-263 plasma concentrations and platelet data from more than 100 patients in the three ongoing Phase 1/2a studies were included in the analysis. ABT-263 plasma concentration data were described using a two-compartment model with first-order absorption and elimination. The relationship between the circulating platelet count and ABT-263 plasma concentration was described with a semi-physiological model that had been developed using data in dogs. Simulations were preformed to compare the 14/21-day dosing schedule and the continuous dosing schedule with a low-dose lead-in period and project the incidence rates of Grades 3 and 4 thrombocytopenia in the dose range of 200 and 350 mg.
Results: The E-R relationship was generally well described by the semi-physiology model. Simulations indicated that, compared to the 14/21-day dosing schedule, continuous dosing preceded with a 7-day lead-in period minimizes platelet variability across cycles. The lead-in treatment appeared to blunt the initial sharp drop in platelet count according to the simulations with 250 mg dose. Although there seemed to be little difference in the incidence rate of Grade 4 thrombocytopenia, continuous dosing showed a trend of lower rate of Grade 3 thrombocytopenia than the 14/21-day dosing schedule. In terms of the rates of Grade 3 and 4 thrombocytopenia, the dose-response curve between 200 and 350 mg was quite shallow.
Conclusions: A continuous dosing preceded with a 7-day lead-in period is superior to the 14/21-day dosing schedule because it minimizes platelet variability across cycles and blunts the initial sharp drop in platelet count. Drug-induced thrombocytopenia is not sensitive to the change in dose does not provide significant differentiation in the dose range of 200 mg and to 350 mg.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B216.
Abstract B218: Lentiviral shRNA screen of human kinases identifies PLK1 as a potential therapeutic target for osteosarcoma
Authors: Duan Zhenfeng , Ji Diana , Weinstein Edward , Choy Edwin , Yang Cao , Mankin Henry , Hornicek Francis 
Published: June 2012

Abstract
Induction of RNA interference in cancer cells has made possible high-throughput genome-wide loss-of-function studies using reverse genetic screening techniques. Kinases play an important role in the growth and survival of tumor cells. We aim to identify kinases that are vital to the survival of osteosarcoma cells and may be a key target in creating novel anticancer therapies. We describe an optimized systematic screen of known kinases using osteosarcoma cell lines (KHOS and U-2OS) and a lentiviral-based short hairpin RNA (shRNA) human kinase library. CellTiter 96® AQueous One Solution Cell Proliferation Assay was used to measure cell growth and survival. We identified several kinases, including human polo-like kinase (PLK1), which inhibit cell growth and induce apoptosis in osteosarcoma cells when knocked down. cDNA rescue and synthetic siRNA assays confirm that the observed phenotypic changes result from the loss of PLK1 gene expression. Furthermore, a small molecule inhibitor to PLK1 inhibited osteosarcoma cell growth and induced apoptosis. Western blot analysis confirmed that PLK1 is highly expressed and activated in several osteosarcoma cell lines as well as in resected tumor samples.
Immunohistochemistry analysis showed that patients with high PLK1 tumor expression levels correlated with significantly shorter survival than patients with lower levels of tumor PLK1 expression. These results demonstrate the capability and feasibility of a high-throughput screen with a large collection of lentiviral kinases and its effectiveness in identifying potential drug targets. The development of more potent inhibitors that target PLK1 may open doors to a new range of anti-cancer strategies in osteosarcoma.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B218.