bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A97: Combination of a bifunctional alkylating agent and arsenic trioxide is effectively against the drug resistant tumor cells
Authors: Pei-Chih Lee , Kakadiya Rajesh , Su Tsann-Long , Lee Te-Chang 
Published: June 2012

Abstract
Inherited or acquired resistance to therapeutic agents is a crucial factor causing the failure of cancer chemotherapy. In this study, we explored the combination effect of a synthetic bifunctional alkylating agent, BO-1012, and arsenic trioxide (ATO) on killing H460 cells, derived from human large cell lung carcinoma and more resistant to BO-1012 and ATO as compared to several other cancer cell lines used, such as H1299, PC3, U87, MCF7, and OECM1 cells. We observed a synergistic enhancement of cell killing effects by treatment of H460 cells with BO-1012 for 1 h and followed with ATO for 72 h as compared to individual agents. By aid of modified comet assay, the repair of BO-1012-induced DNA interstrand crosslinks was significantly inhibited by ATO. Consequently, the protein levels as well as the nuclei foci of H2AX, a marker for DNA double strand breaks, was remarkably increased in H460 cells treated with in combination of BO-1012 and ATO. Accompanied with increased DNA damage, combined treatment resulted in severe G2/M accumulation as well as apoptosis. We further demonstrated that combination treatment with BO-1012 and ATO synergistically reduced tumor volumes of H460 cells subcutaneously inoculated into nude mice, indicating the effectiveness of combined treatment with BO-1012 and ATO against the inherited resistant H460 cells in xenograft mice model. Similar findings were demonstrated by using NTUB1/P cells, cisplatin resistant human bladder carcinoma cells derived from NTUB1 cells. These present results suggest that combination of bifunctional alkylating agents and ATO may be a rationale strategy for treatment of inherited or acquired drug-resistant cancers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A97.
Abstract B10: A phase I, dose-escalation and PK study of IV aflibercept (VEGF Trap) in combination with docetaxel (D), cisplatin (C), and 5-fluorouracil (F) administered every 3 weeks in patients with advanced solid malignancies
Authors: Massard C. , Bahleda R. , Khan A. , Ajan J. , Soria J. C. 
Published: June 2012

Abstract
Background: Aflibercept (AF) is a recombinant fusion protein of the human vascular endothelial growth factor (VEGF) receptor combining the Fc portion of human IgG1 with the extracellular ligand-binding domains of human VEGFR1 and VEGFR2. AF binds and neutralizes all VEGF-A isoforms plus placental growth factor. This study was designed to assess the safety, dose-limiting toxicities (DLTs)/ recommended dose (RD), and PK of AF + DCF.
Methods: This phase I combination trial explored escalating IV doses of AF given on day 1 followed by DCF (fixed dose of D 75mg/m2, C 75mg/m2 both on day 1 and F 750 mg/m2/day from day 1 to 5), every 3 weeks. G-CSF and fluoroquinolone were given as primary prophylaxis.
Patient characteristics: 44 pts (M/F 29/15, median age 53 [range: 33–74], baseline ECOG-PS 0/1/2: 16/27/1) were enrolled in 3 AF dose cohorts: 2 (n = 9), 4 (n = 14) and 6 (n = 21) mg/kg. Primary tumors were mostly gastro-intestinal (28, including 22 gastro-esophageal, 3 pancreas, 2 liver, 1 cholangiocarcinoma), 4 breast, 3 lung, 3 utero-vaginal, 2 thyroid, and 4 others. Sixteen (36%) pts received prior chemotherapy, median number of lines 2 (range 1–6).
Preliminary Results: Pts received a median number of 6, 4, and 7 cycles respectively for each dose group of 2, 4, and 6 mg/kg (range 1–19). One AF-related DLT of pulmonary embolism was observed at the 6 mg/kg AF dose level. Most common Gr ≥ 3 adverse events included: fatigue/asthenia (46%), mucosal inflammation/stomatitis (41%), anorexia (18%), and febrile neutropenia (16%). Mild to moderate arterial hypertension and proteinuria were reported. Grade 1 or 2 epistaxis (61%) and dysphonia (41%) also were reported. Two fatal events were observed: gastrointestinal haemorrhage after C2 (cholangiocarcinoma, AF 6 mg/kg), pulmonary haemorrhage with bronchial necrosis after C12 (NSCL cancer, AF 6 mg/kg). Thirteen (35%) partial responses (PR) in various tumor types, and 20 stable disease (SD) including 14 pts with SD≥2 months were noted. PK analysis will be presented once available.
Conclusions: AF 6 mg/kg combined with DCF q3wks was selected for further investigation, based on DLTs and overall safety profile. This dose is consistent with results from other aflibercept phase 1 studies. Encouraging signs of anti-tumor activity and disease control have been seen.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B10.
Abstract B134: PIK3CA mutations in patients with advanced cancers treated in phase I clinical trials
Authors: Janku Filip , Garrido-Laguna Ignacio , Hong David S. , Tsimberidou Apostolia M. , Naing Aung , Falchook Gerald S. , Wheler Jennifer J. , Moulder Stacy L. , Fu Siqing , Piha-Paul Sarina , Kurzrock Razelle 
Published: June 2012

Abstract
Background: Phosphatidylinositol 3-kinase (PI3K) is thought to play an important role in tumorigenesis. Activating mutations of the p110 subunit of PI3K (PIK3CA) have been identified in a broad spectrum of tumors.
Methods: A mutational analysis (a PCR-based DNA sequencing) of exon 9 (helical domain) and exon 20 (kinase domain) of the PIK3CA was performed using DNA obtained from tumors of patients referred for clinical trials using targeted therapy. Patients with PIK3CA were preferably treated whenever possible with regimens containing PI3K-AKT-mTOR signaling pathway inhibitors.
Results: To date 146 samples from patients with various advanced cancers have been collected. At the time of submission 117 results from mutational analysis were available (ovarian cancer, n=23; colon cancer, n=13; cervical cancer, n=10; endometrial cancer, n=7; breast cancer, n=11; melanoma, n=7; head and neck cancer, n=10; soft tissue sarcoma [not including GIST] n=6; renal cancer, n=4; and other tumor types, n=26). PIK3CA mutations were detected in 14 (12%) patients (3 in exon 9-helical domain, 11 in exon 20-kinase domain). In tumor types with more than 5 patients tested, PIK3CA mutations were most frequent in endometrial cancer (43%, 3 out of 7 patients), ovarian cancer (22%, 5 out of 23 patients), squamous head and neck cancer (14%, 1 out of 7 patients), breast cancer 18% (2 out of 11 patients), and colon cancer (15%, 2 out of 13 patients). No mutations were identified in patients with melanoma or cervical cancer. The small number of patients at this point precludes statistical comparisons. Of the 14 patients with PIK3CA mutations, 10 were treated on a protocol that included a drug targeting the PI3K-AKT-mTOR pathway, and 4 (40%) responded (partial responses). Although numbers are small, in individual disease there were 2 (67%) responses in 3 endometrial cancers, 1 (25%) in 4 ovarian cancers, 1 (100%) in 1 breast cancer, and no response in 1 colorectal cancer patient.
Conclusion: PIK3CA mutations were detected in 12% of patients with various solid tumors. Although numbers are small, response rate appears high (40%) in tumors with PIK3CA mutations treated with PI3K-AKT-mTOR pathway inhibitors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B134.
Abstract B137: Pharmacokinetics and pharmacodynamic biomarkers for the dual PI3K/mTOR inhibitor GDC-0980: Initial phase I evaluation
Authors: Wagner Andrew J. , Burris Howard A. , de Bono Johann S. , Jayson Gordon C. , Bendell Johanna C. , Gomez-Roca Carlos , Dolly Saoirse , Zee Ying-Kiat , Ware Joseph A. , Yan Yibing , Mazina Kathryn , Derynck Mika , Holden Scott , Soria Jean-Charles 
Published: June 2012

Abstract
Background: The PI3K-AKT-mTOR signaling pathway is deregulated in a wide variety of cancers. GDC-0980 is a potent, selective, dual inhibitor of class I PI3K and mTOR kinase with in vitro IC50 of 4.8 nM for p110α/p85 and apparent Ki of 17.3 nM for human mTOR. GDC-0980 potently inhibits tumor growth of xenografts and has demonstrated activity in preclinical models bearing PI3K mutant, PTEN-null, K-ras mutant, as well as PI3K pathway wild-type tumors in vitro and in vivo.
Methods: Two Phase I dose escalation studies were initiated using a 3+3 design in patients (pts) with solid tumors or non-Hodgkin's lymphoma who had progressed on, or were intolerant of, standard therapy. In study PIM4604g, GDC-0980 is administered as a single oral dose followed by a 1-week PK sampling period, and then administered daily (QD) on a 3-week on/1-week off schedule. Steady-state PK is evaluated after 1 week of continuous dosing. A second trial, PIM4605g, evaluating a once weekly (QW) dosing of GDC-0980 with a 4-week cycle was also initiated with a focus on PD evaluation using mandatory tumor biopsies and imaging. Immunohistochemical assays for pS6 PD marker evaluation were developed for clinical evaluation of pre- and post-dose tumor biopsies. Surrogate PD assays include an assessment of pAKT levels in platelet-rich plasma (PRP) coinciding with PK evaluation in both studies and an evaluation of tumor biopsies for marker modulation in PIM4605g.
Results: As of September 2009, a total of 15 patients have been treated in the two Phase I studies. Nine pts were treated in three successive cohorts of 2 mg, 4 mg, and 8 mg GDC-0980 QD in PIM4604g, and 6 pts were treated in the first cohort with 6 mg GDC-0980 QW in PIM4605g. GDC-0980 has been generally well tolerated. There have been no dose-limiting toxicities and no drug-related Grade ≥ 3 events reported in either study. Preliminary PK data suggests that GDC-0980 is rapidly absorbed with dose-appropriate increases in Cmax and AUC under fasting conditions. Preliminary surrogate PD data show decreases in pAKT levels in PRP reflective of drug levels in plasma. Preliminary data from comparison of tumor biopsies obtained at baseline and following administration of GDC-0980 demonstrate a &gt; 50% decrease in pS6 staining by immunostaining consistent with downstream modulation of the PI3K pathway.
Conclusions: GDC-0980 is a potent, oral, dual PI3K/mTOR inhibitor with promising preclinical activity. No significant toxicities have been observed to date in these ongoing Phase I studies at exposures producing PD modulation in surrogate tissue and tumor. Favorable preliminary PK profiles have been observed at initial dose levels.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B137.
Abstract B147: Lack of an additive effect of radiation treatment on PI3K or mTOR inhibition in prostate cancer cell lines
Authors: Bubley Glenn , Huang Qiuying , Lee Mike , Floyd Scott , Jones Graham , Yaffe Michael 
Published: June 2012

Abstract
We assessed the effect of PI3-K inhibition, mTOR inhibition and combined PI3K/mTOR inhibition in combination with ionizing radiation in prostate cancer cell lines. The treatments were studied in a cell lines with wild type PTEN status (CWR Rv1–22) and PTEN deficiency (LNCaP). Initial experiments determined concentrations of rapamycin (an mTOR antagonist) and wortmanin (a PI3-K antagonist) that resulted in an approximate 50% in cell viability at 48 hours. Cells were then treated with these agents both alone, together, or in combination with 8 gray of ionizing radiation and cell viability was assessed at 24, 48 and 72 hours. Regardless of the treatment schedule, i.e either radiation before inhibitor treatment or inhibitor treatment before radiation, we did not observe any additive effects from combination radiation and inhibitor treatment. This was regardless of whether inhibtor treatment was PI3K inhibition, mTOR inhibition, or combined treatment. Flow sorting cell cycle analysis from these studies indicates that the lack of effect might be related to the findings that radiation and PI3K/mTOR inhibition have effects of different phases of the cell cycle. This is a cell based model only and animal model data may be quite different. However, at this time PI3K/mTOR inhibition does not appear to be a mechanism for enhancing radiation sensitivity in prostate cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B147.
Abstract B15: Effect of axitinib (AG-013736) on thyroid function and biomarkers: Results from phase I studies in Japanese patients
Authors: Fujiwara Yutaka , Kiyota Naomi , Chayahara Naoko , Suzuki Akiyuki , Umeyama Yoshiko , Mukohara Toru , Minami Hironobu 
Published: June 2012

Abstract
Background: Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, 3. In a phase I study previously conducted in 12 Japanese patients with solid tumors, fatigue and abnormal thyroid stimulating hormone (TSH) levels were frequently observed.1 An additional phase I study has been conducted in 6 Japanese patients with solid tumors to evaluate the pharmacokinetics (PK), safety, and biomarkers (VEGF, soluble [s]-VEGFRs, and s-KIT). Thyroglobulin was measured to evaluate the direct effects of axitinib on the thyroid in these patients.
Methods: Twelve patients received axitinib at a 5 mg single dose followed by 5 mg twice daily (BID). A further 6 patients received axitinib at 5, 7, and 10 mg single doses followed by 5 mg BID. Based on data obtained from all 18 phase I patients, safety and potential correlations between TSH or biomarkers and exposure to axitinib were investigated.
Results: The plasma PK following single dosing was generally linear with a geometric mean AUC0-∞ of 148, 185, and 292 ng·h/mL following 5, 7, and 10 mg axitinib single doses, respectively. Across both phase I studies, the common treatment-related adverse events were fatigue (83%), diarrhea, anorexia, hand-foot syndrome (67% each), and hypertension (61%). Fifteen patients (83%) experienced TSH elevation. In the first phase I study, grade (G) 3 fatigue was observed in 5 of 12 patients (42%). In the additional phase I study, thyroid hormone replacement therapy was proactively given to patients as appropriate according to TSH level measured at every visit; none of 6 patients experienced G3 fatigue. Elevation of thyroglobulin with peak levels of &gt; 100 ng/mL was observed in 3 of 6 patients (50%) at approximately ≥3 months after initiating treatment. Three patients discontinued therapy during cycle 1 or 2 due to progressive disease; elevation of thyroglobulin was not observed in these patients. In the exploratory analysis, abnormal TSH was highly correlated with exposure to axitinib (r=0.72). Decrease in s-VEGFR2 levels was significantly correlated with exposure to axitinib (r=-0.95). Tumor size decreased in 11 of 17 patients (65%) who had target lesions.
Conclusions: Preliminary data suggest that fatigue may be manageable with thyroid hormone replacement therapy. Elevation of thyroglobulin was observed in all 3 patients who continued treatment with axitinib for longer than 3 months; this may indicate that hypothyroidism observed following axitinib treatment is potentially due to its direct effect on the thyroid. Results from two phase I studies demonstrated a significant correlation between change in s-VEGFR2 or TSH and exposure to axitinib. This suggests that s-VEGFR2 and TSH potentially act as biomarkers of axitinib plasma exposure.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B15.
Abstract B156: Augmenting sensitivity of cancer cells to novel antitumor fusicoccin derivative (ISIR-042) by hypoxia
Authors: Honma Yoshio , Akimoto Miho , Takenaga Keizo , Sassa Takeshi , Kato Nobuo 
Published: June 2012

Abstract
Some diterpene glucosides produced by the plant-pathogenic fungi are modulators of 14-3-3 proteins, and they induced the differentiation of human myeloid leukemia cells and apoptosis in human carcinoma cells in the presence of interferon-alpha (IFN). Combined treatment with IFN and cotylenin A significantly inhibited the growth of human lung cancer cells as xenografts without apparent adeverse effects.
We synthesized several fusicoccin derivatives with antitumor activity, and found that some effective derivatives exhibited antitumor effects in xenografts inoculated with several human cancer cell lines when treated alone or with IFN. Among the derivatives, ISIR-042 was the most effective in inhibition of the tumor growth in xenografts. This compound preferentially induced growth inhibition and apoptosis of some cancer cells under hypoxic conditions. The hypoxia-targeting effects were not observed in the parental compound (cotylenin A) or other fusicoccin derivatives, suggesting that ISIR-042 is the novel antitumor agent with a unique mode of action. Pancreatic cancer is highly aggressive and refractory to existing therapies.
Pancreatic ductal adenocarcinomas contain tumor cells that are at low oxygen tensions (hypoxic), and tumor hypoxia is known to induce the expression of a variety of genes associated with tumor progression and aggressiveness. Novel therapeutic strategies can be devised to improve treatment. Therefore, we examined the antitumor effect of ISIR-042 with IFN in xenografts inoculated with human pancreatic cancer MiaPaCa-2 cells. The combined treatment significantly inhibited the tumor growth in xenografts without appreciable adverse effects, suggesting that combined treatment with ISIR-042 and IFN may have therapeutic value in treating pancreatic cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B156.
Abstract B157: Generation of “Natural Unnatural Product Library” and identification of small molecule XIAP inhibitors
Authors: Kawamura Tatsuro , Otaka Hitomi , Tashiro Etsu , Imoto Masaya 
Published: June 2012

Abstract
For the drug discovery, generation of chemical libraries has been required. Natural products are utilized for drug-lead discovery because of their structural diversity, and indeed, many natural products and their derivatives have been used as approved drugs historically. Here, we generated a natural product-derived chemical library named “Natural Unnatural Product (NUP) library”. To generate NUP library, chemical reagent was added in microbial broth extracts, and many microbial metabolites in the broths extracts were converted into their derivatives. After this reaction, newly synthesized components, NUPs, in the reaction mixtures were detected and isolated by LC-MS system to give a NUP library. On the other hand, X-linked inhibitor of apoptosis (XIAP) is an endogenous direct inhibitor of caspase-3, -7 and -9. Overexpression of XIAP is often seen in several types of human tumor, and it contributes tumor malignancy by inhibiting apoptosis. Therefore, XIAP is considered as a promising molecular target for cancer therapies, and we searched for the compound that inhibited anti-caspase activity of XIAP from our NUP library. As results, three compounds, C38OX3, C38OX6 and C38OX8, were found to restore XIAP-suppressed enzymatic activity of caspase-3 in a dose dependent manner in vitro. Next, we examined whether these XIAP inhibitors could accelerate apoptosis induced with death ligands or anticancer drugs. C38OX6 overcame XIAP-mediated resistance of HeLa cells against TRAIL and anticancer drugs. These findings suggest that our NUPs contain potential drug-leads for the development of new class of anticancer drugs such as XIAP inhibitors. In conclusion, we generated NUP library as source for drug-lead of anticancer drugs and identified three NUPs as XIAP inhibitors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B157.
Abstract B158: Innovative design for a phase 1 trial with intra-patient dose escalation: The Crotoxin study
Authors: Medioni Jacques , Trinquart Ludovic , Benlhassan-Chahour Kadija , Ohnona Jessica , Reid Paul , Chatellier Gilles , Oudard Stephane , Bray Dorothy 
Published: June 2012

Abstract
Introduction: Crotoxin is a neurotoxic phospholipase isolated from the venom of a rattlesnake. It has proven to have significant and broad acting anti-tumor activity: in previous phase 1 clinical studies, comprising 60 enrolled patients, clinical benefit was observed in 26 patients (43%). Traditional designs were used, the dose-limiting toxicity (DLT) being neuromuscular toxicity. Preclinical animal data suggests that, by using a dose escalation protocol, the administration of very high doses can be achieved without adverse toxicity because the host becomes tolerant to the neurotoxic effects. Much higher doses could be administered without adverse toxicity, but maximizing treatment efficacy. Our aim was to develop an innovative design for a Phase 1 study with intra patient dose escalation to induce subject tolerance.
Methods: A new open label intra-patient dose escalation method was planned. The primary objective is to determine the Maximum Tolerated Dose (MTD). DLT was defined as the occurrence of two consecutive grade 2 or 3 neuromuscular events not recovered within 24 hours at a given dose. MTD was defined as the dose where no DLT was observed among three consecutive patients, or no more than one DLT among six patients. Dosing schedule, duration and highest dose was based on the previous clinical experience. Eight possible crotoxin doses will be administered using intrapatient dose escalation, starting from 0.04 and up to 0.32 mg/m2. Each dose will be initially administered for 5 consecutive days with 2 days break during week-end.
Results: Determination of MTD will be as follow: the first patient will be treated up to 0.32 mg/m2 or a lower tolerated dose. This dose is called the ith target ceiling dose (TCDi). Next two patients will be treated up to the TCDi.
→If no DLT is encountered, then TCDi is MTD. → If two or more DLT are encountered, then include 3 new patients up to the next lower dose (TCDi-1) and proceed similarly. →If one DLT encountered, then add 3 more patients up to TCDi. →If no DLT is encountered among those 3 new patients, then TCDi is MTD. →If one or more DLT is encountered among those 3 new patients, then include 3 new patients up to TCDi-1 and proceed similarly.
Conclusion: host could become tolerant with some products using dose escalation and avoid toxicity. This innovative design is expected to allow fast and simple determination of MTD in these situations. The study protocol was approved by our local ethics committee and will start at early November.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B158.