bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lovastatin enhances the antiproliferative effect of trastuzumab in HER2 over expressing breast cancer cells
Authors: Halaweh O. M. , Lobocki C. , Dumasia L. , Drelichman A. 
Published: March 2020

2546 Background: Trastuzumab, a recombinant humanized anti-HER2 monoclonal antibody, has been found to have potent antiproliferative effects in HER2 overexpressing human breast tumors. Lovastatin, an HMG-CoA reductase inhibitor suppresses growth, and induces apoptosis in breast cancer cells. Both agents induce a G0/G1 arrest of cell cycle progression. The purpose of this study was to evaluate the antiproliferative effect of the novel combination of lovastatin and trastuzumab in human breast cancer cell lines. Methods: Increasing doses of lovastatin (0.16-40 μM) and trastuzumab (0.039-1 μg/ml) were tested alone and in combination. Three breast carcinoma cell lines were studied: two HER2 overexpressing lines (BT474 and SKBR3) and one cell line that expresses low levels of the receptor (MCF7). Inhibition of growth was assessed after 7 days of treatment by the MTT colorimetric assay, while apoptosis was detected using an in situ DNA Fragmentation Detection kit. Results: A dose-dependent growth inhibition was demonstrated in all three cell lines tested with lovastatin, while trastuzumab was only effective in the HER2 overexpressing cells. Trastuzumab (0.06 μg/ml) inhibited cell growth by 29.3% and 40.1%, while lovastatin (2.5 μM) caused an inhibition of 19.1% and 43% in the BT474 and SKBR3 cell lines, respectively. The combination of trastuzumab and lovastatin, at these doses, significantly inhibited growth in BT474 and SKBR3 cells by 45.4% and 68.9% (P < 0.001, oneway ANOVA) compared to either agent alone. Conclusions: Lovastatin plus trastuzumab treatment led to increased growth inhibition in HER2 positive breast cancer cell lines. Further studies in an animal model are warranted. This combination may also have important clinical therapeutic implications. No significant financial relationships to disclose.
Saccharomyces cerevisiae as delivery vehicle for a NY-ESO-1 protein vaccine
Authors: Renner C. , Held G. , Neumann F. , Kleber S. , Thiel M. , Karbach J. , Jäger E. , Strahl S. , Wadle A. 
Published: March 2020

2578 Background: Vaccine strategies that target or activate dendritic cells in order to elicit potent cellular immunity are currently the subject of intense research. Here we report that genetically engineered yeast expressing the full-length tumor associated antigen NY-ESO-1 are a versatile host for protein production eliciting MHC class I and II T-cell responses. Methods: The pYD1 yeast display vector was chosen for full length NY-Eso-1 protein (pNY-ESO-1) expression. NY-ESO-1 and SSX-2 (as control) protein were affinity purified on. IFN-g ELISPOT assays were performed in triplicates on nitrocellulose-lined 96-well plates. MHC class I cross-presentation of peptide epitopes was demonstrated by blocking T-cell responses against DCs. For this purpose, antigen or peptide pulsed DCs were labeled with different doses (100, 10, 1 μg/ml) of antibodies specific for HLA-A2/peptide complexes (HLA-A2/ NY-Eso-1157–165; 3M4E5) or an irrelevant antibody (specific for HLA-A2/IMP58–66) as control. Results: Highest level of NY-ESO-1 expression was detected on the cell wall of wt EBY100 strain with lower expression levels on PMT deficient strains PMT-2 and PMT-4. After protein feeding of immature DCs, NY-ESO-1 157–165 peptide cross-presentation was detected by 3M4E5 and an antigen-specific CD8+ T cell clone. There was a strong positive correlation between the amount of Aga2p-NY-ESO-1 protein (0–15μg/ml) and peptide presentation. Specific T-cell recognition of NY-Eso-1 157–165/HLA-A2 complexes was validated by blocking experiments with Fab 3M4E5. Pre-incubation of protein fed DCs with the antibody at different concentrations (0–100 μg/ml) resulted in a significant reduction (p< 0.05) of spot numbers. Efficient presentation and T-cell recognition of epitope 157–165 was only adequately detectable when protein produced by EBY100 wt yeast strain was used (p < 0.05). MHC class II presentation was studied in an autologous setting using a T-cell line recognising the NY-ESO-1 157–170 in HLA-DP4 context revealing that NY-ESO-1 protein produced in yeast was efficiently taken up and presented. Conclusions: Together, these data add further evidence that yeast expressing recombinant proteins can be used for vaccine purposes and that antigen uptake in APC depends on glycoslation of yeast expressed antigens. No significant financial relationships to disclose.
Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer—NCIC IND 160
Authors: Oza A. M. , Elit L. , Biagi J. , Chapman W. , Tsao M. , Hedley D. , Hansen C. , Dancey J. , Eisenhauer E. 
Published: March 2020

3003 Background: PTEN is a tumor suppressor gene and mutations in PTEN causing loss of protein expression/function may play a significant role in the pathogenesis of EC. Loss of PTEN protein expression has been reported in 26–80% of EC and leads to deregulated PI3K/Akt/mTOR signalling which may give neoplastic cells a survival advantage by enhancing angiogenesis, protein translation and cell cycle progression. Inhibition of mTOR, a protein kinase downstream of the PI3K/Akt pathway and target of rapamycins, inhibits proliferation of EC cell lines and formation of EC in PTEN−/+ heterozygous mice. We have evaluated temsirolimus (T) an ester derivative of rapamycin that inhibits mTOR given the frequent loss of PTEN in human EC. Methods: A two stage, phase II study has been conducted to evaluate single agent activity of T in women with recurrent or metastatic EC (chemotherapy naïve, upto 1 prior line of hormonal therapy). Treatment was 25mg i.v. weekly. One cycle is defined as 4 weeks of therapy. Thirty one patients (pts) have been registered; 23 are evaluable for toxicity and 19 for response. Results: Preliminary results have demonstrated encouraging activity and the trial fulfilled predefined criteria for activity. Of 19 pts evaluable for response, 5 have had a confirmed partial response (PR) (26%) and 12 have stable disease (SD) as best response (63%). Two pts had progressive disease (PD) (11%). PTEN, phosphorylated (p) mTOR and p-S6 protein (immunohistochemistry) results are available on 9 pts to date. The preliminary results indicate that responses and stable disease are seen in pts irrespective of PTEN status. Loss of p-mTOR was evident in tumor cells from all pts (range 75–99% loss) and did not correlate with response. Phosphorylated S6 was low in tumor cells in the one pt who had PD (5%), and levels were higher in pts with PR and SD (mean and median 30%). Conclusions: We conclude that Temsirolimus has encouraging single agent activity for in recurrent and metastatic EC, and the findings indicate this is irrespective of PTEN status. We are currently evaluating activity of T in pts previously treated with chemotherapy and molecular correlates in additional specimens. No significant financial relationships to disclose.
A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457 in cancer patients
Authors: Rubin E. H. , Shapiro G. I. , Stein M. N. , Watson P. , Bergstrom D. , Xiao A. , Clark J. B. , Freedman S. J. , Eder J. P. 
Published: March 2020

3009 Background: The AKs are essential for mitotic progression, spindle formation, centrosome maturation, chromosomal segregation, and cytokinesis. Elevated expression occurs frequently in tumors. MK-0457 (VX-680) is a potent AK inhibitor, with Ki values of 0.66, 18 and 4.6 nM for AKs A, B and C, respectively. MK-0457 inhibits proliferation of transformed cells in vitro (IC50’s 15–113 nM), and induces colon and pancreatic cancer xenograft regressions. Methods: After IRB approval, consenting patients (pts) with refractory solid tumors (median 3 prior regimens, range 2–6) and adequate hematologic and organ function were enrolled using an accelerated dose escalation scheme with 1–2 pts/dose level until ≥ grade 2 toxicity, followed by 3–6 pts/level. MK-0457 was administered by continuous 5-day intravenous infusion every 28 days. Dose-limiting toxicity (DLT) was grade 3 non-hematologic or grade 4 hematologic toxicity ≥ 5 days, or grade 4 febrile neutropenia (FN) during cycle 1. PKs were collected pre-dose through 168 h and analyzed for MK-0457 and metabolites by HPLC/mass spec. Steady state volume of distribution (Vdss), clearance (CL), maximal concentration (Cmax) and terminal half-life (t1/2) were determined by WinNonLin. Results: 16 pts received MK-0457 dosed at 0.5, 1, 2, 4, 8, and 12 mg/m2/h. Median number of cycles was 2 (range 1–6). DLT was asymptomatic neutropenia ≥ 5 days at 12 mg/m2/h. At 8 mg/m2/h, 1 pt experienced FN in cycle 2; a second developed a grade 2 allergic reaction. Three pts achieved stable disease as best response, and two of them completed 6 cycles. Plasma concentrations reached steady state rapidly (i.e., within 24 h) and declined biexponentially after the end of infusion; after a rapid initial decay, a slower decaying terminal phase demonstrated a t1/2 ∼15 h. PK parameters include Vdss = 237 ± 107 (SD) L/m2 and CL = 517 ± 141 ml/min/m2. At 8 mg/m2/h, Cmax was ∼650 nM. Conclusion: MK-0457 is generally well tolerated and achieves plasma levels similar to those causing regressions in xenografts. CL is high and exposures achieved are roughly dose proportional. Because 8 mg/m2/h was well tolerated in heavily pre-treated pts, escalation to 10 mg/m2/h is underway. Baseline tumor samples will be assessed for predictive biomarkers at the recommended phase II dose. [Table: see text]
Phase I evaluation of AZD2171, a highly potent, selective VEGFR signaling inhibitor, in combination with gefitinib, in patients with advanced tumors
Authors: Van Cruijsen H. , Voest E. E. , Van Herpen C. M. , Hoekman K. , Witteveen P. O. , Tjin-A-ton M. L. , Punt C. J. , Puchalski T. , Milenkova T. , Giaccone G. 
Published: March 2020

3017 Background: AZD2171 is an oral, highly potent, vascular endothelial growth factor (VEGF) signaling inhibitor. This Phase I trial is evaluating the safety, tolerability, pharmacokinetics (PK) and efficacy of AZD2171, in combination with gefitinib (IRESSA), an inhibitor of EGF receptor tyrosine kinase. Methods: Patients with advanced solid tumors refractory to standard therapies received once-daily, oral AZD2171 (20, 25, 30 or 45 mg) and gefitinib 250 (Part A1) or 500 mg (Part B1) until dose-limiting toxicity was observed. The potential PK interaction of AZD2171 30 mg with gefitinib 250 mg was studied in an expanded cohort (Part A2). Part B2 follows the design of Part A2, with a gefitinib dose of 500 mg. Results: As of September 1, 2005, 70 patients (22–78 years) have received treatment ( Table ). Overall, the most frequently reported adverse events (AEs) were diarrhea, anorexia, fatigue and hypertension (91%, 64%, 51% and 51% of patients; respectively), with evidence of an AZD2171-related dose response for hypertension (reported in 36%, 75%, 47% and 75% of patients at AZD2171 20, 25, 30 and 45 mg; respectively). These were also the most commonly reported CTC grade ≥3 AEs, occurring in <13% of patients, in addition to increases in alanine aminotransferase (7%) and aspartate aminotransferase (4%). The steady-state PK parameters for AZD2171 (30 mg) and gefitinib (250 mg) are comparable with those seen previously with either agent alone. In total, 28 patients had a best RECIST response of stable disease (22 patients were non-evaluable). A patient with mesothelioma (45 mg AZD2171, Part A1) and a patient with renal cancer (20 mg AZD2171, Part B1) had confirmed partial responses. The second patient underwent surgery and is currently disease-free. Conclusions: No unexpected toxicities are associated with AZD2171 (20–45 mg) in combination with gefitinib (250 or 500 mg) and the preliminary response data are encouraging. [Table: see text] [Table: see text]
HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors
Authors: Wong K. K. , Fracasso P. M. , Bukowski R. M. , Munster P. N. , Lynch T. , Abbas R. , Quinn S. E. , Zacharchuk C. , Burris H. 
Published: March 2020

3018 Background: HKI-272 is a potent, low molecular weight, orally active, irreversible pan erbB receptor tyrosine kinase inhibitor. It inhibits the growth of tumor cells that express erbB-1 (epidermal growth factor receptor, EGFR) and erbB-2 (HER-2) in culture and xenografts. HKI-272 also inhibits the growth of cultured cells that contain sensitizing and resistance-associated EGFR mutations (Kwak et al, Proc Natl Acad Sci USA 102:7665–70, 2005). We are conducting a phase 1 study in patients (pts) with advanced-stage tumors that express EGFR or HER-2 to assess HKI-272 for tolerability, safety, pharmacokinetics, and preliminary antitumor activity. Methods: Pts (3–6/cohort) received 40, 80, 120, 180, 240, 320, or 400 mg HKI-272 orally once on day 1 and then once daily beginning on day 8. Timed blood samples were collected on days 1 and 21 for pharmacokinetic analysis. Results: Enrollment of 73 pts is complete. Preliminary data for 51 pts as of 28 Nov 2005 are presented. Patients were a median 60 years and 26% men. The most frequently occurring tumor types at primary diagnosis were breast (23 pts), non-small cell lung (9), and colorectal, ovarian, and renal (3 pts each). Dose escalation ended when 2 pts who received 400 mg HKI-272/day had drug-related dose-limiting toxicity of grade 3 diarrhea. Thus, the maximum tolerated dose (MTD) was 320 mg HKI-272/day. HKI-272-related adverse events (AEs), any grade, that occurred in ≥10% of pts were diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), vomiting (29%), chills (12%), and rash (10%). Grade 3 related AEs that occurred in >1 pt were diarrhea (11) and asthenia (4). HKI-272 Cmax and AUC increased in a dose-dependent manner. At steady state at the MTD, mean values were Cmax: 112±58 ng/mL, AUC: 1618±930 ng.h/mL, t1/2: 15±2.5 h. Day 1 and 21 AUC values were comparable. Tumor assessments (modified RECIST criteria) were made at baseline and at the end of alternate cycles (28 days/cycle). Two breast cancer pts had confirmed partial responses (PRs) and 2 had unconfirmed PRs. Conclusions: When HKI-272 was administered on a continuous, once-daily, oral treatment schedule, the MTD was 320 mg/day, with diarrhea as the most frequently occurring related AE. HKI-272 has antitumor activity in HER-2-positive breast cancer. [Table: see text]
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of a small molecule inhibitor of Poly ADP-Ribose Polymerase (PARP), KU-0059436 (Ku) in patients (p) with advanced tumours
Authors: Fong P. C. , Spicer J. , Reade S. , Reid A. , Vidal L. , Schellens J. H. , Tutt A. , Harris P. A. , Kaye S. , De Bono J. S. 
Published: March 2020

3022 Background: PARP is a DNA strand break and base damage repair enzyme. Ku inhibits PARP-1 and 2 with a mean IC50 of 2nM. Inhibition of PARP leads to defective DNA repair and induces selective cytotoxicity in cells with defective homologous recombination repair through, for example, loss of BRCA 1/2 function (Farmer et al, Nature 2005 Apr 14;434(7035):917–21). This is a first in man Phase I trial of Ku. PD studies included functional evaluation of PARP-1 activity in surrogate and tumor tissue. Methods: Ku was administered once a day for 14 of every 21 days to p with advanced solid tumors refractory to standard treatment. Cohorts of 3–6 p were treated, with a starting dose of 10 mg/day. The dose was doubled in the absence of drug related grade 2 CTC-AE toxicity. Drug related toxicity in cancer patients known to carry a BRCA mutation is being compared to toxicity in other patients. Results: To date 12 p (6 male; median age 55y, range 25–73) with solid tumours have received 25 courses (range 1–8), with 1 p being a known BRCA1 mutation carrier (dose level 40mg). Dose levels evaluated to date include 10, 20, 40, and 80mg per day. Minimal toxicity has been observed to date, with only intermittent grade 1 nausea being reported. PK data to date, up to 40mg per day, supports dose proportionality with a mean elimination half-life of 6.91 hours (Range: 5.3–9.5), a mean clearance of 4.1 L/h (Range: 1.3–9.4) and a mean volume of distribution of 39.8 L (Range: 16.3–86.9). PD studies indicate inhibition of PARP functional activity in peripheral blood mononuclear cells with increasing inhibition observed with increasing dose of Ku. Initial studies in tumor biopsies performed pre-treatment and on day 8 revealed PARP inhibition of >50% at 40 mg/day. A p with metastatic soft tissue sarcoma and progressing disease pretreatment achieved stable disease for 24 weeks. Conclusions: Dose escalation continues with more BRCA carriers planned. PARP inhibition in both surrogate and tumor tissue is achievable with minimal toxicity in cancer patients, and has not resulted in any short term toxicity in a BRCA mutation carrier. [Table: see text]
Phase I, safety, pharmacokinetic and biomarker study of BAY 57–9352, an oral VEGFR-2 inhibitor, in a continuous schedule in patients with advanced solid tumors
Authors: Gelderblom H. , Verweij J. , Steeghs N. , Van Erkel A. , Van Doorn L. , Ouwerkerk J. , Rajagopalan P. , Matthys A. , Voliotis D. , Eskens F. 
Published: March 2020

3040 Background: BAY 57–9352 is a potent competitive inhibitor of the VEGFR-2 (IC50: 6 nM), VEGFR-3 (IC50: 4 nM), PDGFR-β and c-KIT tyrosine kinases. BAY 57–9352 showed tumor efficacy in colon, breast, pancreatic and NSCLC models. Methods: Patients with advanced solid tumors received oral BAY 57–9352 on a continuous basis, in escalating doses. One cycle was defined as 21 days of treatment. Extensive PK and PD (dynamic contrast-enhanced MRI [DCE-MRI]) evaluations were performed. Plasma biomarkers (e.g. VEGF)were also evaluated. Results: Forty patients (median 54 yrs) were enrolled at seven dose levels from 20 mg solution once daily to1500 mg twice daily (bid; 150 mg tablets) for a total of 169 cycles (range 1–17). The most frequent drug-related adverse events were nausea, hypertension, headache, vomiting, hoarseness, rash, dry skin and anorexia. One patient treated at 600 mg bid had a dose-limiting toxicity defined by an increase from grade 2 to 3 hypertension, despite the addition of an ACE-inhibitor and Ca-antagonist on day 8 of cycle 2. Another patient at that same dose level and also on day 8 cycle 2, had grade 3 AST/ALT increase, however this was not assessed as dose-limiting. Both patients continued treatment after dose reductions. Treatment was well tolerated, even at the highest dose levels. One patient with a hemangio-endothelioma (600 mg bid) had a clinical response and one desmoid tumor patient (900 mg bid) had a 53% reduction in tumor volume. BAY 57–9352 AUC increased dose proportionally up to 900 mg bid. The target AUC, based on animal models (5 mg × h/L) was reached in all patients at 900 mg bid. Dose levels exceeding 900 mg bid had similar plasma VEGF biomarker levels. Conclusions: BAY 57–9352 was well tolerated in doses up to 1500 mg bid. Based on safety, PK, PD and biomarker assessments, the recommended dose level is 900 mg bid. A 300 mg tablet is being tested for patient convenience. Combination chemotherapy studies have been started. [Table: see text]
A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM)
Authors: Wakelee H. A. , Adjei A. A. , Halsey J. , Lensing J. L. , Dugay J. D. , Hanson L. J. , Reid J. M. , Piens J. R. , Sikic B. I. 
Published: March 2020

3044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumor cell growth, angiogenesis, and metastasis, including EGFR (erbB1), erbB2, VEGFR2/KDR, and EphB4. Methods: Patients (pts) with ASM were enrolled in successive cohorts to receive XL647 orally as a single dose on day 1 with PK sampling, followed by 5 continuous daily doses starting on day 4 with additional PK sampling. Pts then continued to receive XL647 for 5 consecutive days, followed by a break, with cycles repeating every 14 days. Tumor imaging was conducted at baseline, after the first 3 or 4 cycles, and then after every 4 cycles. Pts were allowed to stay on-study in the absence of unacceptable toxicity until evidence of disease progression. Results: A total of 37 pts have been treated across 9 dose levels to date: 0.06, 0.12, 0.19, 0.28, 0.39, 0.78, 1.56, 3.12, 4.68, and 7.0 mg/kg. One pt at 3.12 mg/kg had a dose limiting toxicity (DLT) of asymptomatic QTc prolongation on electrocardiogram, resulting in expansion of that cohort. The first two pts who received 7.0 mg/kg experienced DLTs of grade 3 diarrhea, requiring dose reduction. Both pts from the 7.0 mg/kg cohort tolerated 4.68 mg/kg well. Expansion of the 4.68 mg/kg cohort to 6 pts occurred without further DLTs and this is considered the maximum tolerated dose (MTD). One serious adverse event, grade 4 pulmonary embolism, was considered possibly related to study treatment in a pt dosed at 0.28 mg/kg. PK analysis indicates that XL647 shows approximately dose-proportional exposure, a mean time to maximal concentration (tmax) of 6–9 hours and an elimination half-life of 50–70 hours. To date, 1 pt (non-small cell lung cancer [NSCLC]) from cohort 1 had a partial response and 7 others (NSCLC [2], chordoma [2], adenoid cystic carcinoma, adrenocortical carcinoma, colorectal) have had prolonged stable disease (>3 months). Conclusions: XL647 has been well tolerated. An MTD of 4.68 mg/kg oral dosing for 5 consecutive days every 14 days has been established. Exploration of additional dosing schedules is ongoing, including continuous daily dosing. [Table: see text]
Response to neoadjuvant chemotherapy as measured by PET predicts outcome after liver resection for colorectal metastases
Authors: Akhurst T. J. , Gonen M. , Tuorto S. , Schwartz L. , Brody L. , Larson S. M. , Fong Y. 
Published: March 2020

3056 Background: Patients with hepatic colorectal metastases are often treated with neoadjuvant chemotherapy prior to liver resection. FDG PET is a standard imaging modality for such patients. We have shown the amount of FDG uptake in liver metastases is reduced by recent chemotherapy (chemo) administration and this is associated with a reduction in FDG uptake mediated by a reduction in hexokinase activity. We sought to determine if the amount of FDG uptake in the hepatic colorectal metastasis post chemo correlates with survival and to compare the prognostic significance of this single biologic scan to standard clinical predictors of outcome. Methods: A group of 149 patients enrolled in a prospective clinical trial examining the efficacy of FDG PET imaging in patients undergoing hepatic resection of colorectal cancer metastases to the liver formed the dataset. The maximal SUV within the liver was recorded for each patient, and the median of those maximums was determined across the patient group. Patients were then stratified by the median SUV, by the presence or absence of any chemo within 6 months of PET and by the clinical risk score (CRS) (a standard score for prognosis based on five clinical parameter (nodal status of primary, disease-free interval before liver metastases, size of largest liver tumor, number of tumors, and CEA). Multivariate analysis (MVA) and hazard ratios of death (HRD) were assessed. Results: The median of maximal SUVs was 7.9. In MVA in the patients without recent chemo, the CRS≥3 was an excellent predictor of survival (HRD=2.53; p=0.008), while SUV>8 was not (HRD=1.02; p=0.96). Conversely, in patients who had chemo within 6 months, SUV>8 (HRD 3.34; p=0.03) was a much superior predictor of outcome than CRS≥3 (HRD=1.25; p=0.57). Conclusions: In those patients without recent chemo CRS is the best predictor of survival confirming the utility of this scoring system, In those patients who had had chemo within 6 months of PET prior to surgery PET SUV was the best predictor of survival. No significant financial relationships to disclose.