bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human phase I trial of a novel epothilone, KOS-1584
Authors: Villalona-Calero M. , Goel S. , Schaaf L. , McCracken B. , Desai K. , Cropp G. , Zhou Y. , Johnson R. G. , Hannah A. L. , Mani S. 
Published: March 2020

2003 Background: KOS-1584 (9,10-didehydroepothilone D) was discovered as part of a screening program to develop a new generation of epothilones with higher potency and an improved pharmacologic/pharmacokinetic (PK) profile. Epothilones stabilize microtubule polymerization, inducing rapid G2/M arrest and apoptosis. Antitumor activity of KOS-1584 (Chou et al 2003) is approximately 3–12 fold more potent when compared to the structurally related Epothilone D. KOS-1584 demonstrates enhanced tumor tissue penetration and reduced exposure to selected tissues (including CNS). We report the results of the initial dose-escalation trial in which KOS-1584 was administered to pts with advanced solid malignancies. Methods: Define the MTD, toxicity profile and PK of KOS-1584 when administered via 3-hour infusion every 3 weeks. PK was determined after the 1st and 2nd infusion. Pharmacodynamics were assessed by serial sampling of PBMCs for microtubule bundle formation. Results: 27 pts (17 F; median age 60; median ECOG PS 1; median prior regimens 3, range 0–7) enrolled in 8 dose levels (between 0.8 - 11.3 mg/m2). To date, no Cycle 1 DLT has been seen. Toxicities (n=24) did not show obvious dose dependency; common toxicity (Grade 1–2) included gastrointestinal (diarrhea, constipation, nausea), fatigue, and ↑AST. Drug-related Grade 3 toxicity: constipation, fatigue and ↑AST (1 each). Drug-related neurotoxicity was not notable. PK/parent (n=25): t½ 17.7 ± 4.6h, Vz 741±330 L and CL 30.2± 16.5 L/h. At 8.5 mg/m2 Cmax 78 ± 29 ng/mL; AUCtot 631 ± 337 ng*h/mL. Cmax and AUCtot increased linearly with dose over the range tested. Vz is ∼5-fold and t½ 2-fold higher than that of Epothilone D. Dose dependent increases in microtubule bundle formation were observed (8.5 mg/m2: 40–50% at end of infusion, compared to 60–65% for ixabepilone and 50–60% for Epothilone D using the same assay at their phase 2 dose). A sigmoidal Emax model described the relationship between plasma concentration and microtubule bundle formation. Activity consisted of 4 pts with extended stable disease (6 cycles leiomyosarcoma and ovarian cancer; 5 cycles colon cancer; a 2nd patient with ovarian cancer is active at 5 cycles). Of these, 3 had document progressive disease prior to study. Conclusions: Accrual is continuing in order to define the optimal dose on the 3-week regimen. [Table: see text]
Biological characteristics in triple negative high risk breast cancer and their clinical implications
Authors: Herr A. , Gluz O. , Ting E. , Mohrmann S. , Werner F. , Schuett G. , Schmutzler R. , Poremba C. , Nitz U. , Danebrock R. 
Published: March 2020

20032 Background: Hormone receptor and Her2neu negative breast cancer (triple negative, TN) presents an aggressive biological subtype with decreased survival. Basal-like BC identified by gene expression arrays (Perou CM, et al. Nature 2000) may be associated with TN breast cancer. Several studies defined the origin of TN or BBC breast cancer in a progenitor epithelial cell that is undifferentiated. Other studies investigated the association of TN with EGFR expression or BRCA1 mutations. The aim of our study was to analyze the expression of stem cell or basal markers in TN high risk breast cancer. Methods: We examined 236 patients from central tumour bank from high risk breast cancer patients (>9 positive LN), who were randomized to the WSG AM-01 trial (phase III tandem HDC versus DD CT). The following markers were profiled by IHC in TMA for all patients: ER, PR, Her2neu, MIB-1, EGFR, p53, Ck 5/6, CK17, c-kit, p63, Vimentin, ABCA3, and BCRP. Their correlation with survival was studied. Results: 65 patients (30%) of 218 patients assessable for hormone receptor and Her2neu staining, were identified as TN, surprisingly not indicating any higher incidence of TN tumors in this selected high risk collective, when compared to other more heterogeneous populations. This phenotype was significantly more frequent in premenopausal women, and was significantly associated with G3, MIB1 and EGFR, CK5/6 and 17, c-kit, vimentin, p53 and BCRP expression. No association with p63 and ABCA3 was found. Poor grading, MIB1+, CK5/6 and 17, c-kit, vimentin and BCRP+ strongly correlated with relapse. Patients with TN tumors had significantly worse overall survival (p = 0.002) in comparison to the remaining group. Conclusions: The triple negative BC-type is frequent in patients with multiple positive lymph nodes and has a poor prognosis. Its association with age and basal and progenitor cell molecular markers suggests correlation with BRCA1 mutations as a potential marker for resistance to alkylating agents (Sorlie, PNAS 2003). Modern experimental (chemo)-therapy designs in this subgroup should take into account the higher incidence of EGFR and basal stem cell marker expression, p53 mutations, the poor differentiation, the expression of chemoresistance markers and the high proliferative activity. No significant financial relationships to disclose.
Changes in the serum proteome associated with docetaxel chemotherapy
Authors: James N. D. , Ward D. , Martin A. , Barton D. , Dunn J. , Porfiri E. 
Published: March 2020

20036 Background: Trapeze is a randomised phase II clinical study involving Docetaxel chemotherapy ± Zoledronic Acid and strontium 89 for the treatment of hormone refractory prostate cancer. A proteomic sub-study is designed to identify novel biomarkers to monitor treatment. Methods: Surface-Ehanced Laser Desorption/Ionisation (SELDI) time-of-flight mass spectrometry combines retentate chromatography and mass spectrometry in a high-throughput platform for proteomic profiling of biological samples. A biofluid such as serum is applied to a ‘proteinchip array’, certain proteins will bind and non-binding species are removed by washing. The bound proteins are vaporised using a laser and detected by mass spectrometry. The peak intensities in the resulting “profiles” can be compared between patient cohorts to identify potential biomarkers. Results: The serum from 6 patients was analysed both before and after 2 cycles of chemotherapy using copper loaded IMAC30 proteinchip arrays. The intensities of 103 peaks were compared between pre- and post-treatment and 11 were found to differ significantly (p < 0.01, paired t-test). Hierarchical clustering was able to distinguish pre- and post-treatment sera. Initial results show these changes to continue in sequential samples taken from the same patient. Conclusions: Chemotherapy produces significant and detectable changes in the serum proteome. This is a significant difference from a recent lung cancer study carried out in our Institution (submitted separately), which showed no detectable changes in pre and post operative lung cancer patients once acute post-operative changes had settled. Work is currently underway to identify the discriminatory proteins in the SELDI profiles. The current Trapeze study accrual rate of approximately 10 patients per month will mean that 80 patients will be included in this treatment cohort by May 2006 and subject to initial findings, individual proteins of interest will be identified and followed throughout the phase II and subsequent phase III to determine if they can be used to assess patients individual response to chemotherapy and provide a biomarker to monitor prostate cancer therapy. No significant financial relationships to disclose.
Capsaicin induces G1/S cell cycle arrest leading to apoptosis of multiple myeloma cells through suppression of STAT3 activation and STAT3-regulated gene products
Authors: Bhutani M. , Pathak A. K. , Sethi G. , Aggarwal B. B. 
Published: March 2020

20039 Background: Agents that can block activated STAT3, a central player for proliferation, cell survival and chemoresistance, have a potential as therapeutic agents for the treatment of Multiple Myeloma (MM). Capsaicin, a spicy component of hot pepper, is a homovanillic acid derivative that preferentially induces certain cancer cells to undergo apoptosis. We have previously shown that Capsaicin blocked activation of NF-kappa B in human myeloid ML-1a cells. In this study we evaluated the effect of Capsaicin on STAT3 in MM cells. Methods: We used U266, a well-characterized MM cell line, which constitutively expresses activated STAT3. MM cells treated with Capsaicin were subjected to western blot analysis with specific antibodies to STAT3, tyrosyl phosphorylated STAT3 and STAT5. The effect of Capsaicin on nuclear-cytoplasmic compartment of STAT3 was studied by immunocytochemistry. The antiproliferative effect of Capsaicin was determined by the MTT assay and the effect on the cell cycle was determined by flowcytometry. Apoptosis of cells was measured using the Live and Dead assay. To determine the downstream targets like antiapoptotic proteins (Bcl-xL, Bcl-2, and Survivin), and cell cycle-regulators (cyclin D1) immunoblot analysis of Capsaicin treated cells was performed. Results: Capsaicin suppressed the constitutive activation of STAT3 in human MM cells in a dose- and time-dependent manner, prior to cell death. Capsaicin’s effect on STAT3 was specific as STAT5 was unaffected. Capsaicin depleted nuclear pool of STAT3 in U266 cells. Abrogation of constitutive STAT3 phosphorylation in MM cells induced G1 cell cycle arrest. The antiapoptotic proteins BCl-xl, suvivin, cyclin D1, and Bcl-2, which are encoded in target genes of STAT3, were down regulated by Capsaicin, followed by induction of apoptosis through activation of caspase-3. We further demonstrated that low dose combined Capsaicin and thalidomide/ bortezomib treatment triggered synergistic cytotoxicity. Conclusions: These findings suggest that the antitumor activity of Capsaicin is at least partially due to inhibition of STAT3 pathway and provide a basis for potential application of Capsaicin for treatment of relapsed and refractory MM. No significant financial relationships to disclose.
High expression of tenascin-C extra domains, markers of angiogenesis, in human lung cancer
Authors: Hillinger S. , Silacci M. , Arni S. , Brack S. , Weder W. , Neri D. 
Published: March 2020

20051 Background: Tumor-associated extracellular matrix molecules are isoforms of proteins with a wide distribution in normal adult tissues, such as fibronectin and tenascin. Large Tenascin-C isoforms are present in almost all normal adult tissues but are upregulated in fetal, regenerating, and neoplastic tissues. In this study we investigated the expression of three tenascin isoforms in tumor tissue samples from lung cancer patients to evaluate the diagnostic and therapeutic value for clinical applications. Methods: In total, 35 corresponding tissue samples (tumor and normal lung tissue of the same patient) have been analyzed by immunohistochemistry using three different human monoclonal antibodies to domains A1 (F16), C (G11) and D (P12). All tumor specimens have been non-small cell lung cancer types. Results: Three isoforms G11, F16 and P12 have exhibited a very intense staining of all types of lung cancer. Almost all samples of squamous cell carcinomas, adenocarcinomas as well as large cell carcinomas have been positively stained. In contrast, none of the corresponding normal lung tissue specimens showed an expression of either tenascin domains. Conclusions: The results show that tenascin-C isoforms are highly expressed around the neovasculature and in the stroma of the majority of non-small cell lung cancers but is undetectable in the normal lung tissue. Therefore these isoforms could represent valuable candidates for the development of antibody based biopharmaceuticals for the treatment of lung cancer. No significant financial relationships to disclose.
Active epidermal growth factor (EGFR) level is a predictive factor for response and survival in patients with lung cancer
Authors: Tek I. , Akbulut H. , Yalcin B. , Buyukcelik A. , Utkan G. , Demirkazik A. , Icli F. 
Published: March 2020

20058 Background: Over expression of epidermal growth factor receptor (EGFR) has been reported as a poor prognostic factor in patients with cancer. However, active EGFR released from the apoptotic tumor cells could serve as a marker for the prediction of clinical outcome in cancer patients. In this study we aimed to study the role of the level of serum active epidermal growth factor receptor in patients with non-small cell lung cancer as a predictive parameter for response and survival. Methods: Thirty-three consecutive patients with advanced non-small cell lung cancer patients (12 with stage IIIB and 21 stage IV or relapsed disease) were included. The median age was 52 (range: 35–69). The patients were given cisplatinum and docetaxel combination regimen as first line treatment. The serum samples were collected before the first cycle of the chemotherapy and every 2 cycles and kept at -80 C. Response to treatment was evaluated every 2 cycles according to the WHO criteria. Serum active EGFR levels were measured by ELISA (BioSource, Camarillo Ca, USA). Results: Median 4 cycles of chemotherapy (range: 2–6) were administered. Median follow-up time was 11 months. Objective response rate was 18.2%. One-year estimated survival rate was 65.9%. There were no significant differences between the extend of the disease and basal active EGFR levels. Likewise, there was no difference between the basal active EGFR levels of responders and non-responders (0,19 ± 0.09 vs 0.21 ± 0,11 fmol/mL, p = 0.899, respectively). However, the patients responded to the treatment had significantly higher level of active EGFR than the non-responders after 2 cycles (3,74 ± 3,65 vs. 0,174 ± 0,13 fmol/mL, p = 0.028, respectively). While the patients with positive basal EGFR levels (higher than the cutoff level of 0.080 fmol/mL) had lower survival rates than that of negative patients (1 yr survival rate: 62.8% vs. 75%, respectively), active EGFR positive patients after 2 cycles of chemotherapy had longer survival than the negative patients (1 yr survival rate: 70.6% vs. 60%, respectively). Conclusions: Our preliminary results show that serum active EGFR levels could be a predictive marker for response evaluation and survival in patients with non-small cell lung cancer treated with chemotherapy. No significant financial relationships to disclose.
Gene expression profile of enzymes involved in gemcitabine (Gem) metabolism in bone marrow mononuclear cells as predictors of myelosuppression
Authors: Ganti A. K. , Parr A. , Nguyen D. , Grem J. L. 
Published: March 2020

2007 Background: The dose-limiting toxicity of gemcitabine (Gem) is hematologic toxicity (heme tox), and there is wide intra-patient variability in the degree of heme tox. This study was done to assess the possible impact of gene expression of enzymes involved in Gem metabolism or mechanism of action on heme tox. Methods: Pre-therapy mononuclear cells were isolated from bone marrow aspirates collected from 71 consenting patients with various advanced malignancies enrolled in an IRB-approved phase I trial in which single agent Gem was given over 30 min weekly for 2 of 3 weeks during cycle 1 at doses ranging from 750–1,560 mg/m2. Gene expression of deoxycytidine kinase (DCK), an activating enzyme, cytidine deaminase (CD) and deoxycytidylate deaminase (DCD), deactivating enzymes, and ribonucleotide reductase M2 (RNR), which is inhibited by Gem diphosphate, was measured by real-time RT-PCR. Target gene expression was relative to beta-actin. Heme tox was calculated as the % decrease in white blood cells (WBC), neutrophils (ANC) and platelets (PLT) from baseline. Results: 71 patients (26 females, 35 males) with a median age of 56 years (range: 20–75) were included in the analysis. The median (25th %, 75th %) gene expression was as follows (x10e3/beta-actin): DCK, 0.34 (0.19, 0.64); CD, 1.88 (1.33, 2.92); DCD, 2.48 (1.15, 7.78); and RNR, 0.39 (0.19, 0.80). A strong linear correlation was noted only between RNR & DCD gene expression (Pearson r = 0.89). When gene expression was categorized as above or below the median value, only CD appeared to influence heme tox (mean ± std dev) ( Table ). T-test p value is shown. Conclusions: Gem is rapidly metabolized to its inactive metabolite by CD. Subjects with a higher relative gene expression of CD tended to have a lesser degree of heme tox following Gem. Correlation with Gem pharmacokinetics in these subjects is planned. [Table: see text] No significant financial relationships to disclose.
Feasibility of testing core needle biopsies ex vivo in the ChemoFx assay
Authors: O’Shaughnessy J. A. , Holmes F. , Beitsch P. , Cunningham J. , Gallion H. , Backner A. , Hellerstedt B. , Pippen J. , Vukelja S. , Dupree B. 
Published: March 2020

20073 Background: Multiple chemotherapy options exist for the treatment of primary breast cancer. While response rates are good, many patients are treated with unnecessary or ineffective chemotherapy. Inadequate treatments are partly due to the lack of accurate predictors of response in individual patients. To predict an individual’s response to therapy, ex vivo chemosensitivity and resistance assays (CSRAs) have long been evaluated, but have been limited by technical difficulties, including the need for large (1–2 gm) amounts of fresh tissue. However, these problems have largely been overcome with new technology. Novel methods used in Precision Therapeutics’ ChemoFx assay allow for testing smaller amounts of tissue (35 mg). The reduced tissue requirement is crucial in the breast cancer setting, as the diagnosis is often made by percutaneous biopsy. The goals of the study were to determine the growth success rate of culturing epithelial cells from breast tissue core needle biopsies and the feasibility of testing the cells in the assay. Methods: A prospective feasibility study involving women with invasive primary breast cancer. One to four core needle biopsy specimens were collected using a 14 gauge needle (est. per patient yield <50 mg) and submitted to Precision Therapeutics. A primary culture of each specimen was established and the ex vivo chemoresponse profiles of each culture were evaluated. Drugs tested included capecitabine, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, paclitaxel, and vinorelbine. Results: 21 of 25 (84%, 95% CI: 68% to 97%) specimens grew successfully; all 21 were tested for chemoresponsiveness with the assay. Of the 4 subjects with unsuccessful ex vivo cultures, 2 had no growth, 1 failed plating for culture, and 1 failed IHC testing due to overgrowth of non-epithelial cells. The average number of drugs tested for each specimen was 7 (range: 1–15). Conclusions: This study demonstrates that core needle biopsies from primary breast tumors can be successfully cultured and tested for chemoresponsiveness using the ChemoFx assay. The ability to perform ex vivo chemoresponse testing on core needle biopsies greatly increases the utility of the assay in adjuvant or neoadjuvant primary breast cancer settings. [Table: see text]
Immunoproteomics strategy for automation of chemoresistance and chemosensitivity array
Authors: Adler Y. , Adler M. J. , Weisenthal L. , Reed J. , Krajewska M. , Olson A. , Krajewski S. 
Published: March 2020

20076 Background: Chemotherapy sensitivity and resistance assays (CSRAs) often guide therapeutic regimen selection based on patient cancer cells response to chemotherapeutics in culture. Current CSRAs rely on highly time- and skill- dependent biochemical and microscopic endpoint assays of apoptosis. Instead, the assay under development uses immunoproteomic array readout of biomarkers. Such automation may broaden the use of CSRAs for guiding clinical use of increasingly costly chemotherapeutic options. Methods: Specimens from 30 ovarian cancer patients were cultured with and without cisplatinum according to established CSRA procedures (http://weisenthal.org/w_ovarian_cp.pdf). Cells pelleted and fixed at experimental points (0 and 96 hrs cisplatin, and 96 hrs non-treated) were paraffin embedded for construction of immunoproteomic microarrays. A panel of 57 NIH cancer cell lines was similarly arrayed. Protein profiling is performed with monospecific antibodies for 35 select markers of cell cycle, apoptosis, cell signalling, and transcription. Immunostaining results, including rate of cell death and marker expression level are quantitated manually (immunoscore assigned for cell core) and automatically (algorithm by Aperio, Inc). Results: Evaluation of readouts differentiates responders from non-responders aiming to predict clinical chemotherapy outcome. For a subset of imunoproteomic markers, observed expression corresponds to either induced apoptosis or to cisplatin resistance. Selected markers were subjected to cytologic analysis and time line westerns; results corroborate protein profiling data. Correspondence to the results of the classic CSRAs and individual patient therapeutic response will be unblinded. Conclusions: Use of immunoproteomic arrays to replicate classic CSRAs by establishing concordant results may allow automated guidance for chemotherapeutic choices. [Table: see text]
Pharmacokinetics of gefitinib predicts the antitumor activity for advanced non-small cell lung cancer (NSCLC)
Authors: Nakamura Y. , Sano K. , Fukuda M. , Takatani H. , Nagashima S. , Kinoshita A. , Fukuda M. , Soda H. , Oka M. , Kohno S. 
Published: March 2020

2009 Background: Little is known about the relationship between the pharmacokinetics and efficacy of gefitinib. Methods: Plasma trough levels of gefitinib were measured on days 0, 3 (D3), and 8 (D8) by HPLC in advanced NSCLC patients treated with gefitinib 250 mg daily. Eligibility criteria included: performance status (PS) ≤ 3, age ≤ 80, stage IIIB-IV, and written informed consent. Results: Fifty patients were enrolled, and 44 patients were assessable. The median [25%-75%] values of D3 and D8 was 662 [440–937] and 1064 [782–1405] ng/ml, respectively. D8/D3 rate was categorized by 1.587 of the median value. In 44 patients, the median time to progression (TTP) was 83 days, and the median overall survival (OS) was 224 days. The differences in TTP were compared by Kaplan-Meier method and log-rank test: D8/D3 (high D8/D3, median 209 days vs. low D8/D3, 43 days; P = 0.0299), smoking (never-smokers, 224 days vs. smokers, 32 days; P = 0.0467), and histology (adenocarcinoma, 97 days vs. non-adenocarcinoma, 27 days; P = 0.0096). Sex, age, PS, previous treatments, and the use of antacids were not significant. Multivariate analysis showed that TTP was associated with D8/D3 (hazard rate, 95%CI; 0.458, 0.234–0.898) and smoking (2.005, 1.030–3.903). Never-smokers with high D8/D3 showed the best TTP, and smokers with low D8/D3 showed the worst TTP. Never-smokers with low D8/D3 and smokers with high D8/D3 showed similar TTP curves. In contrast, OS was associated with smoking (hazard rate, 95%CI; 3.182, 1.506–6.724), but not D8/D3. Conclusions: High D8/D3 was independently associated with better TTP in gefitinib-treated NSCLC patients. Our findings suggest that pharmacokinetics of gefitinib may be involved in its anti-tumor activity. No significant financial relationships to disclose.