bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anticancer drug development pipeline of the pharmaceutical (P) and biotech (B) industries
Authors: Thomas F. P. 
Published: August 2020

e14589 Background: The rapidly growing market for anticancer drugs has attracted numerous companies, and this therapeutic area represents more that a third of all drug development candidates. We studied the pipeline of Pharma (P) and Biotech (B) companies to look at possible differences and 2008 changes in composition. Methods: The anticancer drug pipeline including candidates in Phase I to III and marketed products still actively developed in new indications was reviewed by systematically searching the websites of 41 P and 269 B active in oncology. Results: B, defined as entrepreneurial R&D-focused companies had 463 molecules including 160 in Phase I, 202 in Phase II, 73 in Phase III, and 28 marketed. P develop 219 molecules including 78 in Phase I, 61 in Phase II, 38 in Phase III, and 42 marketed. The number of candidates decreased by 10 in B and increased by 15 in P pipelines during H2, 2008, translating difficult economic conditions for B (with few candidates entering Phase I) and an increased focus of P on oncology (internal R&D efforts and B acquisition that accounts for 39 of its 219 molecules). B licensed out 119 of its candidates to P or other B. The portfolio of B and P analyzed by mechanism of action significantly differs. Symptomatic/adjuvant treatments represent 7.1 vs 5.5%, targeted small molecules 28.7 vs 42.9%, cytotoxics including reformulations 20.5 vs 22.4%, cell/gene therapies, oncolytic viruses, and oligonucleotides 7.3 vs 0%, antibodies and related proteins 19% vs 17.8%; immunotherapy 13.1% vs 5%, photodynamic and radio- therapy 2.8% vs 0.5% for B vs P, respectively. The number of antibodies and targeted small molecules increased during H1, 2008 by 2.1 and 4.4%, respectively. P recently enriched its antibody portfolio through B acquisition, but completely moved out of cytotoxics, except mid-size European and Japanese P. An update as of May,1st 2009 with a trend analysis including the potential impact of the financial crisis on B portfolio will be presented. Conclusions: The oncology pipelines of P and B are broad, different for B and P, and rapidly changing in composition. No significant financial relationships to disclose.
Effect of metronomic use of zoledronic acid (ZOL) on antitumor and antiosteoclastic effects in breast cancer patients with bone metastasis
Authors: Xi-Chun H. , Zhao X. , Xu X. , Guo H. , Wang Z. , Guo X. , Chen J. , Wu J. , Shao Z. , Li J. , Zhu B. 
Published: August 2020

e14603 Background: Zoledronic acid (ZOL) can reduce the risk of skeletal-related events (SREs) and may have direct and indirect antitumor effects, which have been shown in animal models, pilot clinical studies as well as in recent phase III randomized trials. However, the pharmacokinetics of the drug in breast cancer patients remains to be elucidated and optimized. The purpose of this randomized study was to compare the effects of ZOL on osteoclasts and angiogenesis between a weekly low-dose versus a conventional dosage. Methods: Sixty breast cancer patients with bone metastases were recruited in this randomized phase II clinical study. The participants either received ZOL 1mg IV weekly for 4 doses or a single dose of ZOL 4mg IV. No other antitumor treatments were administered. During the first month after initial infusion of ZOL, serial blood samples were collected on day 1, 15 and 29 measuring markers for bone resorption (NTx), angiogenesis (VEGF), and tumor burden (CEA and CA15–3). Results: Compared to a single-dose administration, weekly low dose of ZOL resulted in a greater reduction in serum levels of VEGF and NTx, with a significant trend over time during one month observation. There were no statistically significant differences in circulating levels of CEA and CA15–3 between the two dosing regimens. Patients who received metronomic ZOL had a longer median time to disease progression (TTP) (7.0 months, 95%CI, 6.1–7.9 months) than those who had a single dose of ZOL (2.8 months, 95%CI, 0–5.7 months; p=0.076). Conclusions: The metronomic use of low-dose ZOL 1 mg appeared to be more effective than the conventional regimen in the long-lasting reduction of VEGF and NTx, and in prolonging TTP. This dosing schedule should be further assessed in phase III trials as we demonstrated that ZOL 1mg has greater antitumor properties in our study. No significant financial relationships to disclose.
Sorafenib and radiation: A promising combination in colorectal and pancreas cancer
Authors: Wilson G. D. , Suen A. , Robertson J. , Galoforo S. , Marples B. 
Published: August 2020

e14622 Background: Sorafenib inhibits both RAF kinase, a critical component of the RAS/RAF/MEK/ERK signaling pathway that controls cell proliferation, and VEGFR-2/PDGFR-beta signaling cascade, blocking tumor angiogenesis; this dual activity has great potential for radiosensitization. This study examines the effectiveness of radiation and sorafenib in a series of human colorectal and pancreatic cell lines and xenografts with differing ras mutational status. Methods: Three colorectal cell lines were selected. HT29 and SW48 are wild-type ras whilst SW480 has a mutation in codon 12 . Two pancreatic cancer cell lines were selected, Panc 03.27 is wild-type ras whilst Panc 02.03 has a mutation in codon 12. MTT assays were used to find the best drug concentration and timing to combine with radiation. Radiosensitization was assayed using clonogenic assays with either 5 or 10μg/ml sorafenib. Xenografts were established and randomized to control, sorafenib at 20mg/kg daily (5 days/week) for 3 weeks, radiation given as 2.5 Gy daily fractions (5 days/week) for 3 weeks or a combination of the two with sorafenib administered immediately after radiation Results: The MTT data suggested that sorafenib given immediately after or at least within 2 hours of radiation appeared to give the greatest growth inhibition. Sorafenib had no effect on cell survival in the colorectal cell lines but showed a modest radiosensitization, the surviving fractions at 2 Gy alone or with 5 or 10 μg/ml sorafenib were 34%, 26% and 23% (p=0.0018) in SW48 cells. In pancreatic cells, sorafenib was toxic at 10 μg/ml and reduced survival by 30% at 5 μg/ml without sensitization The endpoint in the xenograft studies was tumor growth to 2000mm3 within a period of 120 days. In SW48 tumors, the number of days to grow to 2,000 mm3 was 13.6 ± 2.2 in the control arm, 37.0 ± 21.2 in the radiation alone arm, 17.0 ± 8.2 in the sorafenib arm and100.8 ± 28.0 in the combined arm (2 of the 5 animals were ‘cured‘). The respective data in the HT29 xenografts was13.2 ± 2.1, 62.6 ± 9.8, 38.2 ± 26.5 and106.2 ± 36.2 days (3 of 5 animals were ‘cured‘. Conclusions: Sorafenib and radiation are a promising combination. Phase I studies are under development in both pancreatic and colorectal cancer at our Instittution. No significant financial relationships to disclose.
A comparison of potency of and intracellular signaling events provoked by, small molecule and protein-based mpl agonists
Authors: Hartley C. , Dyas G. , Archibeque I. , Al-Assaad A. , Sun B. , Lincoln P. , Zhan J. , Arvedson T. , Molineux G. 
Published: August 2020

e14624 Background: Thrombopoietin (TPO) interacts with its receptor (mpl) to initiate signal transduction and increase platelet production. Other mpl agonists have been developed for clinical use: MDGF (a recombinant protein) and romiplostim (a peptibody) are protein-based mpl agonists; eltrombopag (a small molecule) is a nonpeptide mpl agonist. Methods: Mpl agonists were compared for their ability to induce cellular responses and activate relevant signaling pathways in mpl-expressing cells. Proliferation was assessed by ATP bioluminescence in Baf3/mpl cells treated with mpl agonists for 2 days. Differentiation was assessed by flow cytometric-detection of CD41 and CD61 expression on human CD34+ cells cultured with mpl agonists for 7 days. Activation of signaling pathways was determined by Western blot analysis of proteins from serum-starved Baf3/mpl cells treated with mpl agonists for 20 minutes. Experiments were repeated 3 or more times. Results: The TPO concentration that produced a half-maximal (EC50) proliferative response of Baf3/mpl cells was comparable with that of romiplostim (Table). In contrast, a 30-fold greater concentration of MGDF and a 2,000-fold greater concentration of small molecule were required to produce the same degree of proliferation. In addition, a 1,000,000-fold greater concentration of small molecule compared with romiplostim was required to produce an EC50 for differentiation of CD34+ cells. Mpl agonists activated identical signaling pathways in Baf3/mpl cells: a similar dose-response for phosphorylation of JAK2, Stat3, Stat5, Erk1/2, and AKT was observed at their respective EC10, EC50, and EC100 concentrations. Conclusions: In Baf3/mpl cells, the small molecule was between 1,000- and 1,000,000-fold less potent than protein-based mpl agonists when corrected for molecular mass differences. Small molecule and protein-based mpl agonists were indistinguishable when mpl intracellular signaling was compared at similarly effective concentrations. [Table: see text] [Table: see text]
Design and development of high-drug-load paclitaxel (PTX)-antibody conjugates: Synthesis and preliminary evaluation of soluble paclitaxel (sPTX) and sPTX-cetuximab conjugates
Authors: Safavy A. S. , Quiles S. 
Published: August 2020

e14634 Background: Tumor cell surface receptor-targeted therapy of cancer is an effective treatment strategy and monoclonal antibody (MAb)-drug conjugates hold promise as tumor-specific drug delivery systems. We have previously reported the synthesis and biological evaluation of paclitaxel (PTX)-MAb conjugates using the anti-EGFR MAb, cetuximab, as an agent for tumor-targeted drug delivery system (Safavy et al., Bioconjugate Chem 14:302–310, 2003). One limitation of these conjugates was a low drug load, i.e., PTX : MAb ratios of ≤4, and thereby, low target dose delivery. Attempts to synthesize conjugates with PTX : MAb of >4 failed due to their low water solubility. As the source of this problem was identified to be the highly lipophilic PTX moiety, we hypothesized that conjugation of water-soluble PTX analogues may lead to the preservation of the MAb solubility, and thus, to the preparation of conjugates with high PTX : MAb ratios. Methods: Newly available “discrete” poly(ethylene glycol) (dPEG) linkers were utilized for the synthesis of soluble PTX analogues. In contrast to the regular PEGs wit dispersed molecular weight ranges (MWs), the dPEGs are single-MW compounds which make possible the exact dose calculation for the resulting conjugates. Solid-phase peptide synthesis methodology was used to prepare a trifunctional dPEG-lysine (K) linker, which was first conjugated to PTX to yield the water-soluble drug analogue sPTXdPEGKdPEG, containing a free carboxylic acid group. Using the latter functionality, sPTXdPEGLysdPEG was covalently conjugated to cetuximab (C225) at increasing molar ratios. Cell binding assays were performed using MCF-7 human breast carcinoma cell line. Results: sPTXC225 conjugates with PTX : C225 ratios of up to 8 were synthesized through this method, which in contrast to the previously reported conjugates, demonstrated complete aqueous solubility. Cell binding assays indicated preservation of the immunoreactivity of the parent MAb in all conjugates. Conclusions: Water-soluble and high-drug-load PTX-MAbs such as sPTXC225, may be useful for targeted delivery of therapeutically effective doses of paclitaxel and warrant further investigation. No significant financial relationships to disclose.
Effect of the apoptosis signal ceramide (C6) on antitumor activity of chemotherapeutic agents in SCID mice
Authors: Nadeem A. , Wanebo H. , Shrayer D. , Hazelwood S. , Resnick M. 
Published: August 2020

e14642 Introduction: The ceramides are a major signaling pathway for apoptosis in cells undergoing stress or exposure to chemotherapy. We have demonstrated synergistic anti-tumor effects of combining C6 ceramide with paclitaxel, doxorubicin and cisplatin and are currently addressing the question; does C6 augment activity of all the major classes of drugs? Backround: Currently the in vivo anti-tumor effects of C6 with oxaliplatin and Gemcitabine. Methods: Invivo experiments SCID/Beige/Taconic male mice inoculated S.C. with 2X106 L3.6 pancreatic cells were treated 4 days post tumor implant with trice weekly (3x/wk) intraperitoneal (IP) injections of paclitaxel (P) 3.0 m/kg, oxaliplatin (OX) 2.5 mg/kg, cisplatin (CP) 2.5 mg/kg, Gemcitabine (Gem) 10 mg/kg with/without ceramide 10 mg/kg. Mice were observed for 6 weeks and were autopsied when near death. (All controls died by 3rd week). Maximum tumor volume, tumor weight; body weight and survival were recorded. Results: Combination with C6 ceramide augmented the tumor reduction obtained by chemotherapy alone by 57% (while preserving body weight), and increased 6 week survival from 0% (Chemotherapy alone) to 60% with combined therapy. Mean survival was increased from 25 to 37 days. Although short term immunohistochemical studies suggested enhanced apoptosis and increased caspase 3 production by ceramide combinations it may actually be independent of capase activation and mitochondrial activation. Conclusions: Combination therapy with the apoptotic signal C6 ceramide significantly enhanced the anti-tumor effects of the anti microtubule, alkylating Paclitaxel a DNA interculating antibiotic (doxorubicin) the alkylating/DNA adducting agents (cisplatin, oxaliplatin) and an anti metabolite (gemcitabine) suggesting generation of broad based apoptotic signals which interact with major cancer drug classes (tested). No significant financial relationships to disclose.
Use of independent genome-wide assays to discover HOXA signature in colon and rectal cancers and validate a role in tumorigenesis
Authors: Pant S. , Hostetter G. , Armstrong B. , Bittner M. , Shack S. , Savage S. , Weiss G. J. , Ozer H. , Ramanathan R. 
Published: August 2020

e15014 Background: Rectal cancer differs from colon cancer in terms of prognosis. Here we present genome-wide expression analysis of 79 colon and rectal tumors and gene dosage analysis of 34 archival colorectal tumors in paraffin (FFPE). Methods: Expression data were acquired ( http://expo.intgen.org/geo/home.do ) from Affymetrix experiments analyzed with GeneSpring software version 7.3 (Silicon Genetics, CA). Expression data were normalized ’per chip’ normalized to the 50th percentile of all values; and ’per gene’ normalized to the median expression level across all samples. Expression Project for Oncology (expO) samples included colon (n=50) and rectum (n=29). Differentially expressed genes were identified by parametric test for which variances were not assumed equal (Welch ANOVA). Array comparative genomic hybridization (aCGH) were performed separately on an independent set of FFPE colorectal tumors (n=34) by 244 K microarrays for CGH, Agilent Technologies, CA and with platform embedded analyses tools of CGH Analytics software and ADM-1 bioinformatics. Functional assay by knockout of HOXA9 promoter by lentiviral sh-RNAi construct was performed on colon cancer cell lines shown to have increased HOXA9 dosage and expression. Results: The analysis of expO colon and rectal cancers generated 42 genes with significant differential expression, 26 showed an increased expression of > 2 fold in colon versus rectal samples. Transcription factor family HOXA9 was the most highly expressed (3.8 fold) in colon versus rectal cancer. The aCGH data showed a low level gain of the HOXA gene to be the most frequent dosage alteration (38%). Validation by IHC and qRT-PCR showed 80% and 76% concordance, respectively. Functional assay by sh-RNAi in cell lines (compared to vehicle only) showed marked decrease in cellular viability (40 to 60%), marked morphologic change and a significantly increased apoptotic rate. Conclusion: Multiple genome-wide assays have identified HOXA9 as differentially dosed and expressed in colon and rectal tumors. Compelling functional data from sh-RNAi experiments suggests a tumorigenic role for HOXA9 in altered apoptosis. No significant financial relationships to disclose.
Magnitude of benefit of the addition of bevacizumab (BEVA) to first-line chemotherapy (CT) for advanced/metastatic colorectal cancer (MCRC): Meta-analysis of randomized clinical trials
Authors: Vaccaro V. , Cuppone F. , Loupakis F. , Milella M. , Carlini P. , Nisticò C. , Falcone A. , Terzoli E. , Cognetti F. , Bria E. 
Published: August 2020

e15021 Background: The monoclonal antibody against vascular endothelial growth factor BEVA has recently demonstrated to improve survival for MRC patients (pts). Nevertheless, the magnitude of the provided benefit in the daily practice is still controversial. In order to quantify the benefit of adding BEVA to CT for MCRC, a literature-based meta-analysis was conducted. Methods: Survival Hazard Ratios (HR) were extracted from prospective, randomized clinical trials (RCTs, either phase II/III) reports. HR and event-based relative risks (RR) with 95% confidence intervals (CI) were derived through a random-effect model. Differences in primary (progression-free- and overall-survival, PFS/OS) and secondary outcomes (overall, partial and complete response rates, ORR/PR/CR) were explored. Absolute differences (AD) and the number of patients needed to treat (NNT) were calculated. Heterogeneity test and a meta-regression analysis with clinical predictors for outcomes were conducted as well. A sensitivity analysis according to the trial phase-design was accomplished. Results: Five trials (2,728 pts), 2 phase II (313 pts) and 3 phase III (2,415 pts), were gathered. No significant interaction was found in the sensitivity analysis between phase II and III, although a trend showed a better PFS results for BEVA in phase II trials (p=0.057). At the meta-regression analysis female gender and rectal primary site were significant predictors for PFS (p=0.003, p=0.005). Toxicity analysis is ongoing. Conclusions: Although concerns regarding costs and toxicities still exist, BEVA significantly improves the outcome of untreated MCRC pts. The absolute benefit provided into an unselected population for molecular features should be considered of paramount importance for advanced disease. [Table: see text] No significant financial relationships to disclose.
A novel mutation in MUTYH-associated polyposis (MAP) syndrome
Authors: Fostira F. , Panopoulos C. , Papademitriou K. , Lypas G. , Lypas G. , Barbounis V. , Efremidis A. , Yannoukakos D. 
Published: August 2020

e15022 Background: MUTYH-associated polyposis (MAP) syndrome is inherited as a recessive trait and is characterized by the intrinsic phenotypic feature of adenomas present at the individual's colorectum. In the case of non-surgical removal of these polyps, adenoma will transform to carcinoma. Colorectal tumours from mutation carriers display an excess of somatic mutations, specifically G:C to T:A transversions. The risk of colorectal cancer among biallelic mutations carriers seems to be close to 100% by the age of 60. Methods: Four families meeting the MAP phenotypic criteria were studied.Genomic DNA was purified from peripheral blood leukocytes following standard chloroform extraction. The complete coding sequences of the MUTYH-gene, including splice junctions, were amplified by Polymerase Chain Reaction (PCR) and electrophorized in an ABI Prism 310 Genetic Analyzer. Results: Analysis of the MUTYH gene revealed five different germline mutations, one of which novel and never characterized in respects of its pathogenicity. A mutation has been identified on exon 7 of the MUTYH gene at a homozygous state, in an individual with less than one hundred colorectal polyps at the age of forty. Another patient diagnosed with colorectal cancer at the age of 34 carried two maternally and one paternally inherited mutation, located on exon 14. A milder MAP phenotype characterized an individual, who was diagnosed with less than one hundred polyps at the age of 69. Genetic testing revealed that the patient was compound heterozygote for two missense variants located on exons 8 and 12 of the MUTYH gene. Conclusions: A novel mutation located on intron 6 of the MUTYH gene has been identified in two families. Our findings confirm previous observations highlighting the necessity for genetic testing of MUTYH in patients with MAP phenotypic features, as well as his/her extended family, in order to determine the phenotyping expression of each mutation and propose the appropriate clinical surveillance, which includes biennial colonoscopy after the age of 30. In specialized cases surgical intervention might be essential. No significant financial relationships to disclose.
A phase I/II study of combination therapy of S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer
Authors: Choi Y. , Kim T. , Lee S. , Lee J. , Chang H. , Kim H. , Shin J. , Lee J. , Kang Y. 
Published: August 2020

e15023 Background: To investigate S-1 and irinotecan (CPT-11) combination as an alternative to infusional 5- fluorouracil/leucovorin plus CPT-11, we performed a phase I/II trial to determine maximum tolerated dose (MTD), efficacy and toxicity in metastatic or recurrent colorectal cancer. In addition, we evaluated the association between genotypes of candidate genes and phenotypes. Methods: S-1 was administered orally at a dose of 70 mg/m2 (level I-III) or 80 (IV and V) from day 1 to 14. CPT-11 was given i.v. on day 1, stepping up to 175 (level I), 200 (II), 225 (III and IV) or 250 (V) mg/m2 . The treatment was repeated every 3 weeks. The association of the UGT1A1 genotypes (*6, *28, and *60) and CYP2A6 genotypes (*4, *7, and *9) with toxicities or efficacy were analyzed in patients who participated in phase II portion. Results: Twenty-three patients entered the phase I and 30 enrolled in phase II study. The MTD of S-1 and CPT-11 was considered to be 80 mg/m2 and 250 mg/m2, respectively. The dose-limiting toxicities (DLTs) were diarrhea and neutropenia. The recommended dose (RD) was determined at a S-1 dose of 80 mg/m2 and a CPT- 11 dose of 225 mg/m2. The overall response rate was 66.7% (95% CI, 48.7–84.6) at the RD level. Median time to progression was 7.6 months (95 % CI, 5.7–9.5). Median survival time was not reached. Grade3–4 neutropenia was observed in 53.4% of the patients. Grade 3–4 nonhematologic toxicities were diarrhea (16.7%) and asthenia (6.7%). The frequencies of UGT1A1*60, *28, and *6 allele were 25.8%, 10.3%, and 15.5%, respectively. Homozygous for *28 or *6 were not observed. All three double heterozygous for *28 and *6 experienced grade 3–4 neutropenia. The allele frequencies of CYP2A6*4, *7, and *9 were 15.5%, 8.6%, and 29.3%, respectively. There were no association between CYP2A6 genotypes and response rates or toxicities. Conclusions: The combination of S-1 and CPT-11 was effective and had manageable toxicities in patients with metastatic or recurrent colorectal cancer. [Table: see text] No significant financial relationships to disclose.