bluuebunny/crossref_metadata_2025_split huggingface dataset:
A PET imaging study of the vascular disruptive agent OXi4503 to confirm in vivo mechanism of action in a phase I trial
Authors: Price P. M. , Asselin M. , Koetz B. , Dickinson C. , Charnley N. , Lorigan P. , Valle J. , Stratford M. , Rustin G. , Saleem A. 
Published: August 2020

e14510 Background: OXi4500, the active product of OXi4503, reversibly binds at the colchicine binding site on the ß subunit of tubulin. This study investigated its mechanism of action using PET molecular imaging Methods: OXi4503 was administered by 3 weekly IV infusions in a phase 1 trial (32 pts). Between 1.6 & 15.4 mg/m2 dose levels, PET imaging was performed with 15O-labelled water (measuring blood perfusion) pretreatment & at 90min & 24hr after first infusion (8pts) & at 28days (1 pt). [18F]fluorodeoxyglucose (FDG) (measuring proliferative activity) was performed pretreatment & at 28 days (9pts) Results: 9 pts (mean age 48.5yrs) were studied: CRC (2), pancreatic (1), MM (6). 2 pts with MM (3.8 & 6.5 mg/m2) achieved stable disease. Toxicity included pyrexia, lethargy & hypertension. There was a dose-dependent linear increase in peak plasma concentrations & AUC of OXi4503 & OXi4500. Sustained tumour blood perfusion reduction (50% at 90min & 24hr) was seen in all metastases in the CRC pt treated at 15.4 mg/m2 after just one dose & resulted in FDG reduction (23% in all 5 mets) & tumor marker response. Doses between 1.9 & 11.0 mg/m2 produced dose independent reductions in tumour perfusion which were more variable & less marked with 3/8 pts showing a reduction in tumour FDG uptake. The 1pt studied at 28 days (8.5 g/m2) showed further sustained reduction in tumour blood flow (40%). Variable dose independent changes in normal tissue perfusion were seen at all dose levels eg in 3/4 pt splenic perfusion showed a dose-independent decrease (20–30%) at 90min with recovery at 24hr Conclusions: OXi4503 shows significant activity at 15.4 mg/m2 in line with its proposed mechanism of action. Characterisation of the mixed tumour perfusion response at lower doses will aid planning & assessing combination studies. The MTD is now being identified. Sponsored by CRUK. [Table: see text]
Optimal patient selection for CPT-11 chemotherapy in colorectal cancer: Quantitative prediction of tumor response and overall survival using expression data of novel marker genes
Authors: Takemoto H. , Tomita N. , Murata K. , Fukunaga M. , Okamura S. , Ohue M. , Ishida H. , Tanimoto K. , Hiyama K. , Nishiyama M. 
Published: August 2020

e14529 Background: Unlike the toxicity, none of the critical prediction markers of CPT-11 efficacy has been validated to date. With a hypothesis that expression analysis of a set of the key drug sensitivity genes could allow us to predict the therapeutic response, we identified potent marker genes for CPT-11 in in vitro, conducted this prospective study attempting to develop a prediction formula of efficacy using the expression data (2006 ASCO, 2006 ESMO), and demonstrated the latest prediction formula of the best tumor response (BTR), time to treatment failure (TTP), and the overall survival after CPT-11 chemotherapy (OS). Methods: Seven genes identified as possible marker genes for CPT-11 (SN-38)- AMD1, CTSC, EIF1AX, FLJ13089 , DDX54, PTPN2, and TBX3-, and 5 other possible marker genes (ABCG2, CYP3A4, MGMT, POR, and TOP2A) that had already been known as drug sensitivity determinants and selected by our in vitro screening process, were studied. CPT-11 was intravenously administered on Days 1, 8, and 15, every 4 weeks in chemo-naive patients with stage IV colorectal cancer after palliative operation. Tumor samples were collected at surgery and tumor response was evaluated by RECIST. Results: All of the 44 enrolled patients were assessable for BTR (% of initial tumor size), TTP (day), and OS (day) in the clinical study, and we successfully developed the best linear model for each, which converted the quantified expression data of the 7 selected genes into objective BTR, TTP, and OS. We used 20, 16, and 15 tumor specimens and constructed potent prediction formulae for BTR (r=0.9420), TTP (r=0.7103), and OS (r=0.8406), respectively. Utility-confirmation analyses using another 16, 10, 13 clinical samples appeared to show that the formulae could predict BTR (r=0.6491, p=0.007) and OS (r=0.7947, p=0.011). We also fixed the best linear models using 5 other known marker genes, but they had less advantage in prediction. Conclusions: Despite limited data, our developed formulae using the 7 novel genes would provide advantages in prediction of individual response to CPT-11. Based on the positive results of this study, we have initiated a large scale validation study of the formula. [Table: see text]
Evaluation of early sequential 18F-FDG PET imaging as a prognostic indicator and predictor of response to platinum and pemetrexed chemotherapy in malignant pleural mesothelioma (MPM)
Authors: O’Flaherty J. D. , Farrelly C. , Knox M. , Power D. , Lucey J. , O’Byrne K. 
Published: August 2020

e14534 Background: Recent evidence has suggested that baseline SUV and metabolic response measured on sequential PET scans early in the course of chemotherapy may predict for survival and response to chemotherapy. Methods: Patients with MPM suitable for platinum/pemetrexed chemotherapy were studied. Baseline pre-chemotherapy PET and CT scans were performed with a further PET scan before cycle 2. CT scans were repeated mid-treatment and at the end of 6 cycles. PET response was determined by measuring the change in the maximum and mean SUV, PET Vol (volume of tumor above SUV threshold of 3.5) and Total Lesion Glycolysis (TLG, calculated as PET Vol x SUV Max). Metabolic response (MR), as measured by a 25% drop in SUV Max, SUV Mean, PET Vol and TLG was compared to overall survival (OS) and to subsequent response to chemotherapy on CT. CT scans were read using Modified RECIST criteria and CT response was compared to OS. Results: 21 patients had baseline PET scans of whom 17 had a further PET before cycle 2. 19 patients had CT scans evaluable by Modified RECIST criteria. Baseline SUV Max and SUV Mean were found to predict for OS. Median survival was 17.2 months for patients with SUV Max less than 15 versus 6 months for those with SUV Max greater than 15 (p=0.0193). Median survival was 14.1 months for patients with SUV Mean less than 5 versus 6.5 months for those with SUV Mean greater than 5 (p=0.0681). MR defined by SUV Max, SUV Mean, PET Vol or TLG did not predict for OS. MR on PET correlated poorly with CT response with Kappa values of 0.01, 0.05, 0.15 and 0.31 for MR defined by SUV Max, PET Vol, SUV Mean and TLG respectively. CT response using Modified RECIST criteria correlated significantly with OS. Patients with partial response (PR), stable disease (SD) and progressive disease (PD) had median survivals of 25.6 months, 8.6 months and 4.6 months respectively (p=0.0072) Conclusions: MR measured by SUV Max, SUV Mean, PET Volume and TLG on early sequential PET scans did not correlate with CT assessed response to chemotherapy or OS. Baseline SUV Max >15 and SUV Mean >5 were indicative of poor prognosis. CT response as measured by Modified RECIST criteria correlated significantly with OS. No significant financial relationships to disclose.
Target identification by phosphoproteomics: RIN1 modulation of sorafenib-induced cytotoxicity in renal cell carcinoma
Authors: Grozav A. G. , Willard B. , Kinter M. , Vaziri S. A. , Bukowski R. M. , Rini B. I. , Ganapathi M. K. , Ganapathi R. 
Published: August 2020

e14543 Background: Sorafenib (SFB) is a multi-tyrosine kinase inhibitor clinically useful in treatment of metastatic renal cancer. While the inhibition of angiogenesis is considered a major mechanism of action, identification of targets regulating growth inhibitory effects of SFB is necessary to further improve its efficacy and reduce toxicity. Methods: In this study we used targeted phosphoproteomics to identify tyrosine phosphorylated proteins that are differentially affected in control and SFB-treated human CAKI-1 renal cell carcinoma cells. The strategy involved immunoaffinity isolation of phosphotyrosine containing proteins and liquid chromatography - tandem mass spectrometry (MS) for identification of candidate proteins. Results: Among identified proteins, signal transducer and activator of transcription 1 (STAT1) and Ras and Rab interactor 1 (RIN1) were found to be hypophosphorylated in SFB-treated compared to untreated CAKI-1 cells based on quantitative MS analysis, by peptide counts and native peptide reference method. A ∼4-fold decrease in expression and phosphorylation of STAT1 was observed in cells treated with 10 μM SFB for 48h. Up to 8-fold SFB dose-dependent (5–15 μM) decrease in phosphorylation of RIN1 at tyrosine 36, but not in total RIN1 expression, was observed. Similar effects on decreased phosphorylation of STAT1 and RIN1 were also observed in 786-O renal cell carcinoma treated with SFB. Hypophosphorylation of RIN1 at tyrosine 36 was observed in CAKI-1 cells treated with 5 μM sunitinib but not with imatinib (≤ 10 μM). Treatment of CAKI-1 cells with RIN1 targeted, but not control si-RNA led to down-regulation of RIN1 expression and attenuation of antiproliferative effects of SFB. Notably, ∼2-fold higher expression of RIN1 protein (total and phosphorylated) was observed in CAKI-1 cells selected for resistance following continuous exposure to 7.5 μM SFB. However, unlike parent CAKI-1 cells, prolonged exposure of these SFB-resistant CAKI-1 cells to 7.5 μM SFB did not completely abrogate phosphorylation of RIN1 at tyrosine 36. Conclusions: These results demonstrate that RIN1, a Ras effector protein with multiple biochemical functions, is a target for the anti-tumor effects of SFB in kidney cancer cells. [Table: see text]
Evaluation of two different schedules of bevacizumab (BEV) with oxaliplatin (OXA), raltitrexed (TOM), levo-folinic acid (LFA), and 5-fluorouracil (5-FU) during preoperative (preop) pelvic RT in high-risk locally advanced rectal cancer (HR-LARC) patients (pts)
Authors: Avallone A. , Delrio P. , Di Gennaro E. , Pecori B. , Aloi L. , Tatangelo F. , Petrillo A. , Budillon A. , Caracò C. , Sandomenico C. , Comella P. 
Published: August 2020

e14546 Background: OXA, RTX, 5FU, and LFA during preop pelvic RT produced a high rate of complete (TRG1) or subtotal (TRG2) tumor regression in HR-LARC. BEV might enhance response to chemoradiotherapy (CH-RT), but scheduling of BEV could be critical. Therefore, we added BEV to CH-RT in two different schedules to evaluate their feasibility and activity. According to the Simon's two-stage design, assuming a hypothesis of a 50% TRG1 (α=0.05, β=0.20), at least 6/16 TRG1 should be obtained to continue pts accrual in every schedule. Methods: Inclusion criteria were: cT4, cN+, cT3(<5 cm from the anal verge and/or +ve CRM), resectable M1. Pts received 3 biweekly courses(c) of OXA (100 mg/m2)/TOM (2.5 mg/m2) on day 1, and 5FU (800 mg/m2)/LFA(250 mg/m2) on day 2 during pelvic RT (45 Gy). BEV (5 mg/kg) was given biweekly from day -14 for 4 c in schedule A, and from day -4 for 2 c in schedule B. Toxicity was graded with NCI-CTCv3. Changes of circulating endothelial cells (CECs)assessed by flow cytometry in 17 (7 A; 10 B) pts, and glucose metabolism evaluated by FDG-PET in 27 (15 A; 12 B) pts after 1st c of CT were used as surrogate markers of tumor response. The Mann-Whitney test assessed the differences in CECs and FDG-PET related to schedules. TME was planned 8 wks after CH- RT. Results: Until now, 28 pts (16 A; 12 B) were treated: M/F=19/9; median age 57 (range, 43–74) yrs. All but one pt (A) completed the planned CH-RT. Grade 3/4 neutropenia was the most common toxicity with schedule A (7 pts, 44%), while it never occurred with schedule B. No treatment-related or postop death occurred. CECs were more decreased by schedule B than by schedule A (median, -78% vs -29%, p< 0.05). Glucose metabolism was also more reduced by schedule B (median, -78% vs -50%, p < 0.05). All but one pt (refusal) of schedule A, and 7 pts of schedule B proceeded to TME. With schedule A, 2 pts obtained a TRG1, 8 pts a TRG2, 3 pts a TRG3 and 2 pts a TRG4. With schedule B, 4 pts obtained a TRG1 and 3 pts a TRG2. Conclusions: These data suggest the relevance of BEV scheduling during preop CT-RT to optimize safety and efficacy of the combination treatment. Updated results on the whole study population will be presented. No significant financial relationships to disclose.
A pharmacokinetic (PK) and safety study of sorafenib plus capecitabine in advanced solid tumors
Authors: McKay C. E. , Infante J. , Jones S. , Bendell J. , Greco F. A. , Markus T. M. , Spigel D. R. , Yardley D. A. , Woudenberg J. , Lathia C. D. , Burris H. A. 
Published: August 2020

e14548 Background: The addition of a multi-targeted kinase inhibitor such as sorafenib (S) to standard chemotherapy holds promise for improving therapeutic efficacy in multiple advanced solid tumors. This study is designed to evaluate the PK and overall safety of S in combination with capecitabine (C). Methods: Eligibility included patients (pts) with refractory solid tumors, 0–1 ECOG, adequate organ function, and no prior anti-VEGF tyrosine kinase inhibitors. This single institution study enrolled two simultaneous cohorts of 6 pts each followed by an expansion: Cohort A received S 400 mg bid for 21 days and C 750 mg/m2 bid for 14 days of a 21-day cycle. Cohort B received S 400 mg bid for 21 days and C 1,000 mg/m2 bid for 14 days of a 21-day cycle. Intensive PK collections (pre, 30 min, 1, 2, 4, 6, 8, and 12 hr) were obtained following a week of exposure to S alone, C alone (both C and 5FU levels measured), and both S and C in combination. Results: 17 pts dosed since 2/1/08: median age 66 years (range 36–87); ECOG 0 14(82%); and white 15(88%). Tumor types include colon (4), pancreas (2), prostate (2), and other (11). No treatment-related deaths occurred. Target toxicities are outlined in table below. Despite early and aggressive clinical management, hand foot skin reaction (HFS) necessitated dose reductions in 1 pt in cohort A and 4 pts in cohort B. In total, only 1(14%) pt in cohort A required a dose reduction, as opposed to 5(63%) pts in cohort B. The median # of cycles was 2 (range 1–10), and 5 pts (29%) remain on study. Of the 13 pts evaluable for response, 8 (47%) had stable disease following first restaging scans. PK samples are being analyzed to compare Cohort A vs. B. Conclusions: The results of this trial will help guide future trials of S plus C. The 1,000 mg/m2 bid dose of C in combination with full dose S required frequent dose modifications in our pt population secondary to overlapping toxicity (primarily HFS). Alternate schedules should be considered. PK analysis will be presented. [Table: see text] [Table: see text]
Ad-ISF35-transduced autologous cells promote in vitro and in vivo chemosensitization in patients with 17p-/P53-defective chronic lymphocytic leukemia
Authors: Melo-Cardenas J. , Castro J. E. , Cox B. , Sandoval-Sus J. D. , Darrah D. , Urquiza M. , Prussak C. E. , Kipps T. J. 
Published: August 2020

e14552 Background: Transduction of chronic lymphocytic leukemia (CLL) cells with a replication-defective adenovirus (Ad) encoding recombinant CD154 (Ad-ISF35) induces expression of death receptors and Bid via a P53-independent pathway involving induction of P73. Induction of P73 significantly enhances the sensitivity of P53-defective CLL cells to “P53-dependent” drugs, such as Fludarabine (F-ara-A). Patients with P53-defective CLL who received iv infusions of autologous Ad-ISF35-transduced CLL cells were observed to achieve complete remissions (CR) with subsequent treatment using F-ara-A based treatment regimens, suggesting Ad-ISF35 could sensitize P53-defective CLL to chemotherapy. Methods: We examined patients with drug-resistant and/or P53-defective CLL before and after iv infusions of autologous Ad-ISF35-transduced CLL cells who were enrolled in a phase I study examining whether such treatment could sensitize patients to a truncated fludarabine, cyclophosphamide and rituximab (FCR) regimen. We examined CLL cells for sensitivity to F-ara-A in vitro, expression of CD95, DR5, Bid, and P73 and correlated these with the response to treatment in vivo. Results: P53-defective CLL cells were resistant to F-ara-A induced apoptosis with IC50 > 10μM prior to treatment. CLL cells collected from patients≥24 hours after IV infusion of autologous Ad-ISF35-trasduced CLL cells became sensitive to the cytotoxic effects of F-ara-A, with IC50 0.3–1 μM. Enhanced sensitivity to F-ara-A was associated with induced expression of Bid, DR5, CD95, and P73 by circulating CLL cells, an effect lasting≥2 weeks following iv infusion. Consistent with this, we observed complete resolution in lymphocytosis, lymphadenopathy and splenomegaly following 1 cycle of FCR administered 2 weeks after 3 biweekly infusions of Ad-ISF35- transduced CLL cells. Conclusions: IV infusion of autologous Ad-ISF35-transduced CLL cells can induce de novo, systemic expression of death receptors and Bid on bystander CLL cells, which is associated with enhanced sensitivity of P53-defective CLL to the cytotoxic effects of standard chemotherapy [Table: see text]
Safety and efficacy of neratinib (HKI-272) in combination with vinorelbine in patients with solid tumors
Authors: Limentani S. A. , Awada A. , Dirix L. , Beck J. , Dieras V. , Binlich F. , Germa C. , Agrapart V. , Powell C. , Hershman D. 
Published: August 2020

e14554 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. Preclinical studies have shown synergistic antitumor activity with the combination of trastuzumab plus vinorelbine in metastatic breast cancer.The recommended dose of neratinib in monotherapy is 240 mg. In this phase 1 study, a combination dose of neratinib plus vinorelbine that is tolerable was determined in patients (pts) with solid tumors. Methods: This is an open-label, 2-part study of ascending multiple daily oral doses of neratinib (160 mg, 240 mg) in combination with 25 mg/m2 IV vinorelbine (administered on days 1, 8 every 3 wks). Tumor measurements were made every 6 wks by modified RECIST criteria. Results: 6 pts have been treated at each dose level. Data for 12 pts (5 pts still ongoing) as of 30 Oct 2008 are presented (median age [range] of 53.5 [38–75] yrs; 83% female). The median duration of treatment [range] was 1.9 [1.5–2.7] m. There was only 1 dose limiting toxicity (DLT) of grade 3 neuropathy (pt had preexisting grade 1 neuropathy) at 160 mg neratinib-25 mg/m2 vinorelbine, so the dose was escalated to 240 mg neratinib- 25 mg/m2 vinorelbine. In this cohort, there were no DLTs, and since the neratinib and vinorelbine doses reached full standard doses there was no need for further dose escalation. AEs, any causality, all grades in ≥ 15% of pts included diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%), vomiting and anthralgia (33% each), abdominal pain and anorexia, (25% each), anemia and neutropenia (17% each). Grade ≥3 AEs that occurred in ≥1 pt included neutropenia (2 pts), pneumonia (1 pt) and peripheral neuropathy (2 pts). Preliminary efficacy data show that 1 pt with stomach cancer had stable disease, lasting ≥21 weeks. Conclusions: The combination of 240 mg neratinib and 25 mg/m2 vinorelbine was found to be tolerable and to demonstrate early evidence of clinical benefit in pts with solid tumors, to be assessed further in pts with metastatic ErbB-2+ breast cancer in part 2. [Table: see text]
Selective killing of human cancer cells by targeting a fusion mRNA between CYCLIN D1 and TROP2
Authors: Alberti S. , Trerotola M. , Dell’ Arciprete R. , Vacca G. , Veronica B. , Cosmo R. , Rossana L. , Lattanzio R. , Piantelli M. , Guerra E. 
Published: August 2020

e14569 Background: Trop-2 is a calcium signal transducer and a stem cell marker. Trop-2 is widely overexpressed by human cancers and stimulates their growth. A TROP2 mRNA was isolated as post-transcriptionally joined to CYCLIN D1 transcripts, suggesting this as one of the transforming mechanisms of TROP2. Methods: In vitro cell growth assays were utilized to assess the cell growth stimulatory capacity of the chimeric mRNA. Colony assays for growth in soft agarose and tumorigenicity assays in nude mice were utilized to assess for the transforming capacity of the fusion transcript. siRNA constructs were utilized for the stably shut-down of the expression of the CYCLIN D1-TROP2 mRNA. Results: The chimeric mRNA transforms primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. The CYCLIN D1-TROP2 mRNA is expressed by a large fraction of human ovarian, endometrial and gastro-intestinal tumors. The chimera is coexpressed with activated RAS in a subset of tumors, consistent with a cooperative transforming activity. The chimeric mRNA is a bicistronic transcript that independently translates wild type Cyclin D1 and Trop-2 proteins, i.e. it does not generate chimeric, oncogenic proteins. On the other hand, joining to the stable TROP2 mRNA leads to a higher CYCLIN D1 mRNA stability, with inappropriate persistence during the cell cycle and acquisition of transforming capacity. As essentially no normal tissues express the chimeric mRNA, we targeted it for destruction in cancer cells with stably expressed siRNA constructs. Specific targeting led to essential annnihilation of the CYCLIN D1-TROP2 mRNA, in the absence of off-target effects. Silencing of the chimeric mRNA blocked the growth of expressing breast cancer cells. Conclusions: Our findings demonstrate a novel, widespread oncogenic mechanism in human cancers, and open novel avenues for mRNA-targeted anti-cancer therapies. Acknowledgments This work was supported by the the Fondazione of the Cassa di Risparmio della Provincia di Chieti, the Association for the Application of Biotechnology in Oncology (ABO and ABO Project S.p.A., grant no. VE01D0019) and the Marie Curie Transfer of Knowledge Fellowship, contract number 014541. No significant financial relationships to disclose.
Circulating endothelial cells (CECs), progenitors (CEPs), and circulating tumor cells (CTCs) for prediction of response in patients with advanced breast cancer (ABC) receiving metronomic oral vinorelbine (oV): Preliminary results
Authors: Nole F. , Munzone E. , Bertolini F. , Sandri M. T. , Petralia G. , Adamoli L. , Radice D. , Cullura D. , di Pietro A. , Goldhirsch A. 
Published: August 2020

e14572 Background: Metronomic administration of chemotherapy given once or more per week with no extended gaps was shown to be effectively anti-angiogenic, causing growth arrest or apoptosis of endothelial cells in tumor neo-vessels. Preclinical and clinical studies indicate that ultra-low concentrations of various microtubule inhibitors inhibit proliferation or migration of endothelial cells. We investigated in a phase II study the activity of metronomic administration of oV in ABC, kinetics and response prediction of CECs, CEPs, CTCs and of other biomarkers of angiogenesis (soluble VEGF, VEGFr2, TSP1, bFGF). CT perfusion scans were also performed. Methods: From February 2008, 47 pts with ABC received oV (50 mg/die TTW). Currently 20 pts are evaluable for both activity and biomarker assessment. Baseline levels of biomarkers of angiogenesis were correlated with clinical response. Results: Shown in Table . Conclusions: We found that the baseline value of apoptotic cells (expressed as % of total cells) was significantly correlated with outcome. The baseline total, viable, and apoptotic CEC count and CTCs might provide an indirect measure for angiogenic turnover and an indicator of better response to anti-angiogenic therapy, supporting the use of metronomic treatments in patients expressing high levels of baseline CECs. Updated results will be presented together with correlation with perfusion CT scan and levels of CTCs. [Table: see text] No significant financial relationships to disclose.