bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing true tumor volume to unidimensional and bidimensional measurements in lung cancer—A better discriminator of response?
Authors: Schwartz L. H. , Zhao B. , Moskowitz C. , Michelle G. , Rizvi N. A. , Kris M. G. 
Published: March 2020

13020 Background: Accurate evaluation of response is crucial to determine if a treatment is effective for a particular patient or if an experimental agent is effective against a specific tumor type. Current measurement techniques such as WHO and RECIST are limited by only identifying changes in size in the axial plane, and with one or two dimensions. We devised and tested a semi-automated algorithm to calculate tumor volume and other parameters on thin-section CT scans to assess response in patients with non-small cell lung cancer (NSCLC) treated with gefitinib in a clinical trial. Methods: CT scans of 15 measurable pre- and post-gefitinib-treated non-small-cell lung cancers in 15 patients were analyzed. A semi-automated three-dimensional segmentation algorithm was developed for lung cancer and applied to each tumor at baseline and follow-up. The computer automatically identified the boundaries of the tumors in three dimensions and the “true” volume and calculated the greatest diameter and the product of the greatest diameter and its perpendicular. Exact McNemar tests were used to analyze differences between RECIST, WHO and volumetric changes from baseline to follow up. Results: The computer accurately segmented 14 of 15 tumors. One paramediastinal tumor required manual separation from the mediastinum. Seventy-three percent (11/15) of patients had an absolute change of at least 20% in tumor volume, compared with 7% (1/15) and 27% (4/15) with similar changes in uni-dimensional (p < 0.01) and bi-dimensional (p = 0.04) tumor measurements, respectively. Forty-seven percent (7/15) of patients had an absolute change of at least 30% in tumor volume, but an absolute change of at least 30% was found in no patients by uni-dimensional measurement (p = 0.02) and in 13% of patients by bi-dimensional measurement (p = 0.06). Analysis of percentage change using an adjusted/scaled method will also be presented. Conclusions: By measuring tumor volume, greater numbers of patients were identified having absolute changes of at least 20% and 30% than by using RECIST or WHO. Therefore, volumetric changes may have the potential to be an earlier or better marker of regression or progression. No significant financial relationships to disclose.
ARRY-649, a member of a novel class of Eg5 kinesin inhibitors
Authors: Miglarese M. R. , Wallace E. , Woessner R. , Allen S. , Hans J. , Lemieux C. , Dewolf W. , Lyssikatos J. , Lee P. , Koch K. 
Published: March 2020

13045 Background: Inhibitors of the Eg5 motor kinesin selectively disrupt mitotic spindles in dividing cells. This selective targeting of microtubule dynamics in dividing cells is expected to translate to broad-spectrum anti-tumor activity while avoiding neuropathic side effects caused by taxanes. To date, quinazolinone Eg5 inhibitors, exemplified by ispinesib, represent the only Eg5 inhibitors reported in clinical trials. Methods: We used X-ray crystallography, biochemical and cell-based assays, pharmacokinetic profiling and in vivo efficacy studies to identify and optimize a potent series of Eg5 inhibitors. Results: We have discovered a distinct series of potent Eg5 inhibitors, exemplified by ARRY-649. ARRY-649 inhibited Eg5 with an IC50 of 0.7 nM, blocked phosphorylation of histone H3 in HeLa cells with an IC50 of 0.3 nM and showed sub-nanomolar activity against a broad panel of human tumor cells lines in in vitro viability assays. Further evaluation of mechanism-of-action in tumor cell lines revealed that ARRY-649 induced a monopolar spindle phenotype and subsequent apoptosis characteristic of Eg5 inhibition. In contrast to paclitaxel, ARRY-649 retained potent activity against multi-drug resistant human tumor cells lines selected to overexpress P-glycoprotein. ARRY-649 demonstrated robust efficacy in the HT-29 human colon tumor xenograft model and was well-tolerated at efficacious doses and schedules. Durable complete- and partial-regressions were observed upon intraperitoneal administration on a 5 mg/kg q4dx3 schedule in the HT-29 model. Similar results were obtained using the HL-60 myelomonocytic xenograft model. Conclusions: ARRY-649 represents a distinct class of potent Eg5 inhibitors with robust activity in preclinical models of human cancer. Based on these observations, we have progressed novel Eg5 inhibitors toward clinical development. [Table: see text]
Phase II study of docetaxel (D) plus bevacizumab (B) in Her/2 negative metastatic breast carcinoma (MBC)
Authors: Chan D. , Allen H. , Hu E. , Reese D. , Patel G. , Gottlieb C. , Wax A. , Sosa J. , Slamon D. , Kabbinavar F. 
Published: March 2020

13047 Background: Taxol+Bevacizumab (B) has clinical activity in Her/2 negative chemotherapy naive MBC with a PFS (11.4 mo), RR (29.9%), and OS (28.4 mo). We are conducting a single arm Phase 2 trial to assess the efficacy of Docetaxel (D)+B. Primary endpoint: time to progression. Secondary endpoints: response rate (CR + PR), response duration, overall survival and safety. Methods: Eligibility criteria: MBC with no prior therapy; Her/2 negative by FISH, ECOG PS 0 or 1; measurable disease by RECIST, Hgb ≥ 9 g/dL, ANC ≥ 1.5 × 109/L, Platelet count ≥ 100 × 109/L, Creatinine ≤ 2.0 mg/dL, Total bilirubin ≤ 1.0 × upper limit of normal, no CNS metastasis, no MI or stroke within 6 mo, no GI perforation, no major surgery within 28 d, and no bleeding diathesis or coagulopathy. Pts receive B 15 mg/kg IV and D 75 mg/m2 IV Q 3 wk. Response assessed radiographically Q 3 cycles. Treatment is until disease progression or unacceptable toxicity. Results: Since Apr 2005, 43 of the planned 75 pts have been enrolled. 21 pts have had at least one assessment resulting in approximately 40% response rate. Common Gr3/4 AE’s have been neutropenia, febrile neutropenia, hypertension. Gr3 LVEF decline seen in one pt. No treatment related deaths occurred. Conclusions: D+ B is well tolerated, with no new safety concerns and manageable toxicities. D+B appears active in MBC. Updated efficacy and safety data will be presented. Study supported by Genentech, Inc. San Francisco, CA. No significant financial relationships to disclose.
Phase I/II trial of capecitabine (C), dacarbazine (D) and imatinib (I) (CDI) for patients (pts) metastatic medullary thyroid carcinomas (MTC)
Authors: Hoff P. M. , Hoff A. O. , Phan A. T. , Sherman S. I. , Yao J. , White N. , Phan L. , Abbruzzese J. L. , Gagel R. F. 
Published: March 2020

13048 Background: MTC is a rare tumor that responds poorly to conventional chemotherapy. 5-FU and D are frequently used, with an expected response rate of around 15%. MTC is often associated with multiple endocrine neoplasia type 2, an autosomal dominant syndrome caused by a mutation in the RET proto-oncogene which encodes RET, a tyrosine kinase receptor. I is a tyrosine kinase inhibitor with activity against c-Kit, PDGF and possibly RET, and we postulated that its addition to chemotherapy would increase its efficacy against this disease. Methods: We designed a phase I/II trial combining escalating doses of oral C, IV D and oral I. Pts with any advanced solid tumors were eligible for the phase I part of the trial. Results: 13 pts were entered and 12 were eligible (7 MTC, 2 adrenocortical, 1 islet-cell, 1 insular thyroid and 1 small cell). 4 pts did not complete one cycle (1 pt withdrew after 5 days and 2 pts progressed in less than 10 days and were replaced for toxicity analysis, 1 had a DLT and is included). 3 patients were entered in dose level 1, without DLT. 2 out of 6 pts developed DLT at the second dose level (1 G 3 fatigue and 1 G3 hypokalemia). Three additional pts are being entered on dose level 1. The first one had PD after 7 days and is being replaced. For the 11 pts who were evaluable, best response was 3 SD (range 3 to 9 + months) and 8 PD. Conclusions: The combination of CDI is feasible but has resulted in an unexpected pattern of toxicity in this patient population, with fatigue and hypokalemia as the DLT. No significant diarrhea or hand-foot syndrome was seen. Only G1 and 2 fluid retention and neutropenia have been encountered. Only minor reduction in tumor size has been seen among these heavily pretreated pts. Once the phase I is complete, the trial will continue in a phase II setting for untreated MTC pts. [Table: see text] [Table: see text]
Phase I trial of bortezomib and celecoxib in patients with advanced solid tumors
Authors: Dunder S. , Chaudhary U. B. , Green M. , Meyer M. , Brescia F. , Kraft A. , Montero A. , Salzer S. 
Published: March 2020

13051 Background: The ubiquitin-proteosome pathway plays an important role in cell cycle regulation, neoplastic growth, and metastasis. Nuclear factor-kB (NF-kB) is a key transcription factor in cancer, primarily regulated by proteosome-mediated degradation of the inhibitor protein I kappa B alpha-associated protein kinase (IkBa). Interruption of this degradative pathway, with the 26S proteosome inhibitor bortezomib, has displayed significant clinical anti-tumor activity, in multiple myeloma and lymphomas. The role of bortezomib in the treatment of advanced solid tumors, however, is unclear at present. Preclinical work in multiple myeloma cell lines has demonstrated synergy in cytotoxicity and growth inhibiton with the combination of bortezomib and the cyclooxygenase (COX)-2 inhibitors. We therefore hypothesized that the combination of the COX-2 inhibitor celecoxib and bortezomib is a potentially active combination in the treatment of advanced solid tumors. Towards this aim, we are conducting a phase I study to determine the maximum tolerated dose (MTD) and toxicity profile of bortezomib and celecoxib. Methods: Patients with advanced solid tumors and an ECOG PS of 0–2 received escalating doses of bortezomib (1.0–1.6 mg/m2), either weekly for 5 of 6 weeks or twice weekly for 2 of 3 weeks, and celecoxib (200–400 mg twice daily). Accrual was planned to a maximum of 6 cohorts, each with a minimum of 3 patients. Only those dose-limiting toxicities (DLTs) occurring during the first cycle were used to define the MTD. DLTs included any grade 4 hematologic toxicity related to therapy, or any grade 3 or 4 non-hematologic toxicity. Results: To date, 10 patients (median age of 63y) have been treated. Represented tumor types include stage IV: colorectal, pancreatic, bladder, leiomyosarcoma, head and neck squamous cell carcinoma, hepatocellular, and renal cell. A median number of 2 cycles were administered. Thus far, no DLTs have been observed. No cumulative toxicities have been noted. No objective tumor response has been observed, however, stable disease was maintained in one heavily pre-treated patient with metastatic papillary renal cell cancer for 5 months. Conclusions: The combination of bortezomib and celecoxib is safe and well tolerated, with no dose-limiting toxicities thus far. [Table: see text]
Characterization of functional heparan sulfate motifs overexpressed on multiple myeloma cells using single chain antibody variable fragments generated by phage display
Authors: Delcommenne M. , Klingemann H. , Fung H. C. , Gregory S. A. 
Published: March 2020

13060 Background: Multiple myeloma (MM) is the most prevalent plasma cell neoplasm and is characterized by the infiltration of the bone marrow by terminally differentiated B lymphocytes. Although novel drugs have recently been introduced, the disease remains incurable. No therapeutic antibody is as yet available for treatment of MM. One of the key molecules involved in multiple myeloma (MM) tumor progression is syndecan-1, a cell surface heparan sulfate (HS) proteoglycan expressed on both MM cells and normal plasma cells. Syndecan-1 regulates cell interactions with soluble molecules and the extracellular matrix through its heparan sulfate chains. These chains allow it to bind multiple growth factors such as Fibroblast Growth Factor type 2 (FGF-2), WNT, Hepatocyte Growth Factor (HGF), midkine, all of which promote survival and metastasis of MM cells. In addition, syndecan-1 on MM cells binds and internalizes osteoprotegerin, the RANKL antagonist, through its HS chains and depletes it from the bone marrow milieu, which triggers osteoclastogenesis. Methods: Using the phage display technique, we have generated a panel of MM-specific human antibody variable fragments (scFvs) against the MM cell line RPMI-8226. These scFvs were tested against a variety of cell lines and primary normal bone marrow or myeloma cells. The biochemical identity of the targeted antigens was determined. Results: Two of the selected scFvs, D4A4 and D6B10, reacted against heparan sulfate motifs that were highly expressed in MM cell lines and patient MM cells but absent (scFv D6B10) or poorly expressed (scFv D4A4) in normal plasma cells. Binding of scFv D6B10 to MM heparan sulfate chains required NS sulfation, 6-O-sulfation and, to a lesser extent, 2-O-sulfation. Additional experiments indicated that FGF-2, midkine and osteoprotegerin competed with scFv D6B10 for binding to HS. Conclusions: This study indicates that the structure of syndecan-1-associated HS is altered in MM cells and may influence its capacity to bind to growth factors and promote tumor progression. Human therapeutic antibodies derived from scFvs D4A4 and D6B10 may be useful for immune targeting of MM cells and interfering with pro-survival signaling pathways. No significant financial relationships to disclose.
Cullin-3 is a potential novel target for breast cancer chemoprevention and treatment
Authors: Miao W. , Loignon M. , Hu L. , Basik M. , Batist G. 
Published: March 2020

13070 Background: Nrf2 is a master transcription factor regulating multiple phase II carcinogen-detoxifying enzymes. Modulating Nrf2 is a current chemoprevention strategy under investigation. Nrf2 levels are regulated by the Keap1, which functions as a substrate adaptor protein targeting Nrf2 to the Cullin-3 (Cul3)-dependent ubiquitin E3 ligase complex. Methods: We used RT-PCR and Western blot to measure the mRNA and protein levels of Nrf2, Keap1 and Cul3 in human breast cancer cell lines. SiRNA and retrovectors were used to construct stable Cul3 silenced breast cancer cell lines. Agilent DNA microarray analysis was used to study the Cul3-slienced cells. Results: We discovered that Nrf2 protein levels in both nucleus and cytoplasm are significantly decreased in all breast cancer cell lines examined compared to normal human mammary epithelial cells (HMEC). This was confirmed with IHC analysis in 8 out of 10 breast cancer specimens containing normal mammary tissues for comparison. Since RT-PCR showed no change in Nrf2 mRNA levels in the breast cancer cell lines, we examined the degradation pathway of Nrf2, and we found that Cul3 is significantly overexpressed in all three breast cancer cell lines studied compared to HMEC. Silencing Cul3 using siRNA results in restoration of Nrf2 protein level, along with multiple carcinogen-detoxifying enzymes, such as GCS. The Cul3 silenced cells showed remarkable growth retardation compared to the wild type MCF-7 cell line both in vitro and in vivo in a mouse mammary fat pad cancer xenograft model. Microarray analyses of Cul3 siRNA-slinced cells demonstrated upregulation of several detoxifying genes, altered cell cycle markers and several upregulated tumor suppressor genes. Conclusions: Nrf2 is significantly downregulated in breast cancer cells, which is related to the overexpression of Cul3, and may represent sensitivity of these cells to carcinogenic transformation. Knocking down Cul3 constitutively upregulates the Nrf2 as well as multiple carcinogen-detoxifying genes. Moreover, it significantly suppressess the proliferation of cancer cells in vitro and growth of xenograft tumors in vivo. These data suggest that Cul-3 is a potential new target for breast cancer chemoprevention and treatment. No significant financial relationships to disclose.
Uridine glucuronosyltransferase 2B7 polymorphisms and epirubicin pharmacokinetics
Authors: Sawyer M. B. , Scarfe A. , Tonkin K. , Joy A. A. , Damaraju S. , Damaraju V. , Pituskin E. N. , Hanson J. , Clemons M. , Mackey J. R. 
Published: March 2020

13071 Background: Epirubicin (epi) is a widely used anthracycline for the treatment of breast cancer. In contrast to its optical isomer doxorubicin, epi is predominantly glucuronidated by uridine glucuronosyltransferase 2B7 (UGT2B7). UGT2B7 has a T to C polymorphism at position -161 in the enhancer region which correlated with efficacy of morphine glucuronidation (Sawyer et al. Clin Pharmcol Ther 2003). Methods: We performed a prospective pharmacogenetic study of FEC100 (5-fluorouracil 500 mg/m2, Epi 100 mg/m2 and cyclophosphamide 500 mg/m2) given every 3 wks in early stage breast cancer pts. Drug levels were drawn at 1 and 24 hrs. We have determined levels of epi, epi-glucuronide (epiG), epirubicinol (epiol), and epiol-glucuronide (epiolG) in 78 of the 120 pts. The levels of epi and its metabolites were measured using an HPLC with fluorescence detection using the method of Fogli et al with modifications. Patient characteristics-median (range): age 50 (28 - 67), sex 77 F/ 1 M, baseline AST 22 U/L (13–66), ALT 20 U/L (5–90), bilirubin 7 umol/L (2–24), creatinine 73 umol/L (51–126). Results: 14 pts were TT homozygotes, 45 were CT heterozygotes, and 19 were CC homozygotes. Concentrations (ng/ml, median (range)) of epi, epiG, epiol, and epiolG at 1 hr respectively were 91 (39–481), 280 (0–981) 76 (14–212) 76 (0–276). There was no relationship between epiG concentration and genotype: 315 (median) TT, 263 CT, 288 CC. Patients with a TT genotype had a lower epiol concentrations (median, ng/ml) at 24 hr: 12 TT, 23 CT, 25 CC; p = 0.04. Conclusions: This analysis shows a relationship between UGT2B7 genotype and epi pharmacokinetics. We are completing analysis of all 120 samples and plan to perform a formal NONMEM analysis. No significant financial relationships to disclose.
Non-linear relationship between HER-2 expression and response to trastuzumab in breast cancer cells
Authors: Valabrega G. , Montemurro F. , Giordano S. , Aglietta M. 
Published: March 2020

13083 Background: Currently, eligibility for treatment with the mAb trastuzumab (T) in breast cancer patients is assessed by semiquantitative immunohistochemical (IHC) analysis of HER-2 expression, where 3+ score represents overexpression, and/or by Fluorescence In Situ Hybridization (FISH), which detects HER-2 gene amplification. However, both methods do not measure small but potentially significant differences in protein expression. Methods: We modulated HER-2 expression by RNA interference (siRNA) in the human HER-2-overexpressing breast cancer cell line SKBR3. Protein expression was measured by Western Blot analysis. Cells expressing different levels of HER-2 protein were then treated with T, to assess the mAb effect on cell proliferation and apoptosis. Results: Compared with the parental cell line, SKBR3 cells transfected with 10, 20, and 30 nM HER2 specific siRNAs, showed a reduction of HER-2 protein levels of 40%, 55% and 70%, respectively. Despite up to a 70% decrease in HER-2 expression, transfected cells still scored 3+ at IHC (Dako HercepTest®). Interestingly, this reduction rendered cancer cells more sensitive to T treatment. In fact, we found that sensitivity to T follows a bell shaped curve, depending on different amounts of HER-2. When T was administered at the standard dose of 10 μg/mL, cells showing a 40% reduction of the HER-2 resulted more sensitive to the growth inhibitory effect of T, compared with parental SKBR3 cells and with cells showing lower levels of receptor. Furthermore, these cells were sensitive to T concentrations lower than standard (6 vs 10 μg/mL), which were markedly less effective in cells expressing higher or lower levels of HER-2 receptor. Conclusions: The observation that cells expressing significantly different amounts of HER-2 protein are all scored as “overexpressors” by conventional IHC suggests that quantitative analysis of HER-2 receptor in breast cancer might be more appropriate for the selection of candidates to T treatment. Moreover, we showed that the inhibitory effect of T depends in a non-linear manner on the quantity of HER-2 protein and that the level of HER-2 expression can influence the sensitivity to T, which requires an optimal drug/receptor ratio. No significant financial relationships to disclose.
hCNT1 in Waldenström’s macroglobulinemia (WM) and small lymphocytic lymphoma (SLL) patients (pts): A possible predictive biomarker of 2-chloro-2`-deoxyadenosine (2-CDA) clinical activity
Authors: Rabascio C. , Saronni L. , Antoniotti P. , Raia V. , Bertolini F. , Laszlo D. , Cassatella M. , Marziliano N. , Arbustini E. , Martinelli G. 
Published: March 2020

13087 Background: The resistance mechanism to 2-CDA is not completely known. In this study we used pharmacogenomic to identify genetic factors that influence drug response and to better investigate 2-CDA complex intracellular metabolism. Methods: Using Real-time PCR method (ABI-PRISM 7000 machine) we amplified seven genes, encoding for equilibrative and concentrative nucleoside transporter (hENT1, hCNT1), deoxycytidine and deoxyguanosine kinase (dCK, dGK), 5`-nucleotidase (5`NT), ribonucleotide reductase catalytic and regulatory (RR1, RR2) subunits, in bone marrow (BM) at baseline of 17 pts with WM or SLL in order to verify the correlation between gene expression and clinical outcome. All pts were treated with a combination therapy (2-CDA 0.1 mg/kg sc injection and Rituximab at standard schedule). Quantitation was performed using the Delta CT calculation: the value of gene expression was normalised to the calibrator (healthy tissue cells). Results: hCNT1 and 5’NT gene expression analysis has shown lower values in pts than in controls. The other markers didn’t show any significance. Two pts achieving partial remission (PR) presented 100 times lower hCNT1 levels (median 6.8*10−4, range 6.8–6.9*10−4) than pts (n = 10) in complete remission (median 7.9*10−2, range 0.1–4.6*10−1; p = 0.03). Conclusions: hCNT1 seems to be the most important gene involved in 2-CDA clinical activity and its expression may correlate with prognosis. Compared to controls, the low plasmatic RNA level of hCNT1 exhibited by our pts doesn’t seem to be predictive of lack of clinical activity of 2-CDA. However the lower level of hCNT1 plasmatic expression detected in the two pts who achieved only PR could suggest a possible relationship between reduced hCNT1 plasmatic expression and a diminished clinical activity of 2-CDA. Thus it might be important to explore the possibility of standardizing a quantitative method in order to identify a threshold value which could be predictive of drug resistance. No significant financial relationships to disclose.