bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular targeting of IGF-I receptor for human pancreatic cancer
Authors: Adachi Y. , Yamamoto H. , Imsumran A. , Wang Y. , Li R. , Min Y. , Arimura Y. , Lee C. , Shinomura Y. , Carbone D. P. , Imai K. 
Published: March 2020

14051 Background: Pancreatic cancer is one of the worst prognostic diseases. Continuous tumor growth depends on the altered regulation of the cell cycle that is modulated by signals from growth factors and their receptors, including insulin-like growth factors (IGF) and IGF-I receptor (IGF-Ir). It have been reported that blockade of IGF-Ir can suppress tumorigenicity and induce regression of established tumors. Recently several approaches of targeting IGF-Ir have been reported, including monoclonal antibodies and tyrosine kinase inhibitors. Methods: To study the mechanism of this effect and develop potential targeted therapeutics, we have constructed truncated IGF-Irs that function as dominant negative inhibitor (IGF-Ir/dn) and short hairpin RNA for IGF-Ir (shIGF-Ir). Those were cloned into recombinant adenoviruses (ad-IGF-Ir/dn and ad-shIGF-Ir). The effects of these adenoviruses were studied in human pancreatic cancer cell lines, BxPC3, Panc1, and AsPC1. We assessed efficiency of IGF-Ir signaling blockade, the effect of the adenoviruses on cell growth, steady-state, radiation, and chemotherapy induced apoptosis, and in vivo therapeutic efficacy in xenografts. Results: The blockade for IGF-Ir suppressed tumorigenicity of cancer cells both in vitro and in vivo and increased the amount of steady-state apoptosis in cancer cells. IGF-Ir/dn effectively blocked both IGF-I and IGF-II signaling through Akt-1 and shIGF-Ir reduced both IGF-Ir expression and ligands inducing phosphorylaion. The blockade for IGF-Ir increased chemotherapy and radiation induced apoptosis in vitro and the combination therapy with chemotherapy was very effective against established tumors in mice. Conclusions: These data suggest that the blocking of IGF-Ir signals, by ad-IGF-Ir/dn or ad-shIGF-Ir, may be a useful therapeutic strategy for pancreatic cancers. No significant financial relationships to disclose.
Safety and pharmacokinetics (PK) of AMG 706 in combination with panitumumab and gemcitabine-cisplatin in patients (pts) with advanced cancer
Authors: Crawford J. , Burris H. , Stephenson J. , Otterson G. , Stein M. , McGreivy J. , Sun Y. , Ingram M. , Yang L. , Schwartzberg L. S. 
Published: March 2020

14057 Background: AMG 706 is an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF and Kit receptors. Methods: This is an ongoing phase 1b, open-label, dose-finding study of AMG 706 plus panitumumab and gemcitabine-cisplatin. Objectives are to establish the maximum tolerated dose and to assess safety, objective response and PK of AMG 706 with this regimen. Pts =18 yrs with advanced cancer, ECOG 0–1, =1 prior chemotherapy for advanced disease and no prior oral VEGFr MKIs or anti EGFR therapy, received panitumumab (9mg/kg IV day 1 of each 3-wk cycle) plus gemcitabine (1250mg/m2 IV days 1 and 8) and cisplatin (75mg/m2 IV day 1), and escalating doses of AMG 706 given continuously from day 1 of cycle 1. Assessments included dose-limiting toxicities (DLT; cycle 1), PK and tumor response (every 6–9 wks from wk 6). Results: As of Nov 2006, 36 pts (NSCLC n=19; pancreatic cancer n=4; other n=10; unknown primary n=3) were enrolled; 42% had prior chemotherapy. There was 1 DLT: pulmonary embolism, grade 5 (50mg QD). Selected treatment-related adverse events in =10% of pts are shown in the table . 39% of pts receiving AMG 706 had thromboembolic events (TE); 25% receiving study therapy without AMG 706 had TEs. There was 1 case of cholecystitis (grade 1), 1 of gallbladder pain (grade 3). Preliminary data showed that AMG 706 PK at 125 mg QD was comparable to data from monotherapy studies at the same dose level. Based on 29 pts with available response data (too early to evaluate/data unavailable n=7), objective tumor responses per RECIST were: CR n=1, 3% (breast cancer); PR n=9, 31% (NSCLC n=6; pancreatic cancer n=2; unknown primary n=1); SD n=17, 59%; PD n=1, 3%. Conclusions: In this study of pts with advanced cancer, AMG 706 was tolerable when combined with panitumumab and gemcitabine-cisplatin, with little effect on AMG 706 PK. Further studies need to determine if the observed TE rate exceeds gemcitabine-cisplatin background rates. [Table: see text] No significant financial relationships to disclose.
Brief intravenous infusions of oblimersen (Genasense; Bcl-2 antisense) alone and in combination with multiple agents are highly effective in human tumor xenografts
Authors: Brown B. D. , Paine-Murietta G. D. , Julian T. N. , Warrell R. P. 
Published: March 2020

14061 Background: Oblimersen (OBL; Genasense®) is a phosphorothioate-modified antisense oligodeoxynucleotide (ODN) that down-regulates Bcl-2 and may enhance the response to chemotherapy in patients with melanoma and chronic lymphocytic leukemia (CLL). Extensive safety data for Genasense and other systemically administered ODNs have been obtained using low-dose continuous intravenous infusions (CIVI). However, this method is inconvenient and unsuitable for drug combinations that employ frequent or discontinuous dosing. We have now established that OBL can be effectively administered by high-dose, short IV infusions. Methods: We tested multiple treatment schedules of OBL, alone and in combination with paclitaxel, paclitaxel albumin nanoparticles, imatinib, sorafenib, sunitinib, and erlotinib against human tumor xenografts (melanoma A375, NSCLC A549 and H460, colon HT29 and SW620) grown in C.B-17/SCID mice. Results: Periodic OBL monotherapy (high dose IV Q2–3d) yielded consistently superior antitumor efficacy when compared with low- dose daily IV injections. These results have been obtained against all tumor models evaluated to date. This increased efficacy was also observed when OBL was combined with any other therapeutic agent. For combination treatments that included taxanes, efficacy was shown to be schedule dependent. Conclusions: These results, and recent clinical observations, suggest that brief high-dose IV infusions of OBL may significantly increase antitumor activity, and may obviate the need for CIVI. Brief high-dose IV infusions are being incorporated into ongoing clinical trials to evaluate the safety and efficacy of OBL in combination with other agents. No significant financial relationships to disclose.
Imaging of angiogenesis in metastatic breast cancer by positron emission tomography (PET) using [18F]AH11585, an [18F]- labeled alphaVbeta3 (αvβ3) peptide
Authors: Kenny L. M. , Aboagye E. , Cohen P. S. , Miller M. , Turkheimer F. , Al-Nahhas A. , Blunt D. , Coombes R. C. 
Published: March 2020

14067 Background: In vivo imaging of avβ3 expression in tumors and tumor endothelial cells may be a useful biomarker of angiogenesis. [18F]AH11585 is a novel peptide containing an Arginine-Glycine-Aspartic Acid (RGD) motif that binds to avβ3 with high affinity designed for use in PET studies. Methods: 7 patients with metastatic breast cancer (aged 37–68 years) received intravenous injections of [18F]AH11585 and were scanned dynamically by PET over 61.5 mins. Radioactivity concentrations, derived from regions of interest placed on tumour and normal tissues, were analysed mathematically to determine the net irreversible uptake (Ki), fractional retention (FRT) and standardized uptake at 56.5min (SUV) of the radiotracer. Computed tomography (CT) was performed within 4 weeks of the scan. Results: Tumor lesions were clearly visible on PET images in 6/7 patients. In one patient with a palpable supraclavicular lymph node not visible on CT, we were unsure if a hyperintense region visible by PET was tumor. In total 18/19 tumor lesions were identified on both PET and corresponding CT images. Tumors in areas of low background were hyperintense (lung, bone, breast) whereas those in areas of high background were hypointense regions (liver). Tumors with central necrosis showed high uptake of [18F]AH11585 around the periphery only. Mathematical analysis demonstrated irreversible retention of [18F]AH11585 in tumors. [18F]AH11585-PET discriminated between non-liver lesions (n=10) and normal tissues: Ki (p=0.002), FRT (p=0.0039), SUV (p=0.002). Corresponding comparisons for liver lesions (n=8) were significant for FRT (p=0.0078) and SUV (p=0.0078) only. Conclusions: [18F]AH11585 PET is a promisng method for in vivo imaging of avβ3 integrin expression in metastatic breast cancer. No significant financial relationships to disclose.
A novel K-samII/FGF-R2 autophosphorylation inhibitor is therapeutically useful for scirrhous gastric carcinoma with K-samII amplification
Authors: Yashiro M. , Nakamura K. , Sawada T. , Kawajiri H. , Shimizu T. , Miwa A. , Hirakawa K. 
Published: March 2020

14070 Background: Scirrhous gastric carcinoma, a diffusely infiltrating also known as linitis plastica-type carcinoma, carries the highest mortality of all gastric cancers. Scirrhous carcinoma cells with amplification of the activated K-samII gene, which encodes fibroblast growth factor receptor type 2 (FGF-R2), have a growth advantage during tumor progression The poor prognosis carried by scirrhous gastric cancer is closely associated with amplification of the K-samII/FGF-R2, a tyrosine kinase growth factor receptor. Ki23057, a newly developed small molecule acting K-samII/FGF-R2 inhibitor, is a kinase inhibitor that competes with ATP for the binding site in the kinase, thus strongly blocking phosphorylation of FGF-R2. The aim of the current study is to clarify the possibility of molecular target therapy with Ki23057 for treating scirrhous gastric cancer. Methods: Five human gastric cancer cell lines were used. OCUM-2MD3 and OCUM-8 were derived from scirrhous carcinomas. MKN-7, MKN-45 and MKN-74 cells were derived from non-scirrhous carcinomas. In vitro effects of Ki23057 on cell growth were determined by calculating the number of cancer cells. The influences of Ki23057 on the MAP kinase and PI3 kinase signaling pathways and the apoptosis pathway in the gastric cancer cells were also examined. For in vivo experiments, the Ki23057 was administered orally to mouse models of peritoneal dissemination. Results: K-samII amplification was found in OCUM-2MD3 and OCUM-8 cells, but not in MKN-7, MKN-45, or MKN-74 cells. Ki23057 significantly inhibited the proliferation of scirrhous cancer cells, but not non- scirrhous gastric carcinoma cells. Ki23057 decreased phosphorylation of K-samII/FGF-R2, ERK and Akt, and increased apoptosis in scirrhous cancer lines. The oral Ki23057 administration significantly (p<0.001) prolonged survival of mice with peritoneal dissemination following injection of OCUM-2MD3 scirrhous cancer cells. Conclusions: A novel K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, appears therapeutically promising in scirrhous gastric carcinoma with K-samII amplification. No significant financial relationships to disclose.
A phase I study of therapeutic amplitude-modulated electromagnetic fields (THERABIONIC) in advanced tumors
Authors: Pasche B. , Barbault A. , Bottger B. , Bomholt F. , Kuster N. 
Published: March 2020

14072 Background: In vitro studies suggest that low levels of amplitude-modulated electromagnetic fields may modify cell growth. We have identified specific frequencies that may block cancer cell growth. We have developed the THERABIONIC device, a portable and programmable emitter of a 27.12 MHz radiofrequency signal, amplitude-modulated at cancer-specific frequencies ranging from 0.2 to 23,000 Hz with high precision. The device is connected to a spoon-like coupler, which is placed in the patient’s mouth during treatment. The levels of absorbed electromagnetic energy are well below safety limits. Methods: A phase I study consisting of three daily 40 min treatments until disease progression or death. From March 2004 to September 2006, 24 patients with advanced solid tumors were enrolled. The median age was 57.0 ± 12.2 years. 16 patients were female. As of January 2007, 5 patients are still on therapy, 13 patients died of tumor progression, 2 patients are lost to follow-up and one patient withdrew consent. The most common tumor types were breast (7), ovary (5) and pancreas (3). 21 patients had received prior systemic therapy and 16 had documented tumor progression prior to study entry. Results: The median duration of therapy was 15.7 ± 19.9 weeks (range: 0.4–72.0 weeks). There were no NCI grade 2/3/4 toxicities. Three patients experienced grade 1 fatigue during and immediately after treatment. 12 patients reported severe pain prior to study entry. Two of them reported significant pain relief with THERABIONIC treatment. Objective response could be assessed in 13 patients, 6 of whom also had elevated tumor markers. 6 additional patients could only be assessed by tumor markers. Among patients with progressive disease at study entry, one had a partial response for > 14.4 weeks associated with > 50% decrease in CEA, CA 125 and CA 15–3 (previously untreated metastatic breast cancer); one patient had a 50% decrease in CA 19–9 for 12.4 weeks (recurrent and previously systemically-treated pancreatic cancer). Among patients with stable disease at enrollment, four patients maintained stable disease for 17.0, > 19.4, 30.4 and > 63.4 weeks. Conclusions: THERABIONIC is a safe and promising novel treatment modality for advanced cancer. No significant financial relationships to disclose.
Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies
Authors: Falchook G. S. , Dhillon N. , Moulder S. , Duvic M. , Ng C. , Hong D. , Camacho L. , Lim J. , Wang M. , Fayad L. , Kurzrock R. 
Published: March 2020

14087 Background: Bortezomib, a potent proteasome and NF-kB inhibitor, potentiates the activity of chemotherapy in a variety of tumors in vitro and in mouse models, and preclinical data suggest that the combination of bortezomib, gemcitabine, and liposomal doxorubicin is synergistic. Because tolerance to combination therapy may be attenuated in elderly patients, we performed a phase I age- stratified trial to determine the maximum tolerated dose (MTD), toxicity, and antitumor activity of this combination. Methods: Starting doses were bortezomib 0.7 mg/m2 (days 1 and 8), gemcitabine 500 mg/m2 (days 1 and 8), and liposomal doxorubicin 20 mg/m2 (day 1). Two parallel age-stratified arms (< 65 and = 65 years old) were accrued, with at least three patients per dose level per arm. Each treatment cycle was 21 days. Results: 47 patients have enrolled, and the MTD has not yet been reached. For patients < 65 years old, accrual continues at the ninth dose level with bortezomib 1.3 mg/m2 (days 1, 4, 8, 11), gemcitabine 800 mg/m2 (days 1 and 8), and liposomal doxorubicin 40 mg/m2 (day 1). For patients = 65 years old, accrual continues at the fourth dose level with bortezomib 1.0 mg/m2 (days 1, 4, 8, 11), gemcitabine 800 mg/m2 (days 1 and 8) and liposomal doxorubicin 20 mg/m2 (day 1). The most common side effects have been thrombocytopenia and neutropenia, with thrombocytopenia necessitating dose delays and withholding of doses. In the arm with patients = 65 years old, a dose-limiting toxicity of grade 3 fatigue was observed at dose level 4, and that cohort is currently undergoing dose expansion. Seven patients have achieved a partial response, including one patient with small cell lung carcinoma (6 months; 3 prior therapies) and all of six evaluable patients with cutaneous T cell lymphoma (1, 3, 4, 6, 7, and 8 months; median 4 prior therapies). Stable disease = 6 months was observed in 5 patients with various solid tumors (7, 7, 8, 9, and 9 months; median 4 prior therapies). Conclusions: This combination regimen is well tolerated. Dose-limiting toxicity has developed earlier in the elderly cohort, as predicted. Antitumor activity in heavily pretreated patients with advanced malignancies has been observed. No significant financial relationships to disclose.
Interim results of a phase I trial with a novel orally administered synthetic triterpenoid RTA 402 (CDDO-Me) in patients with solid tumors and lymphoid malignancies
Authors: Dezube B. J. , Kurzrock R. , Eder J. P. , Supko J. G. , Meyer C. J. , Camacho L. H. , Andreeff M. , Konopleva M. , Lescale-Matys L. , Hong D. 
Published: March 2020

14101 Background: RTA 402 (CDDO-Me) is a novel synthetic triterpenoid with potent anticancer and anti-inflammatory activity through selective modulation of proteins that respond to changes in oxidative stress, including NF-κB, JNK, and STAT3. Based on preclinical data demonstrating effects on tumors and associated stroma, a Phase 1 dose-finding and pharmacokinetic study was initiated. Methods: RTA 402 is administered orally once a day for the first 21 days of a 28-day cycle. Dose escalation is proceeding according to an accelerated titration design until an MTD is reached. Results: RTA 402 has been administered to 11 patients at 7 dose levels (5 to 300 mg/day). Cycle 1 data are available for 8 patients. No significant drug-related toxicity has been reported and dose escalation continues in 100% increments. The median biological half-life of RTA 402 was 49 h (range, 18–67 h), and all patients receiving doses >20 mg/day were continuously exposed to plasma levels of the drug exceeding 1 ng/mL. Evidence of antitumor and biological activity has been observed in initial patients. A patient with medullary thyroid carcinoma treated at 5 mg/day has received eight cycles of therapy and has had stable disease with a 70% reduction of calcitonin levels. A patient with metastatic melanoma has experienced disease stabilization through four cycles and remains on study. A second melanoma patient has also experienced disease stabilization through two cycles and remains on study. Radiographic evidence of regressing lesions has been observed in both melanoma patients. Additionally, significant reductions in circulating VEGF, MMP-9, TNF, IL-8, and IL-10, up to 65%, 91%, 90%, 73%, and 70%, respectively, have been observed in at least half of patient samples. Cytokine suppression has correlated with improvements in reported pain and fatigue. Conclusions: Orally administered RTA 402 appears well tolerated up to 150 mg/day and with prolonged exposure up to 8 months. Data from initial patients indicate biological activity and suggest clinical benefit, with disease stabilization in several patients who had rapidly progressing disease with high tumor burden. Phase 2 trials are planned. No significant financial relationships to disclose.
The taxane-enhancer STA-4783 induces Hsp70 expression and apoptosis via an oxidative stress mechanism
Authors: Kirshner J. , Du Z. , Kepros J. , Balasubramanyam V. , He S. , Zhang M. , Yang C. , Barsoum J. , Bertin J. 
Published: March 2020

14107 Background: STA-4783 is an inducer of Hsp70 expression and apoptosis that recently completed a successful Phase II clinical trial in melanoma. In a double-blind, randomized, controlled trial in patients with Stage IV disease, STA-4783 plus paclitaxel doubled progression-free survival compared to paclitaxel alone (Perspectives in Melanoma X and the Third International Melanoma Research Congress, 2006). The mechanism by which STA-4783 synergizes with paclitaxel is not fully understood. To identify the major pathway modulated by STA- 4783 in vitro, a transcriptional profiling analysis of drug-treated melanoma cells was performed. Methods: Transcriptional profiling was performed on Hs294T and MDA-MB-435 melanoma cell lines treated with STA-4783. The induction of Hsp70 RNA and other human genes was monitored by Real Time-PCR (RT-PCR) analysis. Measurement of reactive oxygen species (ROS) was performed in human cells using the Carboxy-H2DCFDA probe. Levels of apoptotic cell death were determined by flow cytometry analysis using an Annexin V specific probe. Results: Transcriptional profiling revealed that STA-4783 induced the expression of numerous gene families known to be regulated by oxidative stress, including heat shock proteins and metallothioneins. STA-4783 induced the generation of ROS in cells resulting in the oxidation and activation of the Carboxy-H2DCFDA fluorescent probe. The antioxidants N-Acetyl Cysteine (NAC) and Tiron potently blocked the induction of Hsp70 RNA and apoptotic cell death. Conclusions: STA-4783 induces oxidative stress in cells resulting in Hsp70 induction and apoptotic cell death. Although STA-4783 initially induced a transient protective response, apoptotic cell death occurred due to sustained oxidative stress. Cancer cells produce more ROS than normal cells and are thus more sensitive to insults that induce oxidative stress. The induction of ROS in melanoma cells by STA-4783 may therefore enhance the efficacy of paclitaxel in vivo. STA-4783 belongs to a novel class of anticancer agents that induce cell death by pushing the cancer cell beyond its oxidative stress breaking point. [Table: see text]
PET FES measures in vivo pharmacodynamics of endocrine therapy
Authors: Linden H. M. , Mankoff D. A. , Krohn K. A. , Link J. M. , Stekhova S. , Livingston R. B. , Gralow J. R. , Ellis G. K. , Kurland B. , Peterson L. , Schubert E. K. 
Published: March 2020

14110 Background: Many clinical options are available for management of hormone sensitive breast cancer, including agents which lower estrogen levels such as aromatase inhibitors (AIs) and agents with block ligand binding to receptor such as tamoxifen (TAM) or fulvestrant (FUL). Estrogen receptor (ER) function is essential for sensitivity to hormonal manipulation in breast cancer treatment. We and others have previously shown that functional ER imaging using PET FES predicts response to hormonal therapy using a quantitative threshold of SUV >1.5. Herein we report that FES PET provides a unique insight into in vivo pharmacodynamics of ER therapy. We hypothesized that the impact of therapy on estradiol binding to ER, measured by FES PET, differs between AIs and ER antagonists, and that early changes in receptor expression/occupancy show efficacy of drug at the tumor target. Methods: Patients undergoing treatment with AI, TAM, or FUL underwent baseline PET FDG and FES, and follow-up PET FES imaging at 2–8 weeks post initiation of therapy. Results: We observed the following changes in FES uptake on hormonal therapy: Mean percent change in FES SUV were 54% decline for TAM and FUL vs. 14% decline for AI treated patients (p<.001). Patients on TAM showed complete blockade of tumor FES uptake on therapy (5/5 with residual SUV <1.5), whereas patients on FUL had variable uptake and incomplete blockade at tumor sites in most patients (4/11 with residual SUV <1.5) (p < .05 FUL vs. TAM), despite consistent blockade of uterine FES uptake in patients where the uterus was visualized pre-FUL. Patients on AI therapy (n=14) had variable tumor uptake following treatment initiation. Conclusions: PET FES effectively monitors the in vivo activity of therapy. Estrogen blocking therapies result in a greater change in tumoral estradiol binding than in ligand depletion. TAM effectively blocks uptake of FES as would be predicted by the mechanism of action of this agent. However, FUL (while blocking uterine uptake) incompletely blocks tumor uptake, providing a mechanism to explain reduced activity of this agent in some patients. Ongoing analysis is designed to assess whether early changes in FES predict response or clinical benefit. No significant financial relationships to disclose.