bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of oncolytic adenoviral therapy with chemotherapy for enhanced breast cancer cell killing.
Authors: Stoff-Khalili MA , Nedeljkovic-Kurepa A , Jung JS , Glover BV , Wappenschmidt B , Rhiem K , Bosse K , Mallmann P , Curiel DT , Schmutzler RK , Mathis MJ 
Published: December 2010

Abstract
Abstract #2129
Oncolytic adenoviruses are emerging agents for treatment of cancer by tumor-restricted virus replication, cell lysis and virus spread. A promising oncolytic adenovirus agent, known as Ad5-24-RGD, harbors a 24-bp deletion in the E1A gene that abrogates the binding of E1A to the retinoblastoma tumor suppressor (Rb) and presents enhanced infectivity of primary cancer cells due to insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob. Thus, Ad5-24-RGD has improved cancer cell infection efficiency due to expanded tropism toward alpha-v integrins. It also replicates selectively in cancer cells with Rb/p16 mutations. As with conventional therapy regimes, oncolytic virotherapy, by itself, has limited success in complete tumor eradication in both preclinical animal models and clinical studies. Combination of anticancer agents with different modes of action remains a mainstay in cancer treatment. We undertook one approach towards this end by combining oncolytic adenoviral therapy with chemotherapy. In this study, we investigated a combination treatment of breast cancer cells with Ad5-4-RGD and Docetaxel, a microtubule-stabilizing taxane that is being used in the clinic for the treatment of breast and prostate cancers and small cell carcinoma of the lung. Our results indicate a synergistic effect between Docetaxel and Ad5-24-RGD in breast cancer cell killing at a lower dose than either agent alone. These results suggest that viral replication was not inhibited by this chemotherapy treatment and that chemotherapy could reduce the amount of viral particles needed to help eradicate the tumor. Administration of lower viral loads would simultaneously improve safety and decrease immunogenicity of the vector. Likewise lower doses of chemotherapy agents would decrease toxicity and side effects. The inclusion of oncolytic adenoviruses into multimodal cancer treatment together with chemotherapy has a potential to become powerful therapeutic regimen.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2129.
Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells.
Authors: D'Alessio A , De Luca A , Maiello MR , Palumbo C , Rachiglio A , Gallo M , Normanno N 
Published: December 2010

Abstract
Abstract #2130
Co-expression of EGFR and ErbB-2 occurs in a subset of primary breast carcinoma, and it is associated with worse prognosis. We previously demonstrated that treatment of breast cancer cells that express both receptors with a combination of the EGFR tyrosine kinase inhibitor gefitinib (G) and the anti-ErbB-2 monoclonal antibody herceptin (H) results in a synergistic anti-tumor effect. Such combination failed to show significant activity in a phase I/II clinical trial. However, patients enrolled in this trial were not selected for expression of EGFR. We explored the molecular mechanisms involved in the synergism of G and H in breast cancer cells. Treatment of both SK-BR-3 and BT-474 cells with a combination of G+H produced a more significant reduction of AKT and p42/p44-MAPK (MAPK) activation as compared with treatment with a single agent. The combination also produced a more prolonged blockade of both signalling pathways. In agreement with these findings, treatment with G+H induced a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle as compared with treatment with a single drug. A sub-G0/G1 peak, suggestive of apoptosis, was evident in cells treated with the combination but not with G or H. The combination of G+H produced a more significant increase in the levels of p27kip1 and of hypophosphorylated forms of pRb2, and a more significant decrease in the levels of Cyclin D1 and survivin as compared with a single agent. Analysis of p27kip1 protein stability, in presence of the protein synthesis inhibitor cycloheximide, revealed that both G and the combination of G+H significantly increased the stability of p27kip1, with the combination showing higher effects. Furthermore, breast cancer cells treated with the combination expressed higher levels of p27kip1 mRNA as compared with cells treated with a single drug. The combination also induced a significant increase in the nuclear levels of the FKHRL-1 transcription factor that was not observed in cells treated with G or H alone. Treatment of breast cancer cells with the dual EGFR/ErbB-2 inhibitor lapatinib produced an increase in the levels of p27kip1 and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin comparable to that observed following treatment with the combination of G+H. In addition, an increase in p27kip1 mRNA and in the nuclear levels of FKHRL-1 was induced in breast cancer cells by treatment with lapatinib. These findings suggest that the synergistic anti-tumor effects deriving from EGFR and ErbB-2 blockade are mediated by significant alterations in the expression of cell cycle regulatory proteins, including transcriptional and post-transcriptional regulation of p27kip1 expression.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2130.
A multi-center phase II study of three doses of TAS-108 in postmenopausal women with advanced breast carcinoma following first or second line endocrine therapy.
Authors: Buzdar A , Tan-Chiu E , Schwartzberg L , Perez A , Ellis M , Garin A , Ingle J , Carlson R 
Published: December 2010

Abstract
Abstract #2131
Introduction: TAS-108 is an oral steroidal anti-estrogen agent that selectively inhibits ERα and is mainly metabolized by CYP3A4. The purpose of this study is to investigate the efficacy and safety of TAS-108 administrated orally in three dose levels in patients with locally advanced, locally recurrent inoperable or metastatic breast carcinoma (BC) in four countries (USA, Russia, Mexico and Chile).&#x2028; Methods: Postmenopausal women with confirmed ER and/or PgR positive BC who had previously responded to one or two standard endocrine therapies, with or without one prior chemotherapy were randomly assigned to three doses of TAS-108, 40 mg, 80 and 120 mg daily. Using a modified Panageas' optimal two-stage trinomial design, the enrollment of 60 evaluable patients (first-stage: 19) was required to each individual dose group. Tumor response was assessed every 8 weeks according to RECIST criteria. Adverse events (AEs) were graded by CTC-AE v3.0.&#x2028; Results: A total of 146 patients with mean age of 63 years old were enrolled with 61 patients in the 40 mg group and 66 in the 80 mg group. The 120 mg group was terminated at the end of stage 1 with 19 patients enrolled due to lack of efficacy. The mean duration of study treatment was 172 days for the 40 mg group and 160 days for the 80 mg group. Partial response (PR) was documented in 6 (10%) patients in the 40 mg group and 4 (6.7%) patients in the 80 mg group. The rate of disease stabilization (CR+PR+SD) reported by the investigators was 43% (95%CI, 31%,56%) in the 40 mg group and 45% (95%CI, 32%,58%) in the 80 mg group. Adjudicated clinical benefit (CR+PR+SD more than 24 wks) was observed in 22% of patients in the 40 mg group and 20% of patients in the 80 mg group. Clinical benefit was achieved in 25% of patients with 1 prior hormonal therapy and 15% of patients with more than one line of prior hormonal therapy. Median time to progression (TTP): 15 weeks for the 40 mg group and 15.9 weeks for the 80 mg group. Median duration of clinical benefit was 32 weeks in the 40 mg group and 64 weeks in the 80 mg group. In the 40/80/120 mg groups, the commonly reported treatment-related AEs included nausea (15%/11%/16%), fatigue (10%/11%/16%), headache (10%/6%/16%), hot flushes (10%/5%/32%), diarrhea (2%/6%/5%), constipation (3%/3%/5%), and arthralgia (2%/5%/11%). No endometrial cancer and treatment-related deaths occurred during the study.&#x2028; Conclusions: TAS-108 has demonstrated anti-tumor activity in this population and was generally well tolerated. The 40 mg dose was chosen as the recommended dose for future clinical evaluation in patients with advanced breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2131.
Effects of novel retinoic acid metabolism blocking agent (VN/14-1) on N-methyl-N-nitrosourea (MNU)-induced mammary carcinoma and uterus in the rat model.
Authors: Goss PE , Njar VC , Qi S , Hu H , Gediya LK , Puranik P , Khandelwal A 
Published: December 2010

Abstract
Abstract #2133
Background: All-trans-retinoic acid (ATRA) and other retinoids play key roles in prevention and therapy of many proliferative diseases including cancers. VN/14-1 [4-(±)-(1H-Imidazol-1-yl)-(E)-retinoic acid], which is a new generation novel retinoic acid metabolism blocking agent (RAMBA), works by inhibiting the breakdown of ATRA. The inhibitory effects of VN/14-1 on the growth of human breast cancer cells and human breast tumors in the nude mouse model have been previously demonstrated. The purpose of this study was to evaluate the effects of VN/14-1 on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in immature ovariectomized (OVX) rats.&#x2028; Methods: (1) VN/14-1 (5, 10, and 20 mg/kg/d) was given by oral gavage to grouped female Sprague Dawley (SD) rats bearing MNU-induced mammary carcinoma for 8 weeks, after which tumor weight and volume, as well as histology were measured. (2) VN/14-1 (10 and 20 mg/kg/d) and b-estradiol (10 mg/kg/d) were given alone or in combination, by oral gavage (VN/14-1) and subcutaneous injection (b-estradiol), to immature OVX SD rats for 3 days, after which uterine weight and histology were measured.&#x2028; Results: (1) At the end of the treatment period, the administration of 5, 10 and 20 mg/kg/d VN/14-1 caused significant reductions of 19.1, 34.4 and 44.3%, respectively, in mean tumor weight compared with the control animals (all p &lt; 0.05). The cumulative tumor growth was also significantly slower in groups receiving 5, 10 and 20 mg/kg/d compared to the control group in a dose-dependent manner. (2) Immature OVX rats given VN/14-1 at doses of 10 and 20 mg/kg, had reduction in uterine wet weight of up to 56% compared to OVX controls (P &lt; 0.001). OVX rats given VN/14-1 of 10 and 20 mg/kg in combination with β-estradiol had reduction in uterine wet weight of up to 58% compared to the OVX rats given β-estradiol alone (P &lt; 0.001). The adverse toxic effects such as fatigue and anorexia were occurred in the groups at high dose of 20 mg/kg.&#x2028; Conclusions: RAMBA VN/14-1 was able to inhibit the growth of tumors in the MNU-induced ER positive rat mammary tumor model and antagonized the stimulatory effect of β-estradiol on the uterus. The studies suggest VN/14-1 might be an effective novel therapy for ER positive breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2133.
Safety of the anti-IGF-1R antibody CP-751,871 in combination with exemestane in patients with advanced breast cancer.
Authors: Ryan PD , Neven P , Dirix LY , Barrios CH , Miller WH , Fenton D , Abraham MF , Paccagnella L , Gualberto A , Goss PE 
Published: December 2010

Abstract
Abstract #2136
Background: Aromatase inhibitors (AIs) are established first-line treatment for postmenopausal estrogen receptor (ER)+ metastatic breast cancer. However, not all patients benefit from AIs and those whose tumors initially respond eventually relapse. One hypothesized mechanism for tumor insensitivity to hormonal agents seems to be cross-talk between the ER pathway and other growth factor signaling pathways, in particular the insulin-like growth factor receptor type 1 (IGF-1R). In xenograft breast cancer models, CP-751,871 administration increased tumor growth inhibition induced by tamoxifen. Thus our trial addresses the effect of combining AI with an IGF-1R antagonist.&#x2028; Methods: A phase II, multicenter, randomized, two-arm, comparative, two-stage trial to determine PFS of CP-751,871, a fully human IgG2 monoclonal antibody targeting IGF-1R, in combination with exemestane versus exemestane alone as first-line treatment in patients with hormone receptor positive, advanced breast cancer. Secondary endpoints include clinical benefit (CR, PR, or SD ≥6 months), safety/tolerability and PK. Patients included in the study are post menopausal, ≥18 years with locally advanced/metastatic breast cancer (stage IIIB or IV), ECOG PS 0–2, and adequate hematological, biochemical, and cardiac functions. CP-751,871 is given by intravenous infusion at a dose of 20 mg/kg every 21 days while 25 mg exemestane was given p.o. daily.&#x2028; Results: To date 37 patients have been dosed with CP-751,871 plus exemestane. Median age is 60.5 years (range 34–84). Patients received a median of 9.5 treatment cycles (range 1–22). One GR 4 CP-751,871-related AE (hoarse voice) was reported, which resolved after 3 days without intervention. GR 3 CP-751,871-related toxicities included 8.1% hyperglycemia (n=3), 8.1% GGT elevation (n=3), 5.4% allergic reaction (n=2), 5.4% hearing loss (n=2), 5.4% weight loss (n=2), and 2.7% anorexia (n=1). GR 2 CP-751,871-related AEs &gt;10% were headaches, muscle cramps, and nail changes. Both hyperglycemia and hypersensitivity reactions were manageable (with oral hypoglycemic drug/insulin and antihistamine), while GGT elevation seems to be reversible.&#x2028; Conclusions: CP-751,871 in combination with exemestane is well tolerated. The most frequent GR 3 side effects are either well managed with medications or appear to be reversible. Therefore, CP-751,871, due to its safety profile, is a good targeted agent to combine with standard hormonal therapy. The stage I portion of the study to determine efficacy and toxicity is ongoing.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2136.
The taccalonolides are a novel class of microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms.
Authors: Risinger AL , Jackson EM , Polin LA , Helms GL , Joe PA , Luduena RF , Mooberry SL 
Published: December 2010

Abstract
Abstract #2142
The taccalonolides are a novel class of microtubule stabilizing agents isolated from the tropical plant Tacca chantrieri. Their unique structure and inability to directly bind to or stabilize tubulin in vitro strongly suggest that the taccalonolides cause microtubule stabilization through a distinct mechanism of action. The ability of four taccalonolides, A, E, B and N, to circumvent multidrug resistance mechanisms associated with taxane resistance was studied. The four taccalonolides were able to overcome multidrug resistance mediated by expression of the P-glycoprotein ATP-binding cassette drug transporter in vitro. Furthermore, the taccalonolides A and E were highly active against tumors in a P-glycoprotein expressing Mam17/ADR murine model of breast cancer that is resistant to both doxorubicin and paclitaxel. In addition to P-glycoprotein, the expression of the βIII isotype of tubulin has also been linked with taxane treatment failure. HeLa cells expressing high levels of βIII-tubulin were resistant to paclitaxel, docetaxel, epothilone B and vinblastine. Interestingly, these βIII-tubulin expressing cells were more sensitive to each of the four taccalonolides than the parental cell line. These data demonstrate that the taccalonolides have advantages over the taxanes in clinically relevant drug resistant cell lines and tumor models. Therefore, the taccalonolides represent a novel family of microtubule stabilizing agents with clinical potential.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2142.
MG28, a novel fatty acid synthase inhibitor, overcomes resistance to anti-HER therapies in breast cancer.
Authors: Puig T , Urruticoechea A , Oliveras G , Aguilar H , Turrado C , Cufí S , Ortega-Gutiérrez S , Benhamú B , López-Rodríguez M , Colomer R 
Published: December 2010

Abstract
Abstract #2143
Introduction: Resistance to anti-HER2 therapy is a common feature in Her2 positive breast cancer. The green tea polyphenol epigallocatechin 3-gallate (EGCG) is an effective antitumoral therapy through the blockade of FASN. We have developed polyphenolic compounds that inhibit FASN with greater efficacy than EGCG. Here we report the anticancer activity of MG28, one of the new synthesized FASN inhibitors, alone or in combination with trastuzumab, lapatinib, erlotinib and cetuximab in a HER-amplified breast cancer models.&#x2028; Experimental design: We analysed the cytotoxic effects of MG28 alone and in combination with trastuzumab, lapatinib, erlotinib, or cetuximab in HER2+ and EGFR+ human breast cancer cells. Combinations of MG28 with targeted agents were tested for synergism, additivity and antagonism using the isobologram analysis. We further analysed changes in FASN protein levels, in apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase (PARP)], and in activation of HER2, AKT and MAPK.&#x2028; Results: Combination index analysis showed synergistic cytotoxic effects of MG28 combined with trastuzumab, erlotinib or lapatinib (p &lt; 0.001) and antagonic effects with cetuximab (p &lt; 0.05) in HER2 overexpressing cells. MG28 plus lapatinib was significantly correlated with increased apoptosis and inhibition of phosphorilated HER2 and MAPK. Response to co-exposure of MG28 plus erlotinib was significantly correlated with increased apoptosis and its ability to inhibit HER2, MAPK and AKT phosphorilation. HER2+ cells showed partial resistance to trastuzumab and combined treatment of trastuzumab with MG28 reversed significantly this resistance and thus correlated with increasing cleavage of PARP and its ability to inhibit phosphorylation of HER2 and AKT.&#x2028; Conclusion: FASN inhibition seems to be an effective approach to overcome resistance to anti- HER therapies. Our results provide a new therapeutic strategy for further in vivo – combined treatments using drugs that target HER2, EGFR and FASN.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2143.
A phase I-II trial of Ispinesib, a kinesin spindle protein inhibitor, dosed every two weeks in patients with locally advanced or metastatic breast cancer previously untreated with chemotherapy for metastatic disease or recurrence.
Authors: Gomez H , Castaneda C , Philco M , Pimentel P , Falcon S , Escandon R , Saikali K , Conlan M , Seroogy J , Wolff A 
Published: December 2010

Abstract
Abstract #2148
Kinesin Spindle Protein (KSP) is a mitotic kinesin essential for cell cycle progression. Ispinesib, a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and subsequent cell death. When dosed on a q21d schedule, the maximum tolerated dose (MTD) was 18mg/m2 and neutropenia was the dose-limiting toxicity (DLT), with nadir at 7-10 d and recovery by d15. Activity was observed in a Phase II trial of ispinesib dosed at 18 mg/m2 q21d in patients (pts) with locally-advanced (LA) or metastatic breast cancer (MBC) after anthracycline and taxane failure (response rate 4/45 [9%]). This trial evaluates safety and efficacy of ispinesib in LA or MBC, given on d1 and d15 q28d, thus increasing dose density.&#x2028; Methods: This is a multicenter Phase I-II trial. In Phase I, DLT and MTD of ispinesib given d1 and d15 q28d will be determined. Eligibility criteria: LA or MBC; no prior chemotherapy (CT) except neoadjuvant or adjuvant and ≥ 1 year elapsed since CT; no CNS or leptomeningeal metastases; ECOG 0-1. This is a standard 3+3 dose escalation trial design, starting at 10 mg/m2 and escalating based on tolerability in Cycle 1. Pharmacokinetic data are collected on d1 and d15 of Cycle 1. Phase II of this trial will evaluate efficacy (response rate by RECIST) of ispinesib at the MTD.&#x2028; Results: Phase I of the trial is ongoing. To date, 13 pts have been treated at 3 dose levels: 10 (n=2; 2 cycles, n=1; 6 cycles), 12 (n=1; 1 cycle, n=2; 3 cycles) and 14 mg/m2 (n=7; Cycle 1 ongoing). Among the first 6 pts, 4 were Stage IV, 3 had prior neoadjuvant and 2 adjuvant CT; 2 were chemo-naïve. Four had prior anthracycline and 3 prior taxane. Biomarker status was ER+, PR+, HER2- (n=3), ER+, PR-, HER2- (n=1), ER-, PR-, HER2+ (n=3), ER-, PR-, HER2- (n=4), and unknown (n=2). Mean age was 55 yr; for the first 2 dose levels (n=6 pts), the most frequent toxicity was neutropenia (n=4). Other events included mild GI toxicity. No neuropathy or alopecia has been reported. The only grade 3 or 4 toxicity was neutropenia (n=2). At the 14 mg/m2 dose level, one DLT has been reported: a grade 3 transaminase (AST) elevation in a patient with liver metastases which resolved with a dose delay of 4 days. As a result, this cohort was expanded to include 6 evaluable pts. One additional patient at the 14mg/m2 dose had a dose delay of 5 days due to non-DLT neutropenia.&#x2028; Conclusions: Ispinesib appears to be well tolerated on a q2w dosing schedule at doses tested to date. A dose-density equal to that administered in the prior Phase II trial (0.86 mg/m2/day) was tolerated with the new q2w schedule. Dose escalation is ongoing.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2148.