M B Bally

Merrimack Pharmaceuticals, Cambridge, Massachusetts, United States

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Publications (218)898.46 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Irinotecan is a water-soluble camptothecin derivative with clinical activity against colorectal and small cell lung cancers and is currently a standard of care therapeutic in the treatment of colorectal cancer in combination with 5-fluorouracil. One of the major clinical issues limiting the use of irinotecan is gastrointestinal toxicity manifested as life-threatening diarrhea which is reported in up to 45 % of treated patients. The studies summarized here tested, in a rat model of irinotecan-associated gastro-intestinal toxicity, whether a lipid nanoparticle formulation of irinotecan, Irinophore C™, mitigated early-onset or late-onset diarrhea when given at doses equivalent to unformulated irinotecan that engenders both early- and late-onset diarrhea. Specifically, rats administered intravenously on two consecutive days with unformulated irinotecan at 170 mg/kg then 160 mg/kg experienced transient early-onset diarrhea after each administration and then experienced significant late-onset diarrhea peaking 4 days after treatment. Irinophore C™ given at the identical dose and schedule did not elicit either early- or late-onset diarrhea in any animals. When Irinophore C™ was combined with 5-fluorouracil there was also no early- or late-onset diarrhea observed. Histopathological analysis of the gastro-intestinal tract confirmed that the effects associated with irinotecan treatment were absent in rats given Irinophore C™ at the identical dose. Pharmacokinetic analysis demonstrated significantly higher systemic concentrations of irinotecan in rats given the nanoparticle formulation compared to those given unformulated irinotecan. These results demonstrate that the Irinophore C™ formulation is significantly less toxic than irinotecan, used either as a single agent or in combination with 5-fluorouracil, in a rat model of irinotecan-induced gastrointestinal toxicity.
    Investigational New Drugs 07/2014; · 3.50 Impact Factor
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    ABSTRACT: Triple negative breast cancers (TNBCs) are defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor2 (ERBB2/HER2). Although initially responsive to chemotherapy, most recurrent TNBCs develop resistance, resulting in disease progression. Autophagy is a lysosome-mediated degradation and recycling process that can function as an adaptive survival response during chemotherapy and contribute to chemoresistance. Our goal was to determine whether autophagy inhibition improves treatment efficacy in TNBC cells in tumors either sensitive or refractory to anthracyclines. We employed in vitro and in vivo models of TNBC using cell lines sensitive to epirubicin (EPI) and other anthracyclines, as well as derivative lines, resistant to the same drugs. We assessed basal autophagy levels and the effects of chemotherapy on autophagy in parental and resistant cells. Applying various approaches to inhibit autophagy alone and in combination with chemotherapy, we assessed the effects on cell viability in vitro and tumor growth rates in vivo. We demonstrated that EPI induced autophagic flux in TNBC cells. EPI- resistant lines exhibited at least 1.5 fold increased basal autophagy levels and, when treated with autophagy inhibitors, showed a significant loss in viability, indicating dependence of resistant cells on autophagy for survival. Combination of EPI with the autophagy inhibitor hydroxychloroquine (HCQ) resulted in a significant reduction in tumor growth compared to monotherapy with EPI. Autophagy inhibition enhances therapeutic response in both anthracycline-sensitive and resistant TNBC and may be an effective new treatment strategy for this disease.
    Clinical Cancer Research 04/2014; · 7.84 Impact Factor
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    ABSTRACT: Epithelial ovarian cancers are a group of at least five histologically and clinically distinct diseases, yet at this time patients with these different diseases are all treated with the same platinum and taxane-based chemotherapeutic regimen. With increased knowledge of histotype-specific differences that correlate with treatment responses and resistance, novel treatment strategies will be developed for each distinct disease. Type-specific or resistance-driven molecularly targeted agents will provide some specificity over traditional chemotherapies and it is argued here that nanoscaled drug delivery systems, in particular lipid-based formulations, have the potential to improve the delivery and specificity of pathway-specific drugs and broad-spectrum cytotoxic chemotherapeutics. An overview of the current understanding of ovarian cancers and the evolving clinical management of these diseases is provided. This overview is needed as it provides the context for understanding the current role of drug delivery systems in the treatment of ovarian cancer and the need to design formulations for treatment of clinically distinct forms of ovarian cancer.
    Nanomedicine 03/2014; 9(3):501-22. · 5.26 Impact Factor
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    ABSTRACT: Gefitinib (Iressa(®), ZD1839) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. We report on an early cellular response to gefitinib that involves induction of functional autophagic flux in phenotypically diverse breast cancer cells that were sensitive (BT474 and SKBR3) or insensitive (MCF7-GFPLC3 and JIMT-1) to gefitinib. Our data show that elevation of autophagy in gefitinib-treated breast cancer cells correlated with downregulation of AKT and ERK1/2 signaling early in the course of treatment. Inhibition of autophagosome formation by BECLIN-1 or ATG7 siRNA in combination with gefitinib reduced the abundance of autophagic organelles and sensitized SKBR3 but not MCF7-GFPLC3 cells to cell death. However, inhibition of the late stage of gefitinib-induced autophagy with hydroxychloroquine (HCQ) or bafilomycin A1 significantly increased (p<0.05) cell death in gefitinib-sensitive SKBR3 and BT474 cells, as well as in gefitinib-insensitive JIMT-1 and MCF7-GFPLC3 cells, relative to the effects observed with the respective single agents. Treatment with the combination of gefitinib and HCQ was more effective (p<0.05) in delaying tumor growth than either monotherapy (p>0.05), when compared to vehicle-treated controls. Our results also show that elevated autophagosome content following short-term treatment with gefitinib is a reversible response that ceases upon removal of the drug. In aggregate, these data demonstrate that elevated autophagic flux is an early response to gefitinib and that targeting EGFR and autophagy should be considered when developing new therapeutic strategies for EGFR expressing breast cancers.
    PLoS ONE 10/2013; 8(10):e76503. · 3.53 Impact Factor
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    ABSTRACT: Advances in cancer therapy have increased the rate of survival of young cancer patients; however, female lymphoma patients frequently face a temporary or permanent loss of fertility when treated with traditional cytotoxic agents. The potential loss of fertility is an important concern that can influence treatment decisions for many premenopausal cancer patients. The negative effect of chemotherapeutic agents and treatment protocols to patients' fertility-referred to as fertotoxicity-are thus an increasingly important cancer survivorship issue. We have developed a novel nanoscale formulation of arsenic trioxide, a potent drug for treatment of hematological malignancies, and demonstrate that it has significantly better activity in a murine lymphoma model than the free drug. In parallel, we have developed a novel in vitro assay of ovarian follicle function that predicts in vivo ovarian toxicity of therapeutic agents. Our results reveal that the nanotherapeutic agent is not only more active against lymphoma, but is fertoprotective, i.e., it is much less deleterious to ovarian function than the parent drug. Thus, our in vitro assay allows rapid evaluation of both established and experimental anticancer drugs on ovarian reserve and can inform the selection of efficacious and fertility-sparing treatment regimens for reproductive-age women diagnosed with cancer.
    PLoS ONE 03/2013; 8(3):e58491. · 3.53 Impact Factor
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    ABSTRACT: PURPOSE: To provide proof-of-concept data to support use of Doxil®-liposomal topotecan (Topophore C™) combinations to treat ovarian cancer. EXPERIMENTAL DESIGN: ES-2, OVCAR-3 and SKOV-3 ovarian cancer cell lines were treated with doxorubicin-topotecan combinations by exposing the cells to drugs from 1 to 72h. Pharmacokinetic analysis was performed following administration of liposomal formulations of these drugs alone and in combination. Efficacy assessments were completed in ES-2 and SKOV-3 ovarian cancer models. RESULTS: Based on drug doses capable of achieving 50% reduction in cell viability over 72h; doxorubicin-topotecan combinations were additive in SKOV3 but highly synergistic in ES-2 and OVCAR-3 cells. Favorable drug-drug interactions increased with increased drug exposure time. Topophore C™ pharmacokinetic remained un-affected when co-administered with Doxil®. In the ES-2 model, Doxil® at maximum tolerated dose (MTD 7.5 mg/kg) in combination with free topotecan (MTD 15mg/kg) did not enhance median survival time (MST) over that achieved with topotecan alone. In contrast, MST was increased to 52 days with combination of Topophore C™ (MTD 2.5 mg/kg) and Doxil® (7.5 mg/kg) compared to untreated animals (MST 18 days) or those treated with Topophore C™ alone (MTD 5mg/kg, MST 40 days). In the SKOV-3 model combination treatments showed better therapeutic efficacy when compared to the individual drugs. CONCLUSIONS: Topotecan-doxorubicin combinations produced additive or synergistic effects which were best achieved when the tumor cells were exposed to drugs over extended time. Doxil®-Topophore C™ combinations are therapeutically superior as judged in two ovarian cancer models.
    Clinical Cancer Research 01/2013; · 7.84 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. It has been described as requiring elevated autophagy for growth and inhibiting autophagy has been proposed as a treatment strategy. To date, all preclinical reports and clinical trials investigating pharmacological inhibition of autophagy have used chloroquine or hydroxychloroquine, which interfere with lysosomal function and block autophagy at a late stage. Verteporfin is a newly discovered autophagy inhibitor that blocks autophagy at an early stage by inhibiting autophagosome formation. Here we report that PDAC cell lines show variable sensitivity to verteporfin in vitro, suggesting cell-line specific autophagy dependence. Using image-based and molecular analyses, we show that verteporfin inhibits autophagy stimulated by gemcitabine, the current standard treatment for PDAC. Pharmacokinetic and efficacy studies in a BxPC-3 xenograft mouse model demonstrated that verteporfin accumulated in tumors at autophagy-inhibiting levels and inhibited autophagy in vivo, but did not reduce tumor volume or increase survival as a single agent. In combination with gemcitabine verteporfin moderately reduced tumor growth and enhanced survival compared to gemcitabine alone. While our results do not uphold the premise that autophagy inhibition might be widely effective against PDAC as a single-modality treatment, they do support autophagy inhibition as an approach to sensitize PDAC to gemcitabine.
    Journal of Cancer. 01/2013; 4(7):585-96.
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    ABSTRACT: The PI3K/AKT/mTOR pathway is commonly over activated in glioblastoma (GBM), and Rictor was shown to be an important regulator downstream of this pathway. EGFR overexpression is also frequently found in GBM tumors, and both EGFR and Rictor are associated with increased proliferation, invasion, metastasis and poor prognosis. This research evaluated in vitro and in vivo whether the combined silencing of EGFR and Rictor would result in therapeutic benefits. The therapeutic potential of targeting these proteins in combination with conventional agents with proven activity in GBM patients was also assessed. In vitro validation studies were carried out using siRNA-based gene silencing methods in a panel of three commercially available human GBM cell lines, including two PTEN mutant lines (U251MG and U118MG) and one PTEN-wild type line (LN229). The impact of EGFR and/or Rictor silencing on cell migration and sensitivity to chemotherapeutic drugs in vitro was determined. In vivo validation of these studies was focused on EGFR and/or Rictor silencing achieved using doxycycline-inducible shRNA-expressing U251MG cells implanted orthotopically in Rag2M mice brains. Target silencing, tumor size and tumor cell proliferation were assessed by quantification of immunohistofluorescence-stained markers. siRNA-mediated silencing of EGFR and Rictor reduced U251MG cell migration and increased sensitivity of the cells to irinotecan, temozolomide and vincristine. In LN229, co-silencing of EGFR and Rictor resulted in reduced cell migration, and increased sensitivity to vincristine and temozolomide. In U118MG, silencing of Rictor alone was sufficient to increase this line's sensitivity to vincristine and temozolomide. In vivo, while the silencing of EGFR or Rictor alone had no significant effect on U251MG tumor growth, silencing of EGFR and Rictor together resulted in a complete eradication of tumors. These data suggest that the combined silencing of EGFR and Rictor should be an effective means of treating GBM.
    PLoS ONE 01/2013; 8(3):e59597. · 3.53 Impact Factor
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    ABSTRACT: To investigate the use of liposomal irinotecan (Irinophore C™) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer. The effect of irinotecan (IRI) and/or 5-FU exposure times on cytotoxicity was assessed in vitro against HT-29 or LS174T human colon carcinoma cells. The pharmacokinetics and biodistribution of Irinophore C™ (IrC™) and 5-FU, administered alone or in combination, were compared in vivo. A subcutaneous model of HT-29 human colorectal cancer in Rag2-M mice was utilized to assess the efficacy of IrC™ alone, and in combination with 5-FU. The cytotoxicity of IRI and 5-FU were strongly dependent on exposure time. Synergistic interactions were observed following prolonged exposure to IRI/5-FU combinations. Pharmacokinetics/biodistribution studies demonstrated that the 5-FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with IrC™, versus alone. Significant decreases in 5-FU elimination were also observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrC™ was given intravenously. The elimination of IrC™ was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrC™ was significantly more effective than the combination of IRI/5-FU; surprisingly, IrC™/5-FU combinations were no more effective than IrC™ alone. The administration of combinations of 5-FU (16 mg/kg) and IrC™ (60 mg IRI/kg) showed increased toxicity when compared to IrC™ alone. Treatment with IrC™ alone (60 mg IRI/kg) delayed the time required for a 5-fold increase in initial tumor volume to day 49, compared to day 23 for controls. When IrC™ (40 mg IRI/kg) was used in combination with 5-FU (16 mg/kg), the time to increase tumor volume 5-fold was 43 days, which was comparable to that achieved when using IrC™ alone (40 mg IRI/kg). Single agent IrC™ was well tolerated and has significant therapeutic potential. IrC™ may be a suitable replacement for IRI treatment, but its use with free 5-FU is complicated by IrC™-engendered changes in 5-FU pharmacokinetics/biodistribution which are associated with increased toxicity when using the combination.
    PLoS ONE 01/2013; 8(4):e62349. · 3.53 Impact Factor
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    ABSTRACT: Polyethylene glycol (PEG) has been used widely in liposomal formulations as a strategy to inhibit opsonization by plasma proteins and to prolong liposome plasma circulation time. PEG can be incorporated onto the surface of liposomes either during the spontaneous self-assembling process or inserted after vesicle formation. The advantages of employing the PEG postinsertion method include improved drug encapsulation efficiency and the ability to incorporate PEG conjugates for enhanced cell binding and uptake. In this study, we propose to evaluate a cationic lipid nanoparticle formulation containing two PEGylation steps: pre- and post-siRNA insertion. Our results indicate that formulations consisting of the extra PEG post-insertion step significantly increased siRNA circulation in the plasma by two-folds in comparison with the formulations consisting of only the single PEGylation step. Moreover, this formulation was able to efficiently carry siRNA to the tumor site, increase siRNA stability and significantly downregulate luciferase mRNA expression by >50% when compared with the controls in an intraperitoneal and subcutaneous breast cancer tumor model. Overall, our cationic lipid nanoparticle formulation displayed enhanced plasma circulation, reduced liver accumulation, enhanced tumor targeting, and effective gene knockdown--demonstrating excellent utility for the delivery of siRNA. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 11/2012; · 3.13 Impact Factor
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    ABSTRACT: This study focuses on determining the pharmacokinetics, biodistribution, and efficacy of the ginsenoside aglycone protopanaxadiol (aPPD) administered as a single agent in a novel oral dosage formulation. To obtain these data and to characterize the stability of aPPD, appropriate analytical assay development was carried out. The solubility and stability of aPPD were determined, and the compound was formulated for oral gavage. aPPD levels in blood and tissues following oral administration to nu/nu nude mice were determined using liquid chromatography-mass spectrometry/mass spectrometry. The efficacy of aPPD was determined upon oral administration to nu/nu nude mice bearing PC-3 human prostate cancer xenograft tumors. Immunohistochemical analysis of tumor tissues was performed to establish apoptotic indices and Ki-67 expression as markers of proliferation. The maximum solubility of aPPD in ethanol was 68.4 mg/ml. aPPD administered at a dose of 70 mg/kg yielded a T(max) of approximately 40 min and a C(max) value of 3.9 ± 1.4 μg/ml, and no toxicity was observed. aPPD accumulated largely in the stomach and small intestine and was also present in the brain. This dose engendered a significant delay in PC-3 tumor growth, an increase in apoptotic index, and a decrease in Ki-67 levels. We have shown that aPPD is a stable compound that can be formulated for oral gavage. Pharmacokinetic studies demonstrate the ability of this compound to be absorbed after oral administration. Future studies will assess the activity and pharmacokinetics of aPPD when administered in combination with standard chemotherapy.
    Anti-cancer drugs 06/2012; 23(5):543-52. · 2.23 Impact Factor
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    ABSTRACT: We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on loading method that involves formation of a complex between copper and the water soluble camptothecin. The loading methodology developed for irinotecan was evaluated to develop a LNP topotecan formulation (referred to herein as Topophore C) and test its activity in pre-clinical model of ovarian carcinoma. Topotecan was encapsulated into preformed liposomes containing 300 mM copper sulfate and the divalent metal ionophore A23187. Formulation optimization studies included assessments of loading efficiency, influence of temperature on drug loading and in vitro stability of the resulting formulation. In vivo assessments included drug and liposome pharmacokinetics, drug levels within plasma and the peritoneal cavity following intravenous (i.v.) administration in mice and efficacy studies on ES2 ovarian cancer model. Topotecan loading into liposomes was optimized with encapsulation efficiency of >98 % at a final drug-to-lipid (D/L) mole ratio of 0.1. Higher D/L ratios could be achieved, but the resulting formulations were less stable as judged by in vitro drug release studies. Following Topophore C administration in mice the topotecan plasma half-life and AUC were increased compared to free topotecan by 10-and 22-fold, respectively. Topophore C was 2-to 3-fold more toxic than free topotecan, however showed significantly better anti-tumor activity than free topotecan administered at doses with no observable toxic effects. Topophore C is a therapeutically interesting drug candidate and we are particularly interested in developing its use in combination with liposomal doxorubicin for treatment of platinum refractory ovarian cancer.
    Investigational New Drugs 05/2012; · 3.50 Impact Factor
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    M. Verreault, S. Yip, B. Toyota, M.B. Bally
    Novel Therapeutic Concepts in Targeting Glioma, 04/2012; , ISBN: 978-953-51-0491-9
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    ABSTRACT: Given compelling evidences supporting the therapeutic potential of irinotecan (IRN) for patients with glioblastoma (GBM), the present study evaluated the activity of Irinophore C™ (IrC™), a lipid-based nanopharmaceutical formulation of IRN, in GBM. The levels of IRN and SN-38 were determined in plasma and brain after a single intravenous dose of IRN or IrC™ in tumor-free mice. Treatment with IrC™ significantly increased the plasma AUC(0-24h) of the active (lactone) forms of IRN and SN-38 when compared to free drug (760 and 30-fold increase, respectively). Levels of IRN and SN-38 in brain tissue were also increased significantly (compared to IRN treatment) following IrC™ administration. A tolerability study revealed that IrC™ is better tolerated than IRN. The efficacy of IrC™ and IRN was assessed in an orthotopic model of GBM. The therapeutic efficacy of IrC™ given at 25mg/kg weekly was comparable to the efficacy achieved using twice the dose of IRN. At the maximum tolerated dose, IrC™ (100mg/kg) increased the survival time of tumor-bearing mice of 83% compared to untreated animals. Ki67 immunostaining analysis of IrC™-treated tumors revealed a transient increase in cell proliferation after treatment. The results justify further studies evaluating the use of IrC™ for treating GBM.
    Journal of Controlled Release 02/2012; 158(1):34-43. · 7.63 Impact Factor
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    Jessica Kalra, Marcel B. Bally
    Bioluminescence - Recent Advances in Oceanic Measurements and Laboratory Applications, 02/2012; , ISBN: 978-953-307-940-0
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    ABSTRACT: A number of studies have outlined the antiangiogenic effects of cytotoxic agents when administered frequently at low doses. These studies suggest that the effect of the cytotoxic agent is on the vasculature within the tumor and it is assumed that there is little or negligible cytotoxicity. Liposomal drug delivery systems have the ability to provide a dual mechanism of activity where tumor accumulation can deliver high local concentrations of the drug at the site of action with concomitant slow release of the drug from carriers in the blood compartment that results in antivascular effects, similar to that achieved when dosing frequently at low levels. Although this dual mechanism of activity may be linked to other lipid nanoparticle formulations of anticancer drugs, this article summarizes the evidence supporting direct (cytotoxic) and indirect (antivascular) actions of a liposomal formulation of irinotecan.
    Nanomedicine 11/2011; 6(9):1645-54. · 5.26 Impact Factor
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    ABSTRACT: The activity of therapeutic antibodies can be enhanced by creating multivalent constructs, such as antibody lipid nanoparticles (LNPs). Here, we examine differences between rituximab (Ritux) and Ritux-LNPs in terms of their indirect mechanisms of action: complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). We employed two mantle-cell lymphoma cell lines, Z138 and JVM2, which exhibit different in vivo sensitivities to Ritux along with variable expression levels of cell-surface proteins that regulate ADCC and CDC. In both cell lines, CDC and ADCC were found to be significantly enhanced after treatment with Ritux-LNPs compared with Ritux. In vivo efficacy studies, however, suggested that the therapeutic activities of Ritux and Ritux-LNPs were equivalent, which was subsequently explained in part by pharmacokinetic studies indicating rapid elimination of Ritux-LNP. Although indirect and direct mechanisms of multivalent Ritux are enhanced, its further development requires methods to improve its circulation lifetime.
    Nanomedicine 11/2011; 6(9):1575-91. · 5.26 Impact Factor
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    ABSTRACT: HER2-positive breast cancers exhibit high rates of innate and acquired resistance to trastuzumab (TZ), a HER2-directed antibody used as a first line treatment for this disease. TZ resistance may in part be mediated by frequent co-expression of EGFR and by sustained activation of the mammalian target of rapamycin (mTOR) pathway. Here, we assessed feasibility of combining the EGFR inhibitor gefitinib and the mTOR inhibitor everolimus (RAD001) for treating HER2 overexpressing breast cancers with different sensitivity to TZ. The gefitinib and RAD001 combination was broadly evaluated in TZ sensitive (SKBR3 and MCF7-HER2) and TZ resistant (JIMT-1) breast cancer models. The effects on cell growth were measured in cell based assays using the fixed molar ratio design and the median effect principle. In vivo studies were performed in Rag2M mice bearing established tumors. Analysis of cell cycle, changes in targeted signaling pathways and tumor characteristics were conducted to assess gefitinib and RAD001 interactions. The gefitinib and RAD001 combination inhibited cell growth in vitro in a synergistic fashion as defined by the Chou and Talalay median effect principle and increased tumor xenograft growth delay. The improvement in therapeutic efficacy by the combination was associated in vitro with cell line dependent increases in cytotoxicity and cytostasis while treatment in vivo promoted cytostasis. The most striking and consistent therapeutic effect of the combination was increased inhibition of the mTOR pathway (in vitro and in vivo) and EGFR signaling in vivo relative to the single drugs. The gefitinib and RAD001 combination provides effective control over growth of HER2 overexpressing cells and tumors irrespective of the TZ sensitivity status.
    BMC Cancer 10/2011; 11:420. · 3.33 Impact Factor
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    ABSTRACT: Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression.
    Cancer Research 06/2011; 71(13):4484-93. · 9.28 Impact Factor
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    ABSTRACT: Glioblastoma (GBM) cell lines expressing red fluorescent proteins were evaluated as a tool for non-invasive imaging of orthotopic tumors. mKate2- and mCherry-transduced U251MG GBM lines were sorted by flow cytometry. The growth rates and drug sensitivity of the resulting cell lines were compared to those of the parental line. Following orthotopic implantation, mKate2-expressing cells were detected using multispectral imaging. Flow cytometry-sorted fluorescent populations exhibiting growth curves that were comparable to those of the parental line were selected. mKate2-expressing cells were inoculated orthotopically and formed tumors which were visualized non-invasively, allowing monitoring of tumor growth over time and the assessment of tumor response to temozolomide drug treatment. The strategy reported here led to the successful development of GBM models expressing mKate2 or mCherry. The fluorescence signal intensity measured in the brain of live animals correlates with tumor size, thus providing a method to assess tumor progression and response to treatment.
    Anticancer research 06/2011; 31(6):2161-71. · 1.71 Impact Factor

Publication Stats

6k Citations
898.46 Total Impact Points

Institutions

  • 2013
    • Merrimack Pharmaceuticals
      Cambridge, Massachusetts, United States
  • 1985–2013
    • University of British Columbia - Vancouver
      • • Faculty of Pharmaceutical Sciences
      • • Department of Pathology and Laboratory Medicine
      • • Department of Anesthesiology, Pharmacology and Therapeutics
      • • Division of Medical Oncology
      • • Faculty of Medicine
      • • Department of Biochemistry and Molecular Biology
      Vancouver, British Columbia, Canada
  • 2012
    • University of Manitoba
      • Faculty of Pharmacy
      Winnipeg, Manitoba, Canada
  • 2004–2012
    • BC Cancer Research Centre
      • Department of Experimental Therapeutics
      Vancouver, British Columbia, Canada
  • 1998–2010
    • BC Cancer Agency
      • Advanced Therapeutics
      Vancouver, British Columbia, Canada
  • 2008
    • Advanced Cancer Therapeutics
      Louisville, Kentucky, United States
  • 2007
    • National University of Singapore
      • Department of Pharmacy
      Singapore, Singapore
    • University of Toronto
      • Leslie L. Dan Faculty of Pharmacy
      Toronto, Ontario, Canada
    • Celator® Pharmaceuticals
      Princeton, New Jersey, United States
  • 2004–2007
    • Duke University
      • Department of Biomedical Engineering (BME)
      Durham, NC, United States
  • 2005
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
  • 1999–2004
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 1994
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
  • 1987
    • Terry Fox Laboratory
      Vancouver, British Columbia, Canada