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Xinguo Jiang - One of the best experts on this subject based on the ideXlab platform.
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Lapatinib-loaded human serum albumin nanoparticles for the prevention and treatment of triple-negative breast cancer metastasis to the brain.
Oncotarget, 2016Co-Authors: Xu Wan, Xiaoyao Zheng, Zheming Zhang, Qizhi Zhang, Xiaoyin Pang, Zhiqing Pang, Jingjing Zhao, Tao Jiang, Xinguo JiangAbstract:// Xu Wan 1, 2 , Xiaoyao Zheng 1 , Xiaoyin Pang 1 , Zhiqing Pang 1 , Jingjing Zhao 1 , Zheming Zhang 1 , Tao Jiang 3 , Wei Xu 3 , Qizhi Zhang 1 , Xinguo Jiang 1 1 Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, People's Republic of China 2 Department of Pharmacy, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China 3 Shanghai Zhangjiang Medicine Valley Public Service Platform Co., Ltd., Shanghai, People's Republic of China Correspondence to: Qizhi Zhang, email: qzzhang@fudan.edu.cn Keywords: brain metastasis, triple-negative breast cancer, lapatinib, human serum albumin nanoparticles, modified Nab technology Received: October 27, 2015 Accepted: March 18, 2016 Published: April 12, 2016 ABSTRACT Brain metastasis from triple-negative breast cancer (TNBC) has continued to lack effective clinical treatments until present. However, the feature of epidermal growth factor receptor (EGFR) frequently overexpressed in TNBC offers the opportunity to employ lapatinib, a dual-tyrosine kinase inhibitor of human epidermal growth factor receptor-2 (HER2) and EGFR, in the treatment of brain metastasis of TNBC. Unfortunately, the low oral bioavailability of lapatinib and drug efflux by blood-brain barrier have resulted in low drug delivery efficiency into the brain and limited therapeutic effects for patients with brain metastasis in clinical trials. To overcome such disadvantages, we developed lapatinib-loaded human serum albumin (HSA) nanoparticles, named LHNPs, by modified nanoparticle albumin-bound (Nab) technology. LHNPs had a core-shell structure and the new HSA/phosphatidylcholine sheath made LHNPs stable in bloodstream. Compared to free lapatinib, LHNPs could inhibit the adhesion, migration and invasion ability of high brain-metastatic 4T1 cells more effectively in vitro . Tissue distribution following intravenous administration revealed that LHNPs (i.v., 10 mg/kg) achieved increased delivery to the metastatic brain at 5.43 and 4.36 times the levels of Tykerb (p.o., 100 mg/kg) and lapatinib solution (LS, i.v., 10 mg/kg), respectively. Compared to the marketed Tykerb group, LHNPs had markedly better inhibition effects on brain micrometastasis and significantly extended the median survival time of 4T1 brain metastatic mice in consequence. The improved anti-tumor efficacy of LHNPs could be partly ascribed to down-regulating metastasis-related proteins. Therefore, these results clearly indicated that LHNPs could become a promising candidate for clinical applications against brain metastasis of TNBC.
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In vivo behavior and safety of lapatinib-incorporated lipid nanoparticles.
Current pharmaceutical biotechnology, 2014Co-Authors: Huile Gao, Chen Chen, Jun Chen, Shilei Cao, Qizhi Zhang, Xinguo JiangAbstract:To improve the solubility, bioavailability and anti-tumor effect of lapatinib, lapatinib-incorporated lipid nanoparticles (LTNPs) were prepared and characterized. The particle size of LTNPs was 88.6 nm with a zeta potential of 20 mV. Laptinib was loaded into LTNPs with a non-crystal structure as determined by FT-IR. In vitro, LTNPs could be effectively uptaken into C6 glioma cells at a concentration-dependent manner. In vivo, LTNPs showed a relative higher AUC, which was 5.27- and 3.21-fold as that of Tykerb and lapatinib suspension (LTS) group. LTNPs also showed highest glioma concentration, which may benefit from the enhanced permeability and retention effect and active targeting ability. In toxicity studies, LTNPs displayed a half lethal dose over 250 mg/kg. Repeated administering 30 mg/kg of LTNPs could led to toxicity to hematology which might owe to the bovine serum albumin, a foreign protein to mice. However, there was no organic change observed through HE staining. In conclusion, LTNPs could target to glioma with high concentration and low side effect.
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Incorporation of lapatinib into core-shell nanoparticles improves both the solubility and anti-glioma effects of the drug.
International journal of pharmaceutics, 2013Co-Authors: Huile Gao, Yuchen Wang, Chen Chen, Jun Chen, Yan Wei, Shilei Cao, Xinguo JiangAbstract:Lapatinib is a dual EGFR and HER2 inhibitor that is used to treat HER2-overexpressing cancers. However, its poor water solubility hinders its clinical use. Proteobionics is a promising way to solve this problem. Lapatinib-incorporated core-shell nanoparticles (LTNPs) were prepared and characterized by cryo-transmission electron micrograph. Then, in vitro cellular uptake and in vivo glioma targeting effect were determined by both qualitative and quantitative studies. After that, anti-glioma effect of LTNPs was determined by cytotoxicity and life-span study. Finally, the mechanism was elucidated by western blot. LTNPs elevated the water solubility of the drug from 0.007 mg/mL to over 10 mg/mL, which was better than most commercially available injection solvents. Glioma is an increasing threat to humans' health. Here, we evaluated the treatment effects of LTNPs on glioma and explored their mechanism. LTNPs were taken up by U87 cells, inhibiting their proliferation and causing a G2 phase arrest. The uptake was energy-, time- and concentration-dependent, and several pathways were involved. LTNPs inhibited the phosphorylation of the survival (phosphatidylinositol 3-kinase/Akt) pathways, which caused the anti-proliferative effect. In vivo experiments determined that LTNPs were distributed to and accumulated in glioma by the enhanced permeation and retention effect. The distribution was colocalized with SPARC expression, which may mediate endocytosis. In pharmacokinetics and glioma distribution study, LTNPs displayed a higher blood AUC, glioma concentration and glioma/brain ratio than Tykerb. A pharmacodynamics study confirmed that LTNPs could significantly expand the median survival time of glioma-bearing mice at a cumulative dose of 40 mg/kg, which was only 5% of the dose of the commercially available lapatinib tablet (Tykerb). LTNPs effectively increased the solubility of lapatinib and improved the treatment of glioma. Copyright © 2013 Elsevier B.V. All rights reserved.
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Incorporation of lapatinib into core–shell nanoparticles improves both the solubility and anti-glioma effects of the drug
International Journal of Pharmaceutics, 2013Co-Authors: Huile Gao, Yuchen Wang, Chen Chen, Jun Chen, Yan Wei, Shilei Cao, Xinguo JiangAbstract:Abstract Purpose Lapatinib is a dual EGFR and HER2 inhibitor that is used to treat HER2-overexpressing cancers. However, its poor water solubility hinders its clinical use. Proteobionics is a promising way to solve this problem. Methods Lapatinib-incorporated core–shell nanoparticles (LTNPs) were prepared and characterized by cryo-transmission electron micrograph. Then, in vitro cellular uptake and in vivo glioma targeting effect were determined by both qualitative and quantitative studies. After that, anti-glioma effect of LTNPs was determined by cytotoxicity and life-span study. Finally, the mechanism was elucidated by western blot. Results LTNPs elevated the water solubility of the drug from 0.007 mg/mL to over 10 mg/mL, which was better than most commercially available injection solvents. Glioma is an increasing threat to humans’ health. Here, we evaluated the treatment effects of LTNPs on glioma and explored their mechanism. LTNPs were taken up by U87 cells, inhibiting their proliferation and causing a G2 phase arrest. The uptake was energy-, time- and concentration-dependent, and several pathways were involved. LTNPs inhibited the phosphorylation of the survival (phosphatidylinositol 3-kinase/Akt) pathways, which caused the anti-proliferative effect. In vivo experiments determined that LTNPs were distributed to and accumulated in glioma by the enhanced permeation and retention effect. The distribution was colocalized with SPARC expression, which may mediate endocytosis. In pharmacokinetics and glioma distribution study, LTNPs displayed a higher blood AUC, glioma concentration and glioma/brain ratio than Tykerb. A pharmacodynamics study confirmed that LTNPs could significantly expand the median survival time of glioma-bearing mice at a cumulative dose of 40 mg/kg, which was only 5% of the dose of the commercially available lapatinib tablet (Tykerb). Conclusion LTNPs effectively increased the solubility of lapatinib and improved the treatment of glioma.
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Behavior and anti-glioma effect of lapatinib-incorporated lipoprotein-like nanoparticles
Nanotechnology, 2012Co-Authors: Huile Gao, Zhiqing Pang, Zhi Yang, Shijie Cao, Shuang Zhang, Xinguo JiangAbstract:The purpose of the investigation was to prepare a new type of nanoparticle, namely lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs), and to evaluate the behavior and anti-glioma effect of LTNPs. LTNPs were prepared and characterized using the Cyro-transmission electron microscope (Cryo-TEM) and Raman scan methods. Cellular uptake and subcellular localization studies were performed to evaluate the in vitro behavior of LTNPs. An in vivo imaging technique was used for the evaluation of the targeting of LTNPs. To study the anti-glioma effect, glioma xenografts were used. The particle size of LTNPs was 92.6 nm, and the zeta potential was 28.40 mV. LTNPs contained a surface layer that was obviously different from the core, according to the Cryo-TEM analysis. A Raman scan analysis demonstrated the incorporation of lapatinib in LTNPs, and it also revealed a structure different from free lapatinib. The uptake of LTNP by U87 cells occurred in a concentration- and time-dependent manner. According to the subcellular study, the uptake of LTNPs was endosome mediated. LTNPs could distribute and accumulate in the tumor site by an enhanced permeation and retention effect. Both LTNPs (10 mg kg−1) and LTNPs (30 mg kg−1) could significantly inhibit the growth of U87 xenografts. For a similar antitumor effect, the required cumulative dose of LTNPs was only 5% compared to that of Tykerb (the commercial formulation of lapatinib). This study demonstrated the effective uptake of LTNPs by U87 cells, the passive targeting of LTNPs at tumors and the better antitumor effect of LTNPs.
Hans Gelderblom - One of the best experts on this subject based on the ideXlab platform.
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small molecule tyrosine kinase inhibitors in the treatment of solid tumors an update of recent developments
Annals of Surgical Oncology, 2007Co-Authors: Neeltje Steeghs, Johan W R Nortier, Hans GelderblomAbstract:Small molecule tyrosine kinase inhibitors (TKIs) are developed to block intracellular signaling pathways in tumor cells, leading to deregulation of key cell functions such as proliferation and differentiation. Over 25 years ago, tyrosine kinases were found to function as oncogenes in animal carcinogenesis; however, only recently TKIs were introduced as anti cancer drugs in human cancer treatment. Tyrosine kinase inhibitors have numerous good qualities. First, in many tumor types they tend to stabilize tumor progression and may create a chronic disease state which is no longer immediately life threatening. Second, side effects are minimal when compared to conventional chemotherapeutic agents. Third, synergistic effects are seen in vitro when TKIs are combined with radiotherapy and/or conventional chemotherapeutic agents. In this article, we will give an update of the tyrosine kinase inhibitors that are currently registered for use or in an advanced stage of development, and we will discuss the future role of TKIs in the treatment of solid tumors. The following TKIs are reviewed: Imatinib (Gleevec/Glivec), Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva), Lapatinib (GW-572016, Tykerb), Canertinib (CI-1033), Sunitinib (SU 11248, Sutent), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava).
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Small Molecule Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: An Update of Recent Developments
Annals of surgical oncology, 2006Co-Authors: Neeltje Steeghs, Johan W R Nortier, Hans GelderblomAbstract:Small molecule tyrosine kinase inhibitors (TKIs) are developed to block intracellular signaling pathways in tumor cells, leading to deregulation of key cell functions such as proliferation and differentiation. Over 25 years ago, tyrosine kinases were found to function as oncogenes in animal carcinogenesis; however, only recently TKIs were introduced as anti cancer drugs in human cancer treatment. Tyrosine kinase inhibitors have numerous good qualities. First, in many tumor types they tend to stabilize tumor progression and may create a chronic disease state which is no longer immediately life threatening. Second, side effects are minimal when compared to conventional chemotherapeutic agents. Third, synergistic effects are seen in vitro when TKIs are combined with radiotherapy and/or conventional chemotherapeutic agents. In this article, we will give an update of the tyrosine kinase inhibitors that are currently registered for use or in an advanced stage of development, and we will discuss the future role of TKIs in the treatment of solid tumors. The following TKIs are reviewed: Imatinib (Gleevec/Glivec), Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva), Lapatinib (GW-572016, Tykerb), Canertinib (CI-1033), Sunitinib (SU 11248, Sutent), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava).
Qizhi Zhang - One of the best experts on this subject based on the ideXlab platform.
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Lapatinib-loaded human serum albumin nanoparticles for the prevention and treatment of triple-negative breast cancer metastasis to the brain.
Oncotarget, 2016Co-Authors: Xu Wan, Xiaoyao Zheng, Zheming Zhang, Qizhi Zhang, Xiaoyin Pang, Zhiqing Pang, Jingjing Zhao, Tao Jiang, Xinguo JiangAbstract:// Xu Wan 1, 2 , Xiaoyao Zheng 1 , Xiaoyin Pang 1 , Zhiqing Pang 1 , Jingjing Zhao 1 , Zheming Zhang 1 , Tao Jiang 3 , Wei Xu 3 , Qizhi Zhang 1 , Xinguo Jiang 1 1 Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, People's Republic of China 2 Department of Pharmacy, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China 3 Shanghai Zhangjiang Medicine Valley Public Service Platform Co., Ltd., Shanghai, People's Republic of China Correspondence to: Qizhi Zhang, email: qzzhang@fudan.edu.cn Keywords: brain metastasis, triple-negative breast cancer, lapatinib, human serum albumin nanoparticles, modified Nab technology Received: October 27, 2015 Accepted: March 18, 2016 Published: April 12, 2016 ABSTRACT Brain metastasis from triple-negative breast cancer (TNBC) has continued to lack effective clinical treatments until present. However, the feature of epidermal growth factor receptor (EGFR) frequently overexpressed in TNBC offers the opportunity to employ lapatinib, a dual-tyrosine kinase inhibitor of human epidermal growth factor receptor-2 (HER2) and EGFR, in the treatment of brain metastasis of TNBC. Unfortunately, the low oral bioavailability of lapatinib and drug efflux by blood-brain barrier have resulted in low drug delivery efficiency into the brain and limited therapeutic effects for patients with brain metastasis in clinical trials. To overcome such disadvantages, we developed lapatinib-loaded human serum albumin (HSA) nanoparticles, named LHNPs, by modified nanoparticle albumin-bound (Nab) technology. LHNPs had a core-shell structure and the new HSA/phosphatidylcholine sheath made LHNPs stable in bloodstream. Compared to free lapatinib, LHNPs could inhibit the adhesion, migration and invasion ability of high brain-metastatic 4T1 cells more effectively in vitro . Tissue distribution following intravenous administration revealed that LHNPs (i.v., 10 mg/kg) achieved increased delivery to the metastatic brain at 5.43 and 4.36 times the levels of Tykerb (p.o., 100 mg/kg) and lapatinib solution (LS, i.v., 10 mg/kg), respectively. Compared to the marketed Tykerb group, LHNPs had markedly better inhibition effects on brain micrometastasis and significantly extended the median survival time of 4T1 brain metastatic mice in consequence. The improved anti-tumor efficacy of LHNPs could be partly ascribed to down-regulating metastasis-related proteins. Therefore, these results clearly indicated that LHNPs could become a promising candidate for clinical applications against brain metastasis of TNBC.
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Incorporation of lapatinib into human serum albumin nanoparticles with enhanced anti-tumor effects in HER2-positive breast cancer
Colloids and surfaces. B Biointerfaces, 2015Co-Authors: Xu Wan, Xiaoyao Zheng, Xiaoying Pang, Zheming Zhang, Qizhi ZhangAbstract:Lapatinib, a selective small-molecule dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in HER2-positive patients with advanced metastatic breast cancer. However, its low and variable oral absorption, large required daily dose and serious gastrointestinal side effects all limit its clinical use. Intravenous administration offers a good option to overcome these disadvantages. However, the poor solubility of lapatinib in water and organic solvents causes lapatinib to fail in a common injectable preparation. Considering lapatinib's high albumin binding ability (>99%), in this study, we developed human serum albumin nanoparticles loaded with lapatinib (LHNPs) by Nab technology for intravenous administration and investigated its efficacy against HER2-positive breast cancer. Raman shift, X-ray diffraction and X-ray photoelectron spectroscopy studies demonstrated that lapatinib was successfully incorporated into nanoparticles, and LHNPs exhibited good stability and sustained-release effect in vitro. LHNPs could be effectively taken up by SKBr3 cells in a concentration- and time-dependent manner, and the uptake was mediated by energy-dependent endocytosis, which involved clathrin-dependent pinocytosis. Furthermore, in vitro and in vivo data indicated that LHNPs presented the strong ability to induce apoptosis and superior anti-tumor efficacy in tumor-bearing mice to the commercial tablet Tykerb through the inhibition of HER2 phosphorylation. Subchronic toxicity assays indicated that LHNPs had no hepatic or kidney toxicity. With mature technology for industrial production and enhanced therapeutic effects, LHNPs are likely to have great potential as a safe therapeutic candidate against HER2-positive breast cancer in the clinic.
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The potential use of lapatinib-loaded human serum albumin nanoparticles in the treatment of triple-negative breast cancer.
International journal of pharmaceutics, 2015Co-Authors: Xu Wan, Xiaoyao Zheng, Xiaoying Pang, Zheming Zhang, Tao Jing, Qizhi ZhangAbstract:Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. However, the shared feature of epidermal growth factor receptor (EGFR) expression in TNBC offers the opportunity for targeted molecular therapy for this breast cancer subtype. Previous studies have indicated that lapatinib, a selective small-molecular dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in reducing cancer progression and metastasis, indicating that it might be a candidate for TNBC treatment. However, its poor water solubility, low and variable oral absorption, and large daily dose all limit the clinical use of lapatinib. In this study, we developed human serum albumin (HSA) nanoparticles loaded with lapatinib for intravenous administration to overcome these disadvantages and enhance its efficacy against TNBC. 4T1 cells (a murine TNBC cells) were selected as the cell model because their growth and metastatic spread are very close to those of human breast cancer cells. Lapatinib-loaded HSA nanoparticles (LHNPs) were prepared by Nab technology. LHNPs displayed cytotoxicity similar to the free drug but exhibited superior capacity to induce early apoptosis in 4T1 monolayer cells. Importantly, LHNPs showed improved penetration and inhibition effects in tumor spheroids compared to lapatinib solution (LS). Pharmacokinetic investigations revealed that HSA nanoparticles (i.v.) effectively increased the accumulation of lapatinib in tumor tissue at 2.38 and 16.6 times the level of LS (i.v.) and Tykerb (p.o.), respectively. Consequently, it had markedly better suppression effects both on primary breast cancer and lung metastasis in tumor-bearing mice compared to the commercial drug Tykerb. The improved anti-tumor efficacy of LHNPs may be partly attributed to its close binding to SPARC, which is widely present in the extracellular matrix of tumor tissue. These results demonstrated that LHNPs might be a promising anti-tumor agent for TNBC.
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In vivo behavior and safety of lapatinib-incorporated lipid nanoparticles.
Current pharmaceutical biotechnology, 2014Co-Authors: Huile Gao, Chen Chen, Jun Chen, Shilei Cao, Qizhi Zhang, Xinguo JiangAbstract:To improve the solubility, bioavailability and anti-tumor effect of lapatinib, lapatinib-incorporated lipid nanoparticles (LTNPs) were prepared and characterized. The particle size of LTNPs was 88.6 nm with a zeta potential of 20 mV. Laptinib was loaded into LTNPs with a non-crystal structure as determined by FT-IR. In vitro, LTNPs could be effectively uptaken into C6 glioma cells at a concentration-dependent manner. In vivo, LTNPs showed a relative higher AUC, which was 5.27- and 3.21-fold as that of Tykerb and lapatinib suspension (LTS) group. LTNPs also showed highest glioma concentration, which may benefit from the enhanced permeability and retention effect and active targeting ability. In toxicity studies, LTNPs displayed a half lethal dose over 250 mg/kg. Repeated administering 30 mg/kg of LTNPs could led to toxicity to hematology which might owe to the bovine serum albumin, a foreign protein to mice. However, there was no organic change observed through HE staining. In conclusion, LTNPs could target to glioma with high concentration and low side effect.
Gail D. Lewis Phillips - One of the best experts on this subject based on the ideXlab platform.
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Abstract #3239: Enhanced in vitro and in vivo activity of trastuzumab-DM1 antibody-drug conjugate combined with GDC-0941, a small molecule inhibitor of PI3 kinase
Cancer Research, 2009Co-Authors: Carter Fields, Kathryn Parsons, Wei Wei Prior, Deepak Sampath, Gail D. Lewis PhillipsAbstract:Molecularly targeted therapeutics continue to offer great promise in the treatment of human cancers. The receptor tyrosine kinase, HER2/ErbB2, is a validated clinical target for HER2-amplified breast cancer, as evidenced by the U.S.F.D.A approval of the humanized HER2 antibody trastuzumab (Herceptin®) and the dual HER2/EGFR small molecule tyrosine kinase inhibitor lapatinib (Tykerb®). Although many patients respond to trastuzumab, innate resistance or acquired resistance upon prolonged treatment also occur. Mechanisms of resistance to trastuzumab include upregulation of compensatory signaling pathways through activation of receptor tyrosine kinases such as EGFR, IGF-1R and met, or through mutational activation of the PI3 kinase (PI3K) pathway. An alternative approach for targeting HER2 is the direct covalent coupling of a cytotoxic drug to trastuzumab. We have previously reported the potent in vitro and in vivo efficacy of trastuzumab linked to the microtubule polymerization inhibitor mertansine (trastuzumab-DM1) in trastuzumab-sensitive and -refractory breast tumor models. Inhibition of signaling through PI3K, which is hyperactivated in HER2-amplified breast cancer due to constitutive activity of overexpressed HER2 and/or through mutation of the p110-\#945; subunit of PI3K, offers an additional therapeutic approach. We describe here the enhanced anti-tumor activity of trastuzumab-DM1 combined with the PI3K inhibitor GDC-0941, in HER2-amplified breast cancer lines with mutated PI3K: BT474 (K111N), MDA-361.1 (E545K), and KPL4 (H1047R). Combination treatment in vitro resulted in additive or synergistic inhibition of cell proliferation, as well as increased apoptosis. Similarly, in vivo efficacy was augmented with combined drug treatment compared to single agent activityin the MDA-MB-361.1 and Fo5 HER2-amplified xenograft models. Biochemical analyses of biomarkers for each agent showed inhibition of phospho-Akt and phospho-ERK by both trastuzumab-DM1 and GDC-0941, decreased phosphorylation of Rb and PRAS40 by GDC-0941, and increased levels of the mitotic markers phospho-histone H3 and cyclin B1 after treatment with trastuzumab-DM1. In addition, trastuzumab-DM1 treatment resulted in apoptosis in these breast cancer models as determined by appearance of the 23 kDa PARP-cleavage fragment, decreased levels of Bcl-XL, as well as activation of capases 3 and 7. Addition of GDC-0941 to trastuzumab-DM1 further enhanced apoptosis induction. These studies provide evidence for the use of rational drug combinations in HER2-amplified breast cancer and offer additional therapeutic approaches for patients whose disease progresses on trastuzumab or lapatinib-based therapy. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3239.
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Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate
Cancer research, 2008Co-Authors: Gail D. Lewis Phillips, Elaine Mai, Debra L Dugger, Lisa Crocker, Kathryn Parsons, Walter A Blattler, John M Lambert, Ravi V J Chari, Robert J LutzAbstract:HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development.
Kathryn Parsons - One of the best experts on this subject based on the ideXlab platform.
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Abstract #3239: Enhanced in vitro and in vivo activity of trastuzumab-DM1 antibody-drug conjugate combined with GDC-0941, a small molecule inhibitor of PI3 kinase
Cancer Research, 2009Co-Authors: Carter Fields, Kathryn Parsons, Wei Wei Prior, Deepak Sampath, Gail D. Lewis PhillipsAbstract:Molecularly targeted therapeutics continue to offer great promise in the treatment of human cancers. The receptor tyrosine kinase, HER2/ErbB2, is a validated clinical target for HER2-amplified breast cancer, as evidenced by the U.S.F.D.A approval of the humanized HER2 antibody trastuzumab (Herceptin®) and the dual HER2/EGFR small molecule tyrosine kinase inhibitor lapatinib (Tykerb®). Although many patients respond to trastuzumab, innate resistance or acquired resistance upon prolonged treatment also occur. Mechanisms of resistance to trastuzumab include upregulation of compensatory signaling pathways through activation of receptor tyrosine kinases such as EGFR, IGF-1R and met, or through mutational activation of the PI3 kinase (PI3K) pathway. An alternative approach for targeting HER2 is the direct covalent coupling of a cytotoxic drug to trastuzumab. We have previously reported the potent in vitro and in vivo efficacy of trastuzumab linked to the microtubule polymerization inhibitor mertansine (trastuzumab-DM1) in trastuzumab-sensitive and -refractory breast tumor models. Inhibition of signaling through PI3K, which is hyperactivated in HER2-amplified breast cancer due to constitutive activity of overexpressed HER2 and/or through mutation of the p110-\#945; subunit of PI3K, offers an additional therapeutic approach. We describe here the enhanced anti-tumor activity of trastuzumab-DM1 combined with the PI3K inhibitor GDC-0941, in HER2-amplified breast cancer lines with mutated PI3K: BT474 (K111N), MDA-361.1 (E545K), and KPL4 (H1047R). Combination treatment in vitro resulted in additive or synergistic inhibition of cell proliferation, as well as increased apoptosis. Similarly, in vivo efficacy was augmented with combined drug treatment compared to single agent activityin the MDA-MB-361.1 and Fo5 HER2-amplified xenograft models. Biochemical analyses of biomarkers for each agent showed inhibition of phospho-Akt and phospho-ERK by both trastuzumab-DM1 and GDC-0941, decreased phosphorylation of Rb and PRAS40 by GDC-0941, and increased levels of the mitotic markers phospho-histone H3 and cyclin B1 after treatment with trastuzumab-DM1. In addition, trastuzumab-DM1 treatment resulted in apoptosis in these breast cancer models as determined by appearance of the 23 kDa PARP-cleavage fragment, decreased levels of Bcl-XL, as well as activation of capases 3 and 7. Addition of GDC-0941 to trastuzumab-DM1 further enhanced apoptosis induction. These studies provide evidence for the use of rational drug combinations in HER2-amplified breast cancer and offer additional therapeutic approaches for patients whose disease progresses on trastuzumab or lapatinib-based therapy. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3239.
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targeting her2 positive breast cancer with trastuzumab dm1 an antibody cytotoxic drug conjugate
Cancer Research, 2008Co-Authors: Gail Lewis D Phillips, Elaine Mai, Debra L Dugger, Lisa Crocker, Kathryn Parsons, Walter A Blattler, John M Lambert, Ravi V J Chari, Robert J Lutz, Wai Lee T WongAbstract:HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development.
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targeting her2 positive breast cancer with trastuzumab dm1 an antibody cytotoxic drug conjugate
Cancer Research, 2008Co-Authors: Gail Lewis Phillips, Debra L Dugger, Lisa Crocker, Kathryn Parsons, Walter A Blattler, John M Lambert, Ravi V J Chari, Robert J Lutz, Guangmin Li, Wai Lee T WongAbstract:HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development. [Cancer Res 2008;68(22):9280–90]
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Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate
Cancer research, 2008Co-Authors: Gail D. Lewis Phillips, Elaine Mai, Debra L Dugger, Lisa Crocker, Kathryn Parsons, Walter A Blattler, John M Lambert, Ravi V J Chari, Robert J LutzAbstract:HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development.
