<i>In vivo</i>activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models

Kolinsky, Kenneth; Shen, Ben-Quan; Zhang, Yue; Kohles, Joseph D.; Dugan, Ute; Zioncheck, Thomas F.; Heimbrook, David; Packman, Kathryn; Higgins, Brian

doi:10.1158/1535-7163.mct-08-0596

Cited by 41 publications

(36 citation statements)

References 33 publications

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“…Such efficacy is likely due to a failure in their ability to recruit a vasculature and enable these isolated cells to progress and grow to a size that will be detectable by conventional computed tomography scans. Such residual disease models have been used to study the effect of prolonged VEGF blockade following chemotherapy (43)(44)(45)(46) and have shown that anti-VEGF therapy primarily functions to delay rather than prevent tumor regrowth. However, we believe that these studies are the first to show that in some models of residual tumor burden, prolonged anti-VEGF therapy can prevent tumor regrowth for prolonged periods.…”

Section: Discussionmentioning

confidence: 99%

Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

Bagri¹,

Berry²,

Gunter³

et al. 2010

Clinical Cancer Research

127

102

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Purpose: Inhibition of the vascular endothelial growth factor (VEGF) axis is the basis of all currently approved antiangiogenic therapies. In preclinical models, anti-VEGF blocking antibodies have shown broad efficacy that is dependent on both tumor context and treatment duration. We aimed to characterize this activity and to evaluate the effects of discontinuation of treatment on the dynamics of tumor regrowth. Experimental Design: We evaluated the effects of anti-VEGF treatment on tumor growth and survival in 30 xenograft models and in genetic mouse models of cancer. Histologic analysis was used to evaluate the effects of treatment on tumor vasculature. We used a variety of treatment regimens to allow analysis of the effects of treatment duration and cessation on growth rate, survival, and vascular density. Results: Preclinical tumor models were characterized for their varied dependence on VEGF, thereby defining models for testing other agents that may complement or augment anti-VEGF therapy. We also found that longer exposure to anti-VEGF monoclonal antibodies delayed tumor growth and extended survival in established tumors from both cell transplants and genetic tumor models and prevented regrowth of a subset of residual tumors following cytoablative therapy. Discontinuation of anti-VEGF in established tumors resulted in regrowth at a rate slower than that in control-treated animals, with no evidence of accelerated tumor growth or rebound. However, more rapid regrowth was observed following discontinuation of certain chemotherapies. Concurrent administration of anti-VEGF seemed to normalize these accelerated growth rates. Conclusions: In diverse preclinical models, continuous VEGF suppression provides maximal benefit as a single agent, combined with chemotherapy, or as maintenance therapy once chemotherapy has been stopped. Clin Cancer Res; 16(15); 3887–900. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

Bagri¹,

Berry²,

Gunter³

et al. 2010

Clinical Cancer Research

127

102

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“…Others have reported that parenterally given CSF-1 antibody and CSF-1 antisense oligonucleotides reduced tumor-associated endothelial cell proliferation together with an ∼50% growth suppression of mammary and colon carcinoma xenografts accompanied by substantial extensions in survival (10)(11)(12). Although tumors continued to grow in the presence of CSF-1/CSF-1R inhibition, this was also true of similar xenografts after treatment with bevacizumab, a vascular endothelial growth factor antibody in current clinical use to treat breast and colon cancer in combination with standard therapy (36). Of note, survival benefits provided by CSF-1 antibody was more (Table 2).…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 91%

JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia

Manthey

Johnson

Illig

et al. 2009

Molecular Cancer Therapeutics

106

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There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colonystimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/ 80 + tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.

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“…MK-2206 (Selleck Inc.) was formulated in 30% Captisol (CyDex Pharmaceuticals). Capecitabine (Xeloda; Roche Laboratories) suspensions and clinical grade bevacizumab (Avastin; Genentech, Inc.) were prepared as previously described (21). Irinotecan (Camptosar; Pfizer) was provided in a stock sterile saline solution of 20 mg/mL, which was diluted as required with sterile saline.…”

Section: Test Agents For In Vivo Studiesmentioning

confidence: 99%

“…4A) over 3 weeks. The 400 and 700 mg/kg doses correspond to the previously determined maximum tolerated dose (MTD) for the 14-and 7-day schedules, respectively (21). Bevacizumab (5 mg/kg) was dosed intraperitoneally using a sterile 1-mL syringe and 26-gauge needle (0.2 mL/animal, twice a week) on a Tuesday/Friday schedule.…”

Section: Vemurafenib/erlotinib Combination Studiesmentioning

confidence: 99%

Antitumor Activity of BRAF Inhibitor Vemurafenib in Preclinical Models of BRAF-Mutant Colorectal Cancer

et al. 2012

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The protein kinase BRAF is a key component of the RAS-RAF signaling pathway which plays an important role in regulating cell proliferation, differentiation, and survival. Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report the preclinical characterization of vemurafenib (RG7204; PLX4032; RO5185426), a first-in-class, specific small molecule inhibitor of BRAF V600E in BRAF-mutated CRC cell lines and tumor xenograft models. As a single agent, vemurafenib shows dose-dependent inhibition of ERK and MEK phosphorylation, thereby arresting cell proliferation in BRAF V600 -expressing cell lines and inhibiting tumor growth in BRAF V600E bearing xenograft models. Because vemurafenib has shown limited single-agent clinical activity in BRAF V600E -mutant metastatic CRC, we therefore explored a range of combination therapies, with both standard agents and targeted inhibitors in preclinical xenograft models. In a BRAF-mutant CRC xenograft model with de novo resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor (MK-2206).The addition of vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or irinotecan, or erlotinib resulted in increased antitumor activity and improved survival in xenograft models. Together, our findings suggest that the administration of vemurafenib in combination with standard-of-care or novel targeted therapies may lead to enhanced and sustained clinical antitumor efficacy in CRCs harboring the BRAF V600E mutation.Cancer Res; 72(3); 779-89. Ó2011 AACR.

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In vivoactivity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models

Cited by 41 publications

References 33 publications

Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia

Antitumor Activity of BRAF Inhibitor Vemurafenib in Preclinical Models of BRAF-Mutant Colorectal Cancer

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