The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Induces Tumor Regression in a Genetically Engineered Mouse Model of PIK3CA Wild-Type Colorectal Cancer
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{"title"=>"The dual PI3K/mTOR inhibitor NVP-bez235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer", "type"=>"journal", "authors"=>[{"first_name"=>"Jatin", "last_name"=>"Roper", "scopus_author_id"=>"56797768000"}, {"first_name"=>"Michael P.", "last_name"=>"Richardson", "scopus_author_id"=>"36017472200"}, {"first_name"=>"Wei Vivian", "last_name"=>"Wang", "scopus_author_id"=>"53867583600"}, {"first_name"=>"Larissa Georgeon", "last_name"=>"Richard", "scopus_author_id"=>"14067933700"}, {"first_name"=>"Wei", "last_name"=>"Chen", "scopus_author_id"=>"55574216630"}, {"first_name"=>"Erin M.", "last_name"=>"Coffee", "scopus_author_id"=>"35224619100"}, {"first_name"=>"Mark J.", "last_name"=>"Sinnamon", "scopus_author_id"=>"14322238300"}, {"first_name"=>"Lydia", "last_name"=>"Lee", "scopus_author_id"=>"53866683300"}, {"first_name"=>"Peng Chieh", "last_name"=>"Chen", "scopus_author_id"=>"8859273400"}, {"first_name"=>"Roderick T.", "last_name"=>"Bronson", "scopus_author_id"=>"26643596200"}, {"first_name"=>"Eric S.", "last_name"=>"Martin", "scopus_author_id"=>"8074363400"}, {"first_name"=>"Kenneth E.", "last_name"=>"Hung", "scopus_author_id"=>"7202728430"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"21966435", "doi"=>"10.1371/journal.pone.0025132", "sgr"=>"80053169195", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "scopus"=>"2-s2.0-80053169195", "issn"=>"19326203", "pui"=>"362627642"}, "id"=>"06a2b6c7-2001-3f9c-8bcb-c57b649aaa3d", "abstract"=>"PURPOSE To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC). EXPERIMENTAL DESIGN PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined. RESULTS In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC(50) = 9.0-14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013). CONCLUSIONS These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC.", "link"=>"http://www.mendeley.com/research/dual-pi3kmtor-inhibitor-nvpbez235-induces-tumor-regression-genetically-engineered-mouse-model-pik3ca", "reader_count"=>47, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>11, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>10, "Student > Postgraduate"=>4, "Student > Master"=>5, "Other"=>3, "Student > Bachelor"=>7, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>11, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>10, "Student > Postgraduate"=>4, "Student > Master"=>5, "Other"=>3, "Student > Bachelor"=>7, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>8, "Materials Science"=>1, "Medicine and Dentistry"=>16, "Agricultural and Biological Sciences"=>14, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>16}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>14}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"Poland"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/730843"], "description"=>"<p>(A) Cell viability of HCT116, DLD-1, and SW480 CRC cell lines was assessed by MTS assay after treatment with increasing concentrations (0–500 nM) of NVP-BEZ235 for 48 hours. Results shown are the mean of three independent experiments. (B) Western blot analysis for p-AKT<sup>Thr308</sup>, p-AKT<sup>Ser473</sup>, p-S6<sup>Ser240/244</sup>, p-S6<sup>Ser235/236</sup>, cleaved caspase 3, and cleaved PARP was performed after 2, 6, 24, and 48 hours incubation with (−) 0 or (+) 500 nM NVP-BEZ235.</p>", "links"=>[], "tags"=>["transient", "PI3K", "blockade", "sustained"], "article_id"=>401170, "categories"=>["Cancer", "Molecular Biology", "Chemistry", "Cell Biology"], "users"=>["Jatin Roper", "Michael P. Richardson", "Wei Vivian Wang", "Larissa Georgeon Richard", "Wei Chen", "Erin M. Coffee", "Mark J. Sinnamon", "Lydia Lee", "Peng-Chieh Chen", "Roderick T. Bronson", "Eric S. Martin", "Kenneth E. Hung"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025132.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NVP_BEZ235_treatment_results_in_decreased_cell_viability_transient_PI3K_blockade_inhibition_and_sustained_mTORC1_mTORC2_blockade_/401170", "title"=>"NVP-BEZ235 treatment results in decreased cell viability, transient PI3K blockade inhibition, and sustained mTORC1/mTORC2 blockade.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:21:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/730949"], "description"=>"<p>(A) Cell viability of mutant and wild-type isogenic <i>PIK3CA</i> cells was assessed by MTS assay after treatment with increasing concentrations (0–500 nM) of NVP-BEZ235 for 48 hours. Results shown are the mean of four independent experiments. (B) Western blot analysis for p-AKT<sup>Thr308</sup>, p-AKT<sup>Ser473</sup>, p-S6<sup>Ser240/244</sup>, p-S6<sup>Ser235/236</sup>, cleaved caspase 3, and cleaved PARP was performed after 2, 6, 24, and 48 hours incubation with (−) 0 or (+) 500 nM NVP-BEZ235.</p>", "links"=>[], "tags"=>["nvp-bez235", "viability", "signaling"], "article_id"=>401288, "categories"=>["Cancer", "Molecular Biology", "Chemistry", "Cell Biology"], "users"=>["Jatin Roper", "Michael P. Richardson", "Wei Vivian Wang", "Larissa Georgeon Richard", "Wei Chen", "Erin M. Coffee", "Mark J. Sinnamon", "Lydia Lee", "Peng-Chieh Chen", "Roderick T. Bronson", "Eric S. Martin", "Kenneth E. Hung"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025132.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_NVP_BEZ235_on_cell_viability_and_PI3K_mTOR_signaling_are_independent_of_PIK3CA_status_/401288", "title"=>"Effects of NVP-BEZ235 on cell viability and PI3K/mTOR signaling are independent of <i>PIK3CA</i> status.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:21:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/731076"], "description"=>"<p>Mice with colonic tumors were randomized to treatment with control diluent (N = 8) or 45 mg/kg NVP-BEZ235 (N = 8) by daily oral gavage for 28 days. Resulting colonic tumor growth or regression was serially examined by optical colonoscopy. (A) Tumor Size Index (TSI) was calculated as Tumor Area (T) divided by Lumen Area (L) ×100. (B) Representative tumor colonoscopy still images during the 28 day treatment period. (C) Tumor volume of control and NVP-BEZ235-treated tumors at necropsy (mean 65 mm<sup>3</sup> vs. 5 mm<sup>3</sup>; p = 0.01). (D) Final TSI vs. Tumor Volume (R<sup>2</sup> = 0.89, P<0.0001). Change in mean TSI for (E) control (32% pre-treatment vs. 57% post-treatment, P = 0.01) and (F) treated (32% vs. 20%, P = 0.02) cohorts.</p>", "links"=>[], "tags"=>["gem", "sporadic", "crc"], "article_id"=>401415, "categories"=>["Cancer", "Molecular Biology", "Chemistry", "Cell Biology"], "users"=>["Jatin Roper", "Michael P. Richardson", "Wei Vivian Wang", "Larissa Georgeon Richard", "Wei Chen", "Erin M. Coffee", "Mark J. Sinnamon", "Lydia Lee", "Peng-Chieh Chen", "Roderick T. Bronson", "Eric S. Martin", "Kenneth E. Hung"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025132.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_treatment_of_a_GEM_model_for_sporadic_CRC_results_in_tumor_regression_/401415", "title"=>"<i>In vivo</i> treatment of a GEM model for sporadic CRC results in tumor regression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:22:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/731262"], "description"=>"<p>Mice with colonic tumors were randomized to treatment with control diluent or 45 mg/kg NVP-BEZ235 by daily oral gavage for five days. Western blot analysis of p-AKT<sup>Thr308</sup>, p-AKT<sup>Ser473</sup>, and p-S6<sup>Ser240/244</sup> was performed for tumors treated with (−) control diluent or (+) NVP-BEZ235 for (A) five and (B) 28 days. (C) Immunohistochemistry of p-AKT<sup>Ser473</sup>, p-S6<sup>Ser240/244</sup>, and p-S6<sup>Ser235/236</sup> was performed for tumors treated with control diluent or NVP-BEZ235 for 28 days.</p>", "links"=>[], "tags"=>["nvp-bez235", "gem", "sporadic", "crc", "transient", "PI3K", "blockade", "inhibition", "sustained"], "article_id"=>401594, "categories"=>["Cancer", "Molecular Biology", "Chemistry", "Cell Biology"], "users"=>["Jatin Roper", "Michael P. Richardson", "Wei Vivian Wang", "Larissa Georgeon Richard", "Wei Chen", "Erin M. Coffee", "Mark J. Sinnamon", "Lydia Lee", "Peng-Chieh Chen", "Roderick T. Bronson", "Eric S. Martin", "Kenneth E. Hung"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025132.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_NVP_BEZ235_treatment_of_a_GEM_model_for_sporadic_CRC_results_in_transient_PI3K_blockade_inhibition_and_sustained_mTORC1_mTORC2_blockade_/401594", "title"=>"<i>In vivo</i> NVP-BEZ235 treatment of a GEM model for sporadic CRC results in transient PI3K blockade inhibition and sustained mTORC1/mTORC2 blockade.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:23:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/731446"], "description"=>"<p>(A) Representative immunohistochemistry for the proliferation marker KI-67 after treatment with control diluent or NVP-BEZ2355 for 28 days (p = 0.003). KI-67 proliferation index was calculated as average number of positive tumor cells per high power field. (B) TUNEL immunohistochemistry was performed in tumors treated with control diluent or NVP-BEZ235 for 28 days (p = 0.9). TUNEL staining was quantified as percent positive cells per high powered field. (C) Representative immunohistochemistry for the endothelial marker PECAM after treatment with control diluent or 45 mg/kg NVP-BEZ2355 (p = 0.013). Microvessel density was calculated as average number of positive vessels per high power field.</p>", "links"=>[], "tags"=>["nvp-bez235", "gem", "sporadic", "crc", "inhibits", "blocks"], "article_id"=>401784, "categories"=>["Cancer", "Molecular Biology", "Chemistry", "Cell Biology"], "users"=>["Jatin Roper", "Michael P. Richardson", "Wei Vivian Wang", "Larissa Georgeon Richard", "Wei Chen", "Erin M. Coffee", "Mark J. Sinnamon", "Lydia Lee", "Peng-Chieh Chen", "Roderick T. Bronson", "Eric S. Martin", "Kenneth E. Hung"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025132.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_NVP_BEZ235_treatment_of_a_GEM_model_for_sporadic_CRC_inhibits_proliferation_has_no_effect_on_apoptosis_and_blocks_tumor_angiogenesis_/401784", "title"=>"<i>In vivo</i> NVP-BEZ235 treatment of a GEM model for sporadic CRC inhibits proliferation, has no effect on apoptosis, and blocks tumor angiogenesis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:24:23"}

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Relative Metric

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