Dana Buckman - Academia.edu (original) (raw)
Papers by Dana Buckman
Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor... more Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor) may have therapeutic benefit based on nonclinical and emerging clinical findings. However, the eventual emergence of drug resistant tumors motivates the pre-emptive identification of potential mechanisms of clinical resistance. We rendered a MET amplified gastric cancer cell line, GTL16, resistant to c-Met inhibition with prolonged exposure to a c-Met inhibitor, PF-04217903 (METi). Characterization of surviving cells identified an amplified chromosomal rearrangement between 7q32 and 7q34 which overexpresses a constitutively active SND1-BRAF fusion protein. In the resistant clones, hyperactivation of the downstream MAPK pathway via SND1-BRAF conferred resistance to c-Met receptor tyrosine kinase inhibition. Combination treatment with METi and a RAF inhibitor, PF-04880594 (RAFi) inhibited ERK activation and circumvented resistance to either single agent. Alternatively, treatment with a M...
Journal of Microbiological Methods, 2019
Cancer research, 2003
Traditional chemotherapeutic drugs are often restricted by severe side effects and lack of tumor ... more Traditional chemotherapeutic drugs are often restricted by severe side effects and lack of tumor specificity. Peptide prodrugs cleavable by peptidases present in the tumor environment have been explored to improve the therapeutic index of cytotoxic drugs. One such prodrug of doxorubicin (Dox), CPI-0004Na [N-succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl-Dox (sALAL-Dox)] has been shown to have an improved antitumor efficacy profile with reduced toxicity compared with Dox in tumor xenograft models (V. Dubois et al., Cancer Res., 62: 2327-2331, 2002). In this study, we demonstrate that CD10, a cell surface metalloprotease expressed on a variety of tumor cell types, is capable of cleaving CPI-0004Na and related peptide prodrugs such as N-succinyl-beta-alanyl-L-isoleucyl-L-alanyl-L-leucyl-Dox (sAIAL-Dox). This proteolytic cleavage generates leucyl-Dox, which is capable of entering cells and generating intracellular Dox. In a [(3)H]thymidine proliferation assay, analogues of CPI-0004Na s...
![Research paper thumbnail of [18F]FLT-PET Imaging Does Not Always "Light Up" Proliferating Tumor Cells](https://attachments.academia-assets.com/84212755/thumbnails/1.jpg)
](Clinical Cancer Research, 2011
Purpose: [ 18 F]FLT (3 0-Fluoro-3 0 deoxythymidine)-PET imaging was proposed as a tool for measur... more Purpose: [ 18 F]FLT (3 0-Fluoro-3 0 deoxythymidine)-PET imaging was proposed as a tool for measuring in vivo tumor cell proliferation. The aim of this article was to validate the use of [ 18 F]FLT-PET imaging for measuring xenograft proliferation and subsequent monitoring of targeted therapy. Experimental Design: In exponentially growing xenografts, factors that could impact the outcome of [ 18 F]FLT-PET imaging, such as nucleoside transporters, thymidine kinase 1, the relative contribution of DNA salvage pathway, and the ratio of FLT to thymidine, were evaluated. The [ 18 F]FLT tracer avidity was compared with other proliferation markers. Results: In a panel of proliferating xenografts, [ 18 F]FLT or [ 3 H]thymidine tracer avidity failed to reflect the tumor growth rate across different tumor types, despite the high expressions of Ki67 and TK1. When FLT was injected at the same dose level as used in the preclinical [ 18 F]FLT-PET imaging, the plasma exposure ratio of FLT to thymidine was approximately 1:200. Thymidine levels in different tumor types seemed to be variable and exhibited an inverse relationship with the FLT tracer avidity. In contrast, high-dose administration of bromdeoxyuridine (BrdUrd; 50 mg/kg) yielded a plasma exposure of more than 4-fold higher than thymidine and leads to a strong correlation between the BrdUrd uptake and the tumor proliferation rate. In FLT tracer-avid models, [ 18 F]FLT-PET imaging as a surrogate biomarker predicted the therapeutic response of CDK4/6 inhibitor PD-0332991. Conclusions: Tumor thymidine level is one of the factors that impact the correlation between [ 18 F]FLT uptake and tumor cell proliferation. With careful validation, [ 18 F]FLT-PET imaging can be used to monitor antiproliferative therapies in tracer-avid malignancies. Clin Cancer Res; 18(5); 1-10. Ó2011 AACR.
Clinical Cancer Research, 2009
Checkpoint kinase 1 (Chk1) plays a critical role in the activation of mitotic spindle checkpoint ... more Checkpoint kinase 1 (Chk1) plays a critical role in the activation of mitotic spindle checkpoint and DNA damage checkpoint. We examined the preclinical use of the Chk1 inhibitor PF-00477736 as a docetaxel-sensitizing agent. Specifically, we investigated the correlation between PF-00477736^mediated modulation of biomarkers and the sensitization of docetaxel efficacy. Experimental Design: In vitro and in vivo studies using COLO205 and other cell lines were done to assess PF-00477736^induced enhancement of docetaxel efficacy and effects on associated biomarkers. Results: PF-00477736 significantly enhanced the docetaxel-induced efficacy in tumor cells and xenografts. Docetaxel induced dose-and time-dependent increase in the levels of phosphorylated Chk1 (Ser 345), phosphorylated histone H3 (Ser 10), and gH2AX foci and promoted the cytoplasmic localization of phosphorylated Cdc25C (Ser 216). PF-00477736 cotreatment suppressed docetaxel-induced changes in phosphorylated histone H3 and cytoplasmic phosphorylated Cdc25C (Ser 216) levels and concurrently sensitized the docetaxel-induced apoptosis. Docetaxel alone or in combination with PF-00477736 induced significant antiproliferative activity in xenografts, shown via [ 18 F]FLT-PET imaging. However, changes in [ 18 F]FLT uptake did not reflect the potentiation of docetaxel efficacy. In contrast, bioluminescence imaging showed that PF-00477736 sensitized docetaxel-induced suppression of tumor survival. Conclusions: Docetaxel triggers mitotic spindle checkpoint activation at low concentrations and activates both the DNA damage checkpoint and the spindle checkpoint at high concentrations. In combination with docetaxel, PF-00477736 abrogates the mitotic checkpoint, as well as the DNA damage checkpoint, and results in sensitization to docetaxel. Chk1inhibitor PF-00477736 offers a therapeutic potential for the enhancement of taxane therapy.
Cancer Research, 2010
PF-03084014, a small molecule γ-secretase inhibitor (GSI), has previously been shown to inhibit N... more PF-03084014, a small molecule γ-secretase inhibitor (GSI), has previously been shown to inhibit Notch signaling and demonstrated antitumor efficacy. The aim of this report is to gain insights into the mechanism PF-03084014-induced activity. The cell-based evaluation of PF-03084014 across 30 breast cancer (BC) cell lines indicated significant growth inhibition in only a subset of cell lines (3/30). In contrast, PF-03084014 demonstrated cell cycle arrest and induction of apoptosis by FACS analysis across the majority of a panel of T-acute lymphoblastic leukemia (T-ALL) cell lines. In vivo BrdU uptake of tumor and [ 18 F]FLT-PET imaging studies demonstrated that PF-03084014 at an efficacious dose (120 mg/kg) caused cell cycle arrest in Sup T1 tumors but not in MDA-MB-231 xenografts, although PF-03084014 suppressed the expression of Notch target genes and tumor growth in both models. These results suggest that the primary mechanism(s) for PF-03084014-induced efficacy in T-ALL and BC models may be different, possibly because the tumor-host microenvironment in the BC model plays an important role during Notch signaling activation. IHC analysis in a panel of solid tumors demonstrated that Notch ligands including jagged 1, 2 and Dll4 were predominately expressed in the host vasculature and stromal cells. To investigate the potential antiangiogenic activity of PF-03084014, an in vitro endothelial cell/fibroblast co-culture tube formation assay was utilized. PF-03084014 disrupted the multicellular lumen-like structures at 100 nM, indicating defective differentiation of endothelial cells in early stage angiogenesis. Ultrasound imaging was utilized to further investigate the antiangiogenic properties of PF-03084014 including both the quantitative measurement of the total tumor vessel volume using 3-D scanning methods and an assessment tumor blood vessel function by measuring blood flow after iv injection of microbubble contrast agents. When MDA-MB-231 tumor bearing mice were administered with an efficacious dose of PF-03084014 consecutively for 4 days, ultrasound imaging revealed a significant (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5218.
Cancer Research, 2010
[18F]FLT-PET imaging has been increasingly employed as a surrogate biomarker in early clinical tr... more [18F]FLT-PET imaging has been increasingly employed as a surrogate biomarker in early clinical trials to evaluate the mechanism of cancer drug candidates. In this report, we have assessed the preclinical application of [18F]FLT-PET imaging modality for several investigative agents that are currently under clinical development, including PF-03732010 (P-cadherin mAb), PD-0332991 (CDK4 inhibitor) and PF-03084014 (γ-secretase inhibitor). Docetaxel was also utilized as a standard comparator. Our goals included 1) building a preclinical understanding of the [18F]FLT tracer avidity in various xenograft models; 2) selecting models with appropriate tracer avidity and target molecular profiles for respective agents; 3) correlating suppression of [18F]FLT uptake with the changes of other pharmacodynamic endpoints and measures of antitumor efficacy; and 4) bridging preclinical and clinical [18F]FLT-PET imaging studies. Among the tested tumor models, [18F]FLT tracer avidity did not always correlate with the tumor growth rate. Affymetrix array and LC/MS analyses indicated that multiple factors including the expression levels of thymidine kinase 1 (TK1) and pyrimidine transporters, as well as the intrinsic thymidine level in tumor each contributed to the [18F]FLT tracer avidity. In the MDA-MB-435HAL-subrenal capsule model, administration of PF-03732010 resulted in a time- and dose-dependent inhibition of [18F]FLT tracer uptake, which corresponded with the modulation of β-catenin and Ki67 levels via IHC analysis. As β-catenin partners with P-cadherin for mediating the proliferation and invasiveness of tumor cells, this result suggests that the suppression in [18F]FLT uptake correspond with the target modulation. However, when we tested the [18F]FLT-PET imaging in the MDA-MB-231 model, treatment with an efficacious dose of PF-03084014 (GSI) exhibited an insignificant effect on the tracer uptake despite evidence in modulation of target genes. The GSI-induced impact on the tumor BrdU uptake was also minimal suggesting that the observed antitumor efficacy was not primarily mediated by modulation of cell cycle. In the Rb wild-type MDA-MB-231 and HCT116 tumor models, administration of an efficacious dose level of PD-0332991 (CDK4/6i) demonstrated a significant decline of [18F]FLT tracer uptake. Concurrent hypophosphorylation of RbSer780 and reduced BrdU uptake by IHC was also observed, indicating that [18F]FLT tracer uptake highly reflected the target modulation and predicted therapy. Therefore [18F]FLT-PET imaging modality presents a ideal proof-of-mechanism biomarker for PD-0332991. Collectively, these results indicate a potential applications for [18F]FLT-PET imaging in early clinical studies to demonstrate an impact on target endpoints depending on the mechanism of action of anticancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1758.
Cancer Research, 2010
Integrin a5b1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicat... more Integrin a5b1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicated in angiogenesis, tumor survival, and metastasis. Antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells has been shown to contribute to clinical efficacy for several IgG1 monoclonal antibody (mAb) therapeutics. Taking advantage of these two mechanisms, we generated a fully human, fragment crystalizable (Fc)-engineered IgG1 mAb, PF-04605412 (PF-5412), which specifically neutralizes a5 and binds the Fcg receptors (FcgR) with enhanced affinity. In vitro, PF-5412 potently inhibited a5b1-mediated intracellular signaling, cell adhesion, migration, and endothelial cell (EC) tubulogenesis. PF-5412 induced significantly greater ADCC in a5expressing tumor cells and ECs compared with a wild-type IgG1 (IgG1/wt) or IgG2 of identical antigen specificity. The degree of ADCC correlated with the abundance of natural killer (NK) cells in the peripheral blood mononuclear cells but was independent of donor FcgRIIIa polymorphism. In animal studies, PF-5412 displayed robust and dose-dependent antitumor efficacy superior to that observed with IgG1/wt, IgG2, or IgG4 of identical antigen specificity. The degree of efficacy correlated with a5 expression, macrophage and NK cell infiltration, and NK activity in the tumor. Depletion of host macrophages abrogated antitumor activity, suggesting a critical contribution of macrophage-mediated antitumor activity of PF-5412. Combination of PF-5412 with sunitinib significantly improved antitumor efficacy compared with either agent alone. The dual mechanism of action and robust antitumor efficacy of PF-5412 support its clinical development for the treatment of a broad spectrum of human malignancies. Cancer Res; 70(24); 10243-54. Ó2010 AACR.
Cancer Immunology, Immunotherapy, 2002
Journal of Probiotics & Health, 2018
Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor... more Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor) may have therapeutic benefit based on nonclinical and emerging clinical findings. However, the eventual emergence of drug resistant tumors motivates the pre-emptive identification of potential mechanisms of clinical resistance. We rendered a MET amplified gastric cancer cell line, GTL16, resistant to c-Met inhibition with prolonged exposure to a c-Met inhibitor, PF-04217903 (METi). Characterization of surviving cells identified an amplified chromosomal rearrangement between 7q32 and 7q34 which overexpresses a constitutively active SND1-BRAF fusion protein. In the resistant clones, hyperactivation of the downstream MAPK pathway via SND1-BRAF conferred resistance to c-Met receptor tyrosine kinase inhibition. Combination treatment with METi and a RAF inhibitor, PF-04880594 (RAFi) inhibited ERK activation and circumvented resistance to either single agent. Alternatively, treatment with a M...
Journal of Microbiological Methods, 2019
Cancer research, 2003
Traditional chemotherapeutic drugs are often restricted by severe side effects and lack of tumor ... more Traditional chemotherapeutic drugs are often restricted by severe side effects and lack of tumor specificity. Peptide prodrugs cleavable by peptidases present in the tumor environment have been explored to improve the therapeutic index of cytotoxic drugs. One such prodrug of doxorubicin (Dox), CPI-0004Na [N-succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl-Dox (sALAL-Dox)] has been shown to have an improved antitumor efficacy profile with reduced toxicity compared with Dox in tumor xenograft models (V. Dubois et al., Cancer Res., 62: 2327-2331, 2002). In this study, we demonstrate that CD10, a cell surface metalloprotease expressed on a variety of tumor cell types, is capable of cleaving CPI-0004Na and related peptide prodrugs such as N-succinyl-beta-alanyl-L-isoleucyl-L-alanyl-L-leucyl-Dox (sAIAL-Dox). This proteolytic cleavage generates leucyl-Dox, which is capable of entering cells and generating intracellular Dox. In a [(3)H]thymidine proliferation assay, analogues of CPI-0004Na s...
Clinical Cancer Research, 2011
Purpose: [ 18 F]FLT (3 0-Fluoro-3 0 deoxythymidine)-PET imaging was proposed as a tool for measur... more Purpose: [ 18 F]FLT (3 0-Fluoro-3 0 deoxythymidine)-PET imaging was proposed as a tool for measuring in vivo tumor cell proliferation. The aim of this article was to validate the use of [ 18 F]FLT-PET imaging for measuring xenograft proliferation and subsequent monitoring of targeted therapy. Experimental Design: In exponentially growing xenografts, factors that could impact the outcome of [ 18 F]FLT-PET imaging, such as nucleoside transporters, thymidine kinase 1, the relative contribution of DNA salvage pathway, and the ratio of FLT to thymidine, were evaluated. The [ 18 F]FLT tracer avidity was compared with other proliferation markers. Results: In a panel of proliferating xenografts, [ 18 F]FLT or [ 3 H]thymidine tracer avidity failed to reflect the tumor growth rate across different tumor types, despite the high expressions of Ki67 and TK1. When FLT was injected at the same dose level as used in the preclinical [ 18 F]FLT-PET imaging, the plasma exposure ratio of FLT to thymidine was approximately 1:200. Thymidine levels in different tumor types seemed to be variable and exhibited an inverse relationship with the FLT tracer avidity. In contrast, high-dose administration of bromdeoxyuridine (BrdUrd; 50 mg/kg) yielded a plasma exposure of more than 4-fold higher than thymidine and leads to a strong correlation between the BrdUrd uptake and the tumor proliferation rate. In FLT tracer-avid models, [ 18 F]FLT-PET imaging as a surrogate biomarker predicted the therapeutic response of CDK4/6 inhibitor PD-0332991. Conclusions: Tumor thymidine level is one of the factors that impact the correlation between [ 18 F]FLT uptake and tumor cell proliferation. With careful validation, [ 18 F]FLT-PET imaging can be used to monitor antiproliferative therapies in tracer-avid malignancies. Clin Cancer Res; 18(5); 1-10. Ó2011 AACR.
Clinical Cancer Research, 2009
Checkpoint kinase 1 (Chk1) plays a critical role in the activation of mitotic spindle checkpoint ... more Checkpoint kinase 1 (Chk1) plays a critical role in the activation of mitotic spindle checkpoint and DNA damage checkpoint. We examined the preclinical use of the Chk1 inhibitor PF-00477736 as a docetaxel-sensitizing agent. Specifically, we investigated the correlation between PF-00477736^mediated modulation of biomarkers and the sensitization of docetaxel efficacy. Experimental Design: In vitro and in vivo studies using COLO205 and other cell lines were done to assess PF-00477736^induced enhancement of docetaxel efficacy and effects on associated biomarkers. Results: PF-00477736 significantly enhanced the docetaxel-induced efficacy in tumor cells and xenografts. Docetaxel induced dose-and time-dependent increase in the levels of phosphorylated Chk1 (Ser 345), phosphorylated histone H3 (Ser 10), and gH2AX foci and promoted the cytoplasmic localization of phosphorylated Cdc25C (Ser 216). PF-00477736 cotreatment suppressed docetaxel-induced changes in phosphorylated histone H3 and cytoplasmic phosphorylated Cdc25C (Ser 216) levels and concurrently sensitized the docetaxel-induced apoptosis. Docetaxel alone or in combination with PF-00477736 induced significant antiproliferative activity in xenografts, shown via [ 18 F]FLT-PET imaging. However, changes in [ 18 F]FLT uptake did not reflect the potentiation of docetaxel efficacy. In contrast, bioluminescence imaging showed that PF-00477736 sensitized docetaxel-induced suppression of tumor survival. Conclusions: Docetaxel triggers mitotic spindle checkpoint activation at low concentrations and activates both the DNA damage checkpoint and the spindle checkpoint at high concentrations. In combination with docetaxel, PF-00477736 abrogates the mitotic checkpoint, as well as the DNA damage checkpoint, and results in sensitization to docetaxel. Chk1inhibitor PF-00477736 offers a therapeutic potential for the enhancement of taxane therapy.
Cancer Research, 2010
PF-03084014, a small molecule γ-secretase inhibitor (GSI), has previously been shown to inhibit N... more PF-03084014, a small molecule γ-secretase inhibitor (GSI), has previously been shown to inhibit Notch signaling and demonstrated antitumor efficacy. The aim of this report is to gain insights into the mechanism PF-03084014-induced activity. The cell-based evaluation of PF-03084014 across 30 breast cancer (BC) cell lines indicated significant growth inhibition in only a subset of cell lines (3/30). In contrast, PF-03084014 demonstrated cell cycle arrest and induction of apoptosis by FACS analysis across the majority of a panel of T-acute lymphoblastic leukemia (T-ALL) cell lines. In vivo BrdU uptake of tumor and [ 18 F]FLT-PET imaging studies demonstrated that PF-03084014 at an efficacious dose (120 mg/kg) caused cell cycle arrest in Sup T1 tumors but not in MDA-MB-231 xenografts, although PF-03084014 suppressed the expression of Notch target genes and tumor growth in both models. These results suggest that the primary mechanism(s) for PF-03084014-induced efficacy in T-ALL and BC models may be different, possibly because the tumor-host microenvironment in the BC model plays an important role during Notch signaling activation. IHC analysis in a panel of solid tumors demonstrated that Notch ligands including jagged 1, 2 and Dll4 were predominately expressed in the host vasculature and stromal cells. To investigate the potential antiangiogenic activity of PF-03084014, an in vitro endothelial cell/fibroblast co-culture tube formation assay was utilized. PF-03084014 disrupted the multicellular lumen-like structures at 100 nM, indicating defective differentiation of endothelial cells in early stage angiogenesis. Ultrasound imaging was utilized to further investigate the antiangiogenic properties of PF-03084014 including both the quantitative measurement of the total tumor vessel volume using 3-D scanning methods and an assessment tumor blood vessel function by measuring blood flow after iv injection of microbubble contrast agents. When MDA-MB-231 tumor bearing mice were administered with an efficacious dose of PF-03084014 consecutively for 4 days, ultrasound imaging revealed a significant (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5218.
Cancer Research, 2010
[18F]FLT-PET imaging has been increasingly employed as a surrogate biomarker in early clinical tr... more [18F]FLT-PET imaging has been increasingly employed as a surrogate biomarker in early clinical trials to evaluate the mechanism of cancer drug candidates. In this report, we have assessed the preclinical application of [18F]FLT-PET imaging modality for several investigative agents that are currently under clinical development, including PF-03732010 (P-cadherin mAb), PD-0332991 (CDK4 inhibitor) and PF-03084014 (γ-secretase inhibitor). Docetaxel was also utilized as a standard comparator. Our goals included 1) building a preclinical understanding of the [18F]FLT tracer avidity in various xenograft models; 2) selecting models with appropriate tracer avidity and target molecular profiles for respective agents; 3) correlating suppression of [18F]FLT uptake with the changes of other pharmacodynamic endpoints and measures of antitumor efficacy; and 4) bridging preclinical and clinical [18F]FLT-PET imaging studies. Among the tested tumor models, [18F]FLT tracer avidity did not always correlate with the tumor growth rate. Affymetrix array and LC/MS analyses indicated that multiple factors including the expression levels of thymidine kinase 1 (TK1) and pyrimidine transporters, as well as the intrinsic thymidine level in tumor each contributed to the [18F]FLT tracer avidity. In the MDA-MB-435HAL-subrenal capsule model, administration of PF-03732010 resulted in a time- and dose-dependent inhibition of [18F]FLT tracer uptake, which corresponded with the modulation of β-catenin and Ki67 levels via IHC analysis. As β-catenin partners with P-cadherin for mediating the proliferation and invasiveness of tumor cells, this result suggests that the suppression in [18F]FLT uptake correspond with the target modulation. However, when we tested the [18F]FLT-PET imaging in the MDA-MB-231 model, treatment with an efficacious dose of PF-03084014 (GSI) exhibited an insignificant effect on the tracer uptake despite evidence in modulation of target genes. The GSI-induced impact on the tumor BrdU uptake was also minimal suggesting that the observed antitumor efficacy was not primarily mediated by modulation of cell cycle. In the Rb wild-type MDA-MB-231 and HCT116 tumor models, administration of an efficacious dose level of PD-0332991 (CDK4/6i) demonstrated a significant decline of [18F]FLT tracer uptake. Concurrent hypophosphorylation of RbSer780 and reduced BrdU uptake by IHC was also observed, indicating that [18F]FLT tracer uptake highly reflected the target modulation and predicted therapy. Therefore [18F]FLT-PET imaging modality presents a ideal proof-of-mechanism biomarker for PD-0332991. Collectively, these results indicate a potential applications for [18F]FLT-PET imaging in early clinical studies to demonstrate an impact on target endpoints depending on the mechanism of action of anticancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1758.
Cancer Research, 2010
Integrin a5b1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicat... more Integrin a5b1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicated in angiogenesis, tumor survival, and metastasis. Antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells has been shown to contribute to clinical efficacy for several IgG1 monoclonal antibody (mAb) therapeutics. Taking advantage of these two mechanisms, we generated a fully human, fragment crystalizable (Fc)-engineered IgG1 mAb, PF-04605412 (PF-5412), which specifically neutralizes a5 and binds the Fcg receptors (FcgR) with enhanced affinity. In vitro, PF-5412 potently inhibited a5b1-mediated intracellular signaling, cell adhesion, migration, and endothelial cell (EC) tubulogenesis. PF-5412 induced significantly greater ADCC in a5expressing tumor cells and ECs compared with a wild-type IgG1 (IgG1/wt) or IgG2 of identical antigen specificity. The degree of ADCC correlated with the abundance of natural killer (NK) cells in the peripheral blood mononuclear cells but was independent of donor FcgRIIIa polymorphism. In animal studies, PF-5412 displayed robust and dose-dependent antitumor efficacy superior to that observed with IgG1/wt, IgG2, or IgG4 of identical antigen specificity. The degree of efficacy correlated with a5 expression, macrophage and NK cell infiltration, and NK activity in the tumor. Depletion of host macrophages abrogated antitumor activity, suggesting a critical contribution of macrophage-mediated antitumor activity of PF-5412. Combination of PF-5412 with sunitinib significantly improved antitumor efficacy compared with either agent alone. The dual mechanism of action and robust antitumor efficacy of PF-5412 support its clinical development for the treatment of a broad spectrum of human malignancies. Cancer Res; 70(24); 10243-54. Ó2010 AACR.
Cancer Immunology, Immunotherapy, 2002
Journal of Probiotics & Health, 2018