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Clodia Osipo - One of the best experts on this subject based on the ideXlab platform.
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Abstract P6-05-25: Ratio of notch receptors is critical for response to notch inhibition by a Gamma-Secretase Inhibitor in triple negative breast cancer cells
Cancer Research, 2013Co-Authors: Andrei Zlobin, R Kuprys-olsauskas, Deep Shah, Clodia OsipoAbstract:Background: Women with triple-negative breast cancer have the worst prognosis, and have few targeted therapy options. Notch receptor genes are potent breast oncogenes, overexpressed in triple-negative breast cancer, and critical for survival of breast cancer stem cells. However, the contribution of each Notch receptor and the significance of the ratio of receptors to growth and sensitivity to Notch Inhibitors have not yet been fully explored. We hypothesized that each Notch receptor has distinct roles in the etiology of triple negative breast cancer and designed a study to explore these roles in a panel of three triple negative cell lines and primary, human triple negative breast cancer tissue. Methods: Human cell lines BT-549, MDA-MB-231, and MDA-MB-468 were used to measure endogenous mRNA transcript levels of Notch ligands, receptors, and gene targets important for canonical Notch signaling (i.e. Hes-1, Hes-5, Hey-1, and Deltex-1), apoptosis (Noxa), inflammation (MMP-9 and IL-8), and cancer stem cells (ALDH1) by means of real time PCR under conditions where all four receptors were inhibited by a pan-Inhibitor, Gamma-Secretase Inhibitor or each receptor was individually knocked down using RNA interference. Furthermore, both anchorage-dependent and –independent growth were measured by counting cells and methylcellulose colony forming assay, respectively. In addition, the RNA from formalin-fixed, paraffin-embedded specimen from women-diagnosed with TNBC who had undergone breast surgery was also analyzed for comparable gene expression for similar targets following Laser capture micro-dissection. Results: The results showed that only MDA-MB-468 cells were sensitive to growth inhibition by a GSI while MDA-MB-231 and BT549 were resistant. Transcripts of Notch-4, Deltex-1, Hes-1 and Hes-5, as well as IL-8 and MMP-9 were significantly increased in MDA-MB-468 as compared to BT549 or MDA-MB-231 cells that were resistant. Interestingly, the cancer stem marker, ALDH1 was significantly increased only in MDA-MB-468 while the apoptotic marker, Noxa was decreased compared to resistant cells: BT549 and MDA-MB-231. The PCR and growth results from the Notch-1 knocked down were similar to GSI inhibition. However, knocked down of Notch-2 resulted in resistance to GSI. Notch-3 knocked down showed an increase in Notch-1, Notch-2, and Notch-4 transcripts implying that Notch-3 might suppress the other Notch receptors. Notch-4 knocked down alone had little effect on growth of any of the three cell lines. The results from human specimens showed an inverse relationship between Notch-1 and Notch-2, and Notch-1 and Notch-4. For example, Notch-1, Jagged-1, and Hes-5 genes were up-regulated in triple negative tumor tissue (n = 20), while the Notch-4 gene was down-regulated as compared to normal control specimens from reduction mammoplasty (n = 4). Conclusions: The results from this study indicate that Notch-1 is probably the growth driver in certain triple negative cancer types.. Furthermore, the ratios of Notch receptors and their activity states could predict sensitivity to Notch inhibition by a GSI or other Inhibitors. Lastly, these results suggest that the best predictor genes for Notch activation are: Notch-1, Hes-1, and ALDH1. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-25.
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abstract 861 analysis of predictive genes in triple negative breast cancer in response to a Gamma Secretase Inhibitor
Cancer Research, 2013Co-Authors: Roma Olsauskaskuprys, Clodia OsipoAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Defined by the lack of estrogen and progesterone receptors and amplification of human epidermal growth factor receptor-2 (HER-2), triple negative breast cancer (TNBC) is a devastating disease with no approved, targeted therapy to date. Characterized by aggressive behavior which includes high rates of metastasis and very poor prognosis, TNBC is presently treated with DNA-damaging agents such as cisplatin or carboplatin. The overall survival outcomes for women with TNBC is dismal and consequently TNBC research requires identification of biomarkers that specifically mediate signaling pathways that lead to disease progression and metastasis. Notch receptors which are necessary for self-renewal and survival of breast cancer stem cells are excellent candidate biomarkers to investigate in various subtypes of TNBC. Based on the critical need to identify predictive biomarkers, we hypothesized that inhibition of the Notch pathway via γ-Secretase inhibition (GSI) will provide an effective blockade of TNBC growth in specific subtypes where predictive Notch gene expression profiles are significantly up or downregulated. A panel of three TNBC cell lines were used in this study: MDA-MB-231 (mesenchymal stem-like), MDA-MB-468 (basal-like 1), and BT549 (luminal). Using real-time PCR, Notch pathway-associated genes were measured which include Notch-1 and Notch-4 receptors, Notch target genes (i.e. Deltex-1, Hes-1, Hes-5, and Hey-1), and genes such as IL-8 and MMP-9 which are associated with aggressive tumor behavior. Both anchorage-dependent and anchorage-independent growth assays were measured in response to MRK-003 GSI, carboplatin, and the combination. We have identified for the first time a TNBC line (MDA-MB-468) that expressed the highest level of Hes-1, a Notch gene target, and is the most sensitive to single agent MRK-003 GSI treatment. We also identified that this cell line with the highest sensitivity to MRK-003 GSI upregulates Notch-4 and IL-8 in response to the GSI to a greater extent than either of the two other TNBC lines. Furthermore, the addition of carboplatin at its IC50 concentration significantly increased the sensitivity of MRK-003 GSI in otherwise insensitive TNBC lines. These results suggest for the first time that: 1) Hes-1 could potentially be a valuable predictive biomarker of Notch activity in TBNC; 2) induction of Notch-4 and/or IL-8 could predict response to MRK-003 GSI; and 3) carboplatin might provide a means to increase sensitivity to MRK-003 GSI in resistant TNBC. Citation Format: Roma Olsauskas-Kuprys, Clodia Osipo. Analysis of predictive genes in triple negative breast cancer in response to a Gamma-Secretase Inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2013-861
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erbb 2 inhibition activates notch 1 and sensitizes breast cancer cells to a Gamma Secretase Inhibitor
Oncogene, 2008Co-Authors: Clodia Osipo, Todd E Golde, P Patel, Paola Rizzo, Anthony G Clementz, L Hao, Lucio MieleAbstract:ErbB-2 overexpression in breast tumors is associated with poor survival. Expression of Notch-1 and its ligand, Jagged-1, is associated with the poorest survival, including ErbB-2-positive tumors. Trastuzumab plus chemotherapy is the standard of care for ErbB-2-positive breast cancer. A proportion of tumors are initially resistant to trastuzumab and acquired resistance to trastuzumab occurs in metastatic breast cancer and is associated with poor prognosis. Thus, we investigated whether Notch-1 contributes to trastuzumab resistance. ErbB-2-positive cells have low Notch transcriptional activity compared to non-overexpressing cells. Trastuzumab or a dual epidermal growth factor receptor (EGFR)/ErbB-2 tyrosine kinase Inhibitor (TKI) increased Notch activity by 2- to 6-fold in SKBr3, BT474 and MCF-7/HER2-18 cells. The increase in activity was abrogated by a Notch Inhibitor, Gamma-Secretase Inhibitor (GSI) or Notch-1 small-interfering RNA (siRNA). Trastuzumab decreased Notch-1trade mark precursor, increased amount and nuclear accumulation of active Notch-1(IC) and increased expression of targets, Hey1 and Deltex1 mRNAs, and Hes5, Hey1, Hes1 proteins. Importantly, trastuzumab-resistant BT474 cells treated with trastuzumab for 6 months expressed twofold higher Notch-1, twofold higher Hey1, ninefold higher Deltex1 mRNAs and threefold higher Notch-1 and Hes5 proteins, compared to trastuzumab-sensitive BT474 cells. The increase in Hey1 and Deltex1 mRNAs in resistant cells was abrogated by a Notch-1 siRNA. Cell proliferation was inhibited more effectively by trastuzumab or TKI plus a GSI than either agent alone. Decreased Notch-1 by siRNA increased efficacy of trastuzumab in BT474 sensitive cells and restored sensitivity in resistant cells. Trastuzumab plus a GSI increased apoptosis in sensitive cells by 20-30%. A GSI alone was sufficient to increase apoptosis in trastuzumab-resistant BT474 cells by 20%, which increased to 30% with trastuzumab. Notch-1 siRNA alone decreased cell growth by 30% in sensitive and more than 50% in resistant BT474 cells. Furthermore, growth of both trastuzumab sensitive and resistant cells was completely inhibited by combining trastuzumab plus Notch-1 siRNA. More importantly, Notch-1 siRNA or a GSI resensitized trastuzumab-resistant BT474 cells to trastuzumab. These results demonstrate that ErbB-2 overexpression suppresses Notch-1 activity, which can be reversed by trastuzumab or TKI. These results suggest that Notch-1 might play a novel role in resistance to trastuzumab, which could be prevented or reversed by inhibiting Notch-1.
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erbb 2 inhibition activates notch 1 and sensitizes breast cancer cells to a Gamma Secretase Inhibitor
Oncogene, 2008Co-Authors: Clodia Osipo, Todd E Golde, P Patel, Paola Rizzo, Anthony G Clementz, L Hao, Lucio MieleAbstract:ErbB-2 overexpression in breast tumors is associated with poor survival. Expression of Notch-1 and its ligand, Jagged-1, is associated with the poorest survival, including ErbB-2-positive tumors. Trastuzumab plus chemotherapy is the standard of care for ErbB-2-positive breast cancer. A proportion of tumors are initially resistant to trastuzumab and acquired resistance to trastuzumab occurs in metastatic breast cancer and is associated with poor prognosis. Thus, we investigated whether Notch-1 contributes to trastuzumab resistance. ErbB-2-positive cells have low Notch transcriptional activity compared to non-overexpressing cells. Trastuzumab or a dual epidermal growth factor receptor (EGFR)/ErbB-2 tyrosine kinase Inhibitor (TKI) increased Notch activity by 2- to 6-fold in SKBr3, BT474 and MCF-7/HER2-18 cells. The increase in activity was abrogated by a Notch Inhibitor, γ-Secretase Inhibitor (GSI) or Notch-1 small-interfering RNA (siRNA). Trastuzumab decreased Notch-1™ precursor, increased amount and nuclear accumulation of active Notch-1IC and increased expression of targets, Hey1 and Deltex1 mRNAs, and Hes5, Hey1, Hes1 proteins. Importantly, trastuzumab-resistant BT474 cells treated with trastuzumab for 6 months expressed twofold higher Notch-1, twofold higher Hey1, ninefold higher Deltex1 mRNAs and threefold higher Notch-1 and Hes5 proteins, compared to trastuzumab-sensitive BT474 cells. The increase in Hey1 and Deltex1 mRNAs in resistant cells was abrogated by a Notch-1 siRNA. Cell proliferation was inhibited more effectively by trastuzumab or TKI plus a GSI than either agent alone. Decreased Notch-1 by siRNA increased efficacy of trastuzumab in BT474 sensitive cells and restored sensitivity in resistant cells. Trastuzumab plus a GSI increased apoptosis in sensitive cells by 20–30%. A GSI alone was sufficient to increase apoptosis in trastuzumab-resistant BT474 cells by 20%, which increased to 30% with trastuzumab. Notch-1 siRNA alone decreased cell growth by 30% in sensitive and more than 50% in resistant BT474 cells. Furthermore, growth of both trastuzumab sensitive and resistant cells was completely inhibited by combining trastuzumab plus Notch-1 siRNA. More importantly, Notch-1 siRNA or a GSI resensitized trastuzumab-resistant BT474 cells to trastuzumab. These results demonstrate that ErbB-2 overexpression suppresses Notch-1 activity, which can be reversed by trastuzumab or TKI. These results suggest that Notch-1 might play a novel role in resistance to trastuzumab, which could be prevented or reversed by inhibiting Notch-1.
Bo Huang - One of the best experts on this subject based on the ideXlab platform.
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long term follow up of desmoid fibromatosis treated with pf 03084014 an oral Gamma Secretase Inhibitor
Annals of Surgical Oncology, 2018Co-Authors: Victor Villalobos, Bo Huang, Rossano Cesari, Francis Hall, Antonio Jimeno, Lia Gore, Kenneth A Kern, Jeffrey Schowinsky, Patrick J Blatchford, Brianna HoffnerAbstract:Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in β-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral Gamma Secretase Inhibitor, PF-03084014. PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated. Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0–96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5–21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily. PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0–96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.
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phase i study of the Gamma Secretase Inhibitor pf 03084014 in combination with docetaxel in patients with advanced triple negative breast cancer
Oncotarget, 2017Co-Authors: Marzia Locatelli, Philippe Aftimos, Patricia Lorusso, Ahmad Awada, Bo Huang, Rossano Cesari, Yuqiu Jiang, Claire E Dees, Mark Pegram, Naveed ShaikAbstract:// Marzia A. Locatelli 1 , Philippe Aftimos 2 , E. Claire Dees 3 , Patricia M. LoRusso 4,9 , Mark D. Pegram 5 , Ahmad Awada 2 , Bo Huang 6 , Rossano Cesari 7 , Yuqiu Jiang 8 , M. Naveed Shaik 8 , Kenneth A. Kern 8 and Giuseppe Curigliano 1 1 Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy 2 Medical Oncology Clinic, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium 3 Department of Hematology and Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA 4 Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA 5 Breast Cancer Research Program, Stanford Cancer Institute, Stanford, CA, USA 6 Pfizer Oncology, Groton, CT, USA 7 Pfizer Oncology, Milan, Italy 8 Pfizer Oncology, San Diego, CA, USA 9 Yale Cancer Center, New Haven, CT, USA Correspondence to: Giuseppe Curigliano, email: // Keywords : breast cancer, triple-negative, PF-03084014, Gamma Secretase, NOTCH signaling Received : July 25, 2016 Accepted : November 22, 2016 Published : November 30, 2016 Abstract Background: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective Gamma-Secretase Inhibitor in patients with advanced triple-negative breast cancer. Methods: The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. Results and Conclusions: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m 2 . At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients ( N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).
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Phase I study of the Gamma Secretase Inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer
2017Co-Authors: Locatelli, Marzia A., Bo Huang, Aftimos Philippe, Claire Dees, Lorusso, Patricia M., Pegram, Mark D., Awada Ahmad, Cesari Rossano, Jiang Yuqiu, Shaik M. NaveedAbstract:The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study ({"type":"clinical-trial","attrs":{"text":"NCT01876251","term_id":"NCT01876251"}}NCT01876251), we evaluated PF-03084014, a selective Gamma-Secretase Inhibitor in patients with advanced triple-negative breast cancer
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Phase I study of the Gamma Secretase Inhibitor PF-03084014 in combination with docetaxel in patients with advanced triplenegative breast cancer
'Impact Journals LLC', 2017Co-Authors: Locatelli, Marzia Adelia, Aftimos Philippe, Awada Ahmad, Shaik M. Naveed, Kern, Kenneth K.a., Curigliano Giuseppe, Claire Dees E., Lorusso, Patricia Mucci, Pegram Mark, Bo HuangAbstract:Background: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective Gamma-Secretase Inhibitor in patients with advanced triple-negative breast cancer. Methods: The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. Results and Conclusions: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).SCOPUS: ar.jinfo:eu-repo/semantics/publishe
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Phase I study of the Gamma Secretase Inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer
'Impact Journals LLC', 2017Co-Authors: M.a. Locatelli, Philippe Aftimos, Ahmad Awada, Bo Huang, Rossano Cesari, Yuqiu Jiang, Claire E Dees, P.m. Lorusso, M.d. Pegram, M.n. ShaikAbstract:BACKGROUND: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective Gamma-Secretase Inhibitor in patients with advanced triple-negative breast cancer. METHODS: The dose-finding part was based on a 2 73 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. RESULTS AND CONCLUSIONS: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%])
Sharon R Pine - One of the best experts on this subject based on the ideXlab platform.
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abstract 4834 preclinical analysis of the notch Gamma Secretase Inhibitor bms 906024 in combination with chemotherapy in the treatment of lung adenocarcinoma
Cancer Research, 2016Co-Authors: Katherine M Morgan, Francis Y Lee, Erin Michaud, Bruce S Fischer, Sharon R PineAbstract:Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer (NSCLC) cases, primarily through loss of the endogenous Notch Inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor. Notch activity is associated with poor overall survival among NSCLC patients whose tumors are wildtype for TP53. Here, we characterized the interaction between BMS-906024, a clinically relevant Gamma Secretase Inhibitor (GSI) that inhibits Notch activation, and front-line chemotherapy in preclinical models of NSCLC. MTS drug synergy assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy were performed on a panel of human NSCLC cell lines, most of which were derived from adenocarcinomas. Analysis of the drug effects with CalcuSyn yielded significantly lower CI values for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.001). The synergy between BMS-906024 and paclitaxel was significantly greater in Kras-wildtype than Kras-mutant cells (average CI = 0.39 vs 0.68, respectively; P = 0.009), while there was no correlation with EGFR or TP53 status. Treatment of lung adenocarcinoma xenografts in NOD scid Gamma mice confirmed enhanced antitumor activity for the combination treatment of BMS-906024 and paclitaxel by mechanisms currently under investigation. These results are a step toward identification of the optimal combination of the GSI BMS-906024 with standard chemotherapies, as well as potential biomarkers that could be used to predict patient response to Notch-targeted therapy. Citation Format: Katherine M. Morgan, Francis Lee, Erin Michaud, Bruce S. Fischer, Sharon R. Pine. Preclinical analysis of the Notch Gamma Secretase Inhibitor BMS-906024 in combination with chemotherapy in the treatment of lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4834.
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abstract 2535 synergistic anti tumor activity of the notch Gamma Secretase Inhibitor bms 906024 and paclitaxel in the treatment of lung adenocarcinoma
Cancer Research, 2015Co-Authors: Katherine M Morgan, Francis Y Lee, Erin Michaud, Bruce S Fischer, Joseph R Bertino, Sharon R PineAbstract:Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer cases, primarily through loss of the endogenous Notch Inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor. Notch activity is associated with poor overall survival among non-small cell lung cancer patients whose tumors are wildtype for TP53. We set out to evaluate the combination of Notch-targeted therapy with front-line chemotherapy as an effective treatment for non-small cell lung cancer. Our study focused on lung adenocarcinoma, the most common histological subtype in lung cancer. To target Notch, we utilized the Gamma Secretase Inhibitor (GSI) BMS-906024 which inhibits Notch activation. BMS-906024 is currently in Phase 1 clinical trials for patients with T-cell acute lymphoblastic leukemia and metastatic solid tumors, including lung cancer. Human cell lines representing the major genetic subtypes of lung cancer, most of which were derived from adenocarcinomas, underwent MTS drug synergy assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy. The dosing and timing for BMS-906024 administration were optimized by examination of maximal Notch1 inhibition. Analysis of the drug effects with CalcuSyn yielded Combination Index (CI) values, in which a CI of 0.5 or less was considered as strong synergism for the drug combination. We found that there were significantly lower CI values for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.001). We then grouped the cell lines by major genetic subtype (wildtype versus mutant or null for EGFR, Kras or TP53). The synergy between BMS-906024 and paclitaxel was significantly greater in Kras-wildtype than Kras-mutant cells (average CI = 0.39 vs 0.68, respectively; P = 0.009), while there was no correlation with EGFR or TP53 status. These results are a step toward identification of potential biomarkers that could be used to predict patient response to Notch-targeted therapy, which could have a positive impact on the care of lung adenocarcinoma patients and be informative for treatment decisions. Citation Format: Katherine M. Morgan, Francis Lee, Erin Michaud, Joseph R. Bertino, Bruce S. Fischer, Sharon R. Pine. Synergistic anti-tumor activity of the Notch Gamma Secretase Inhibitor BMS-906024 and paclitaxel in the treatment of lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2535. doi:10.1158/1538-7445.AM2015-2535
Rossano Cesari - One of the best experts on this subject based on the ideXlab platform.
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long term follow up of desmoid fibromatosis treated with pf 03084014 an oral Gamma Secretase Inhibitor
Annals of Surgical Oncology, 2018Co-Authors: Victor Villalobos, Bo Huang, Rossano Cesari, Francis Hall, Antonio Jimeno, Lia Gore, Kenneth A Kern, Jeffrey Schowinsky, Patrick J Blatchford, Brianna HoffnerAbstract:Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in β-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral Gamma Secretase Inhibitor, PF-03084014. PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated. Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0–96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5–21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily. PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0–96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.
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phase i study of the Gamma Secretase Inhibitor pf 03084014 in combination with docetaxel in patients with advanced triple negative breast cancer
Oncotarget, 2017Co-Authors: Marzia Locatelli, Philippe Aftimos, Patricia Lorusso, Ahmad Awada, Bo Huang, Rossano Cesari, Yuqiu Jiang, Claire E Dees, Mark Pegram, Naveed ShaikAbstract:// Marzia A. Locatelli 1 , Philippe Aftimos 2 , E. Claire Dees 3 , Patricia M. LoRusso 4,9 , Mark D. Pegram 5 , Ahmad Awada 2 , Bo Huang 6 , Rossano Cesari 7 , Yuqiu Jiang 8 , M. Naveed Shaik 8 , Kenneth A. Kern 8 and Giuseppe Curigliano 1 1 Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy 2 Medical Oncology Clinic, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium 3 Department of Hematology and Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA 4 Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA 5 Breast Cancer Research Program, Stanford Cancer Institute, Stanford, CA, USA 6 Pfizer Oncology, Groton, CT, USA 7 Pfizer Oncology, Milan, Italy 8 Pfizer Oncology, San Diego, CA, USA 9 Yale Cancer Center, New Haven, CT, USA Correspondence to: Giuseppe Curigliano, email: // Keywords : breast cancer, triple-negative, PF-03084014, Gamma Secretase, NOTCH signaling Received : July 25, 2016 Accepted : November 22, 2016 Published : November 30, 2016 Abstract Background: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective Gamma-Secretase Inhibitor in patients with advanced triple-negative breast cancer. Methods: The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. Results and Conclusions: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m 2 . At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients ( N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).
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Phase I study of the Gamma Secretase Inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer
'Impact Journals LLC', 2017Co-Authors: M.a. Locatelli, Philippe Aftimos, Ahmad Awada, Bo Huang, Rossano Cesari, Yuqiu Jiang, Claire E Dees, P.m. Lorusso, M.d. Pegram, M.n. ShaikAbstract:BACKGROUND: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective Gamma-Secretase Inhibitor in patients with advanced triple-negative breast cancer. METHODS: The dose-finding part was based on a 2 73 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. RESULTS AND CONCLUSIONS: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%])
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a phase 1 study of the novel Gamma Secretase Inhibitor pf 03084014 in patients with t cell acute lymphoblastic leukemia and t cell lymphoblastic lymphoma
Blood Cancer Journal, 2015Co-Authors: Cristina Papayannidis, Bo Huang, Rossano Cesari, Daniel J Deangelo, Wendy Stock, Mohammed Naveed Shaik, Xianxian Zheng, Jennifer M Reynolds, Patricia A English, Mark OzeckAbstract:A Phase 1 study of the novel Gamma-Secretase Inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma
Patricia Lorusso - One of the best experts on this subject based on the ideXlab platform.
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phase i study of the Gamma Secretase Inhibitor pf 03084014 in combination with docetaxel in patients with advanced triple negative breast cancer
Oncotarget, 2017Co-Authors: Marzia Locatelli, Philippe Aftimos, Patricia Lorusso, Ahmad Awada, Bo Huang, Rossano Cesari, Yuqiu Jiang, Claire E Dees, Mark Pegram, Naveed ShaikAbstract:// Marzia A. Locatelli 1 , Philippe Aftimos 2 , E. Claire Dees 3 , Patricia M. LoRusso 4,9 , Mark D. Pegram 5 , Ahmad Awada 2 , Bo Huang 6 , Rossano Cesari 7 , Yuqiu Jiang 8 , M. Naveed Shaik 8 , Kenneth A. Kern 8 and Giuseppe Curigliano 1 1 Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy 2 Medical Oncology Clinic, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium 3 Department of Hematology and Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA 4 Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA 5 Breast Cancer Research Program, Stanford Cancer Institute, Stanford, CA, USA 6 Pfizer Oncology, Groton, CT, USA 7 Pfizer Oncology, Milan, Italy 8 Pfizer Oncology, San Diego, CA, USA 9 Yale Cancer Center, New Haven, CT, USA Correspondence to: Giuseppe Curigliano, email: // Keywords : breast cancer, triple-negative, PF-03084014, Gamma Secretase, NOTCH signaling Received : July 25, 2016 Accepted : November 22, 2016 Published : November 30, 2016 Abstract Background: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective Gamma-Secretase Inhibitor in patients with advanced triple-negative breast cancer. Methods: The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. Results and Conclusions: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m 2 . At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients ( N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).
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a phase i dose escalation study of the novel Gamma Secretase Inhibitor pf 03084014 in patients pts with advanced solid tumors
Journal of Clinical Oncology, 2011Co-Authors: Wells A Messersmith, Patricia Lorusso, Sophia Randolph, Arvind Dasari, M.n. Shaik, James M Cleary, Xiaoxi Zhang, Rachel Courtney, Geoffrey I ShapiroAbstract:3100 Background: Aberrant Notch signaling is implicated in tumor genesis. Gamma Secretase plays a key role in Notch-dependent signaling. The reversible, noncompetitive, selective Gamma Secretase in...
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abstract 5466 clinically relevant plasma protein binding of ro4929097 a Gamma Secretase Inhibitor targeting notch signaling
Cancer Research, 2011Co-Authors: Patricia LorussoAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Purpose. Aberrant activation of the Notch pathway contributes to tumor initiation and/or progression. RO4929097 (RO) is an orally bioavailable, small-molecule Inhibitor of γ-Secretase, which inhibits Notch signaling in tumor cells. RO is being evaluated in phase I/II clinical trials as monotherapy or in combination with other anticancer agents (e.g., Hedgehog Inhibitor GDC-0449). RO exhibits large inter-individual pharmacokinetic (PK) variability, which may contribute to difference in treatment outcome. Unbound drug plasma concentration is believed to be more relevant to pharmacological and toxicological effects than total drug. Thus, it is desirable to determine RO binding in plasma and factors influencing this process. The objective of this study was to investigate RO binding to plasma proteins and blood cells, and to examine the influence of GDC-0449 on RO plasma protein binding and PK in cancer patients. Method. An equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining RO fraction unbound (fu) in human plasma. RO binding in plasma from four different species and in isolated plasma protein solutions, as well as drug partitioning in human blood cells were investigated. The PK of total and unbound RO was evaluated in 5 cancer patients who received daily oral RO 20 mg alone or in combination with daily oral GDC-0449 150 mg. Results. RO4929097 was extensively bound in human, dog, rat, and mouse plasma, with a mean fu value of 4.7%, 2.1%, 10.6%, and 1.5%, respectively. In human whole blood, the blood-to-plasma concentration ratio was 0.73. In isolated protein solutions, ∼ 88% and 95% of RO4929097 was bound to human serum albumin (HSA, 40 mg/ml) and alpha1-acid glycoprotein (AAG, 1.4 mg/ml), with a binding constant of 1.8 × 104 M−1 and 1.0 × 106 M−1, respectively. The presence of 25 μM of GDC-0449 increased RO fu by 8.4 and 1.1 folds in AAG (1.4 mg/ml) and HSA (40 mg/ml) solution, respectively. In cancer patients, RO fu exhibited a large intra- and inter-individual variability (range, 0.2 – 3.0%; mean, 1.0 ± 0.7%); co-administration of GDC-0449 increased RO fu by 3.7 to 8.5 folds. Co-administration of GDC-0449 significantly decreased the plasma exposure to total RO, but did not have apparent influence on the unbound RO exposure. Conclusion. RO is highly bound to plasma proteins (mainly to AAG), with a large inter-species and inter-individual variability. Consideration of protein binding is important in the scale-up of RO PK and pharmacodynamic parameters from animal models to humans. Changes in protein binding caused by drug-drug interactions (such as by GDC-0449) or disease states (e.g., increased AAG concentration in cancer patients) can influence the plasma exposure to the total but not unbound RO. Measurement of unbound RO plasma concentration is recommended to avoid misleading conclusions or unadvisedly adjusting RO dose based on total plasma levels. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5466. doi:10.1158/1538-7445.AM2011-5466
