78 results on '"Brian B. Haines"'
Search Results
2. Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability
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Edward M. Kennedy, Terry Farkaly, Peter Grzesik, Jennifer Lee, Agnieszka Denslow, Jacqueline Hewett, Jeffrey Bryant, Prajna Behara, Caitlin Goshert, Daniel Wambua, Ana De Almeida, Judith Jacques, Damian Deavall, James B. Rottman, Joseph C. Glorioso, Mitchell H. Finer, Brian B. Haines, Christophe Quéva, and Lorena Lerner
- Subjects
oncolytic virus ,virotherapy ,HSV-1 ,microRNA attenuation ,cancer ,interferon ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Development of next-generation oncolytic viruses requires the design of vectors that are potently oncolytic, immunogenic in human tumors, and well tolerated in patients. Starting with a joint-region deleted herpes simplex virus 1 (HSV-1) to create large transgene capability, we retained a single copy of the ICP34.5 gene, introduced mutations in UL37 to inhibit retrograde axonal transport, and inserted cell-type-specific microRNA (miRNA) target cassettes in HSV-1 genes essential for replication or neurovirulence. Ten miRNA candidates highly expressed in normal tissues and with low or absent expression in malignancies were selected from a comprehensive profile of 800 miRNAs with an emphasis on protection of the nervous system. Among the genes essential for viral replication identified using a small interfering RNA (siRNA) screen, we selected ICP4, ICP27, and UL8 for miRNA attenuation where a single miRNA is sufficient to potently attenuate viral replication. Additionally, a neuron-specific miRNA target cassette was introduced to control ICP34.5 expression. This vector is resistant to type I interferon compared to ICP34.5-deleted oncolytic HSVs, and in cancer cell lines, the oncolytic activity of the modified vector is equivalent to its parental virus. In vivo, this vector potently inhibits tumor growth while being well tolerated, even at high intravenous doses, compared to parental wild-type HSV-1.
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- 2020
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3. A Quantitative Volumetric Micro-Computed Tomography Method to Analyze Lung Tumors in Genetically Engineered Mouse Models
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Brian B. Haines, Kimberly A. Bettano, Melissa Chenard, Raquel S. Sevilla, Christopher Ware, Minilik H. Angagaw, Christopher T. Winkelmann, Christopher Tong, John F. Reilly, Cyrille Sur, and Weisheng Zhang
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Two genetically engineered, conditional mouse models of lung tumor formation, K-rasLSL-G12D and K-rasLSL-G12D/p53LSL-R270H, are commonly used to model human lung cancer. Developed by Tyler Jacks and colleagues, these models have been invaluable to study in vivo lung cancer initiation and progression in a genetically and physiologically relevant context. However, heterogeneity, multiplicity and complexity of tumor formation in these models make it challenging to monitor tumor growth in vivo and have limited the application of these models in oncology drug discovery. Here, we describe a novel analytical method to quantitatively measure total lung tumor burden in live animals using micro-computed tomography imaging. Applying this methodology, we studied the kinetics of tumor development and response to targeted therapy in vivo in K-ras and K-ras/p53 mice. Consistent with previous reports, lung tumors in both models developed in a time- and dose (Cre recombinase)-dependent manner. Furthermore, the compound K-rasLSL-G12D/p53LSL-R270H mice developed tumors faster and more robustly than mice harboring a single K-rasLSL-G12D oncogene, as expected. Erlotinib, a small molecule inhibitor of the epidermal growth factor receptor, significantly inhibited tumor growth in K-rasLSL-G12D/p53LSL-R270H mice. These results demonstrate that this novel imaging technique can be used to monitor both tumor progression and response to treatment and therefore supports a broader application of these genetically engineered mouse models in oncology drug discovery and development.
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- 2009
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4. Supplementary Tables 1-4 and Figures 1-4 from ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity
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Christophe Quéva, Lorena Lerner, Edward M. Kennedy, Sonia Feau, Melissa W. Hayes, Mitchel H. Finer, Allison Colthart, Michael Ball, Caitlin Goshert, Judith Jacques, Prajna Behera, Lingxin Kong, Daniel Wambua, Jacqueline Hewett, Terry Farkaly, Jennifer S. Lee, Peter Grzesik, Agnieszka Denslow, and Brian B. Haines
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Supplemental Tables and Figures
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- 2023
5. Data from ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity
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Christophe Quéva, Lorena Lerner, Edward M. Kennedy, Sonia Feau, Melissa W. Hayes, Mitchel H. Finer, Allison Colthart, Michael Ball, Caitlin Goshert, Judith Jacques, Prajna Behera, Lingxin Kong, Daniel Wambua, Jacqueline Hewett, Terry Farkaly, Jennifer S. Lee, Peter Grzesik, Agnieszka Denslow, and Brian B. Haines
- Abstract
ONCR-177 is an engineered recombinant oncolytic herpes simplex virus (HSV) with complementary safety mechanisms, including tissue-specific miRNA attenuation and mutant UL37 to inhibit replication, neuropathic activity, and latency in normal cells. ONCR-177 is armed with five transgenes for IL12, FLT3LG (extracellular domain), CCL4, and antagonists to immune checkpoints PD-1 and CTLA-4. In vitro assays demonstrated that targeted miRNAs could efficiently suppress ONCR-177 replication and transgene expression, as could the HSV-1 standard-of-care therapy acyclovir. Although ONCR-177 was oncolytic across a panel of human cancer cell lines, including in the presence of type I IFN, replication was suppressed in human pluripotent stem cell–derived neurons, cardiomyocytes, and hepatocytes. Dendritic cells activated with ONCR-177 tumor lysates efficiently stimulated tumor antigen–specific CD8+ T-cell responses. In vivo, biodistribution analyses suggested that viral copy number and transgene expression peaked approximately 24 to 72 hours after injection and remained primarily within the injected tumor. Intratumoral administration of ONCR-177 mouse surrogate virus, mONCR-171, was efficacious across a panel of syngeneic bilateral mouse tumor models, resulting in partial or complete tumor regressions that translated into significant survival benefits and to the elicitation of a protective memory response. Antitumor effects correlated with local and distant intratumoral infiltration of several immune effector cell types, consistent with the proposed functions of the transgenes. The addition of systemic anti–PD-1 augmented the efficacy of mONCR-171, particularly for abscopal tumors. Based in part upon these preclinical results, ONCR-177 is being evaluated in patients with metastatic cancer (ONCR-177-101, NCT04348916).
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- 2023
6. Supplementary Table S9 from Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma
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Sriram Sathyanarayanan, Jon C. Aster, X. Shirley Liu, Warren S. Pear, Bradley E. Bernstein, Birgit Knoechel, Brandon E. Kremer, Theresa Zhang, Gary Gilliland, Stephen Fawell, Leigh Zawel, Christopher Moskaluk, Brian B. Haines, Jason Laskey, Michael Kluk, Philip W. Garrett-Engele, John MacLean, Chris Ware, Jing Yuan, Chongzhi Zang, Hongfang Wang, Li Pan, Andrew Truong, Serguei Lejnine, and Alexander Stoeck
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human Breast tumor Notch gene coverage annotations.
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- 2023
7. Supplementary Figures 1-4; Supplementary Tables 1 & 2 from High Levels of Expression of P-glycoprotein/Multidrug Resistance Protein Result in Resistance to Vintafolide
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Christopher P. Leamon, Isabelle Dussault, Emmett V. Schmidt, Kristen L. Picard, Andrey Loboda, Theresa Zhang, Michael Nebozhyn, Serguei Lejnine, Marilynn Vetzel, Melissa Nelson, Alicia Bloomfield, Ryan Dorton, Marlene C. Hinton, Brian B. Haines, Razvan Cristescu, Joseph A. Reddy, Alexander Stoeck, Jennifer O'Neil, and Amy D. Guertin
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Supplementary Figure 1: Assessment of kidney cancer cell lines A498, 786-O, and A704 via flow cytometry revealed surface expression of P-gp in all lines; Supplementary Figure 2: 786-O and A704 cells were transduced with lentiviral FR1, and flow cytometric analysis shows increased surface FR1 expression; Supplementary Figure 3: NCI/ADR-RES or NCI/ADR-RES-FR cells with known FR levels were treated with increasing concentrations (10-9 M to 10-5 M) of vintafolide for 2 h; Supplementary Figure 4: Ovarian tumors positive for P-gp tend to express lower levels of FR; Supplementary Table 1: P-gp inhibitor elacridar reverses P-gp-mediated DAVLBH and vintafolide resistance; Supplementary Table 2: Functional multi-drug transporter efflux assay.
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- 2023
8. Supplementary Figures S1 - S7 from Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma
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Sriram Sathyanarayanan, Jon C. Aster, X. Shirley Liu, Warren S. Pear, Bradley E. Bernstein, Birgit Knoechel, Brandon E. Kremer, Theresa Zhang, Gary Gilliland, Stephen Fawell, Leigh Zawel, Christopher Moskaluk, Brian B. Haines, Jason Laskey, Michael Kluk, Philip W. Garrett-Engele, John MacLean, Chris Ware, Jing Yuan, Chongzhi Zang, Hongfang Wang, Li Pan, Andrew Truong, Serguei Lejnine, and Alexander Stoeck
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S1: NOTCH gene rearrangement in breast cancer cell lines and human breast tumors. S2: NOTCH gene rearrangement and sensitivity to MRK-003. S3: HES4 expression is associated with NOTCH gene-rearrangement or activating mutation in NOTCH. S4: HES4 expression is a poor prognostic marker in TNBC. S5: Proliferation inhibition by combination therapy with MRK-003 and ERK inhibitor (SCH772984). S6: Effect of MRK-003 treatment on CD44+/CD24 high stem-like cell population. S7: N1ICD level correlates with mutation status and is predictive of MRK-003 response in xenograft models.
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- 2023
9. Supplementary Methods from Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma
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Sriram Sathyanarayanan, Jon C. Aster, X. Shirley Liu, Warren S. Pear, Bradley E. Bernstein, Birgit Knoechel, Brandon E. Kremer, Theresa Zhang, Gary Gilliland, Stephen Fawell, Leigh Zawel, Christopher Moskaluk, Brian B. Haines, Jason Laskey, Michael Kluk, Philip W. Garrett-Engele, John MacLean, Chris Ware, Jing Yuan, Chongzhi Zang, Hongfang Wang, Li Pan, Andrew Truong, Serguei Lejnine, and Alexander Stoeck
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File includes genomic analysis, cell cycle and cell proliferation analysis.
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- 2023
10. Supplementary Figure Legends from An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies
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Stuart D. Shumway, Andrew Bloecher, Theresa Zhang, Christopher Winter, Brian B. Haines, Razvan Cristescu, William Arthur, Andrey Loboda, Serguei Lejnine, Astrid Kral, Jing Li, Yaping Liu, Brian Roberts, Melissa Chenard, Igor Feldman, Yair Benita, and Jennifer O'Neil
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Supplementary figure, table and data legend
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- 2023
11. Supplementary Figure 2. Experiment that was used to select drug concentrations for combination screen. from An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies
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Stuart D. Shumway, Andrew Bloecher, Theresa Zhang, Christopher Winter, Brian B. Haines, Razvan Cristescu, William Arthur, Andrey Loboda, Serguei Lejnine, Astrid Kral, Jing Li, Yaping Liu, Brian Roberts, Melissa Chenard, Igor Feldman, Yair Benita, and Jennifer O'Neil
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We ran 8 titration point curves (shown in gray) and then picked 4 concentration points that cover best the response curve for all cell lines (shown in red). The first point is the top plateau, the last is the bottom plateau and the other 2 are in between.
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- 2023
12. Supplementary Tables S1 - S8 from Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma
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Sriram Sathyanarayanan, Jon C. Aster, X. Shirley Liu, Warren S. Pear, Bradley E. Bernstein, Birgit Knoechel, Brandon E. Kremer, Theresa Zhang, Gary Gilliland, Stephen Fawell, Leigh Zawel, Christopher Moskaluk, Brian B. Haines, Jason Laskey, Michael Kluk, Philip W. Garrett-Engele, John MacLean, Chris Ware, Jing Yuan, Chongzhi Zang, Hongfang Wang, Li Pan, Andrew Truong, Serguei Lejnine, and Alexander Stoeck
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Table S1: Analysis of Notch gene rearrangements in triple negative breast cancer subtypes. Table S2: Genes whose expression correlates with Notch gene-rearrangement status in cancer cell lines. Table S3: Genes whose expression correlates with Notch gene-rearrangement in triple negative breast cancer. Table S4. Novel mutations identified in the NRR and PEST domains of NOTCH1 in solid tumors. Table S5: Notch NRR and PEST domain mutation frequency. Table S6: NOTCH1 mutational status, N1-ICD levels, MYC expression in Adenoid Cystic Carcinoma models. Table S7: Primary antibodies. Table S8: RT-PCR Primers.
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- 2023
13. Supplementary Data-Single Agent Response from An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies
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Stuart D. Shumway, Andrew Bloecher, Theresa Zhang, Christopher Winter, Brian B. Haines, Razvan Cristescu, William Arthur, Andrey Loboda, Serguei Lejnine, Astrid Kral, Jing Li, Yaping Liu, Brian Roberts, Melissa Chenard, Igor Feldman, Yair Benita, and Jennifer O'Neil
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raw single agent response data; response is represented as fractional viability
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- 2023
14. Supplementary Data-Response Legends from An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies
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Stuart D. Shumway, Andrew Bloecher, Theresa Zhang, Christopher Winter, Brian B. Haines, Razvan Cristescu, William Arthur, Andrey Loboda, Serguei Lejnine, Astrid Kral, Jing Li, Yaping Liu, Brian Roberts, Melissa Chenard, Igor Feldman, Yair Benita, and Jennifer O'Neil
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Legend for raw response data
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- 2023
15. Supplementary Data-Combination Response from An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies
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Stuart D. Shumway, Andrew Bloecher, Theresa Zhang, Christopher Winter, Brian B. Haines, Razvan Cristescu, William Arthur, Andrey Loboda, Serguei Lejnine, Astrid Kral, Jing Li, Yaping Liu, Brian Roberts, Melissa Chenard, Igor Feldman, Yair Benita, and Jennifer O'Neil
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raw combination response data; response is represented as fractional viability
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- 2023
16. Supplementary Figure Legends from High Levels of Expression of P-glycoprotein/Multidrug Resistance Protein Result in Resistance to Vintafolide
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Christopher P. Leamon, Isabelle Dussault, Emmett V. Schmidt, Kristen L. Picard, Andrey Loboda, Theresa Zhang, Michael Nebozhyn, Serguei Lejnine, Marilynn Vetzel, Melissa Nelson, Alicia Bloomfield, Ryan Dorton, Marlene C. Hinton, Brian B. Haines, Razvan Cristescu, Joseph A. Reddy, Alexander Stoeck, Jennifer O'Neil, and Amy D. Guertin
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Legends for Supplementary Figures 1-4 and Supplementary Tables 1 & 2
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- 2023
17. Supplementary Figure 1. Hierarchical clustering of response to single agent treatments. from An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies
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Stuart D. Shumway, Andrew Bloecher, Theresa Zhang, Christopher Winter, Brian B. Haines, Razvan Cristescu, William Arthur, Andrey Loboda, Serguei Lejnine, Astrid Kral, Jing Li, Yaping Liu, Brian Roberts, Melissa Chenard, Igor Feldman, Yair Benita, and Jennifer O'Neil
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Hierarchical clustering was performed on the response data across the cell line panel to the single agent treatments. Drugs with similar mechanisms of action clustered together.
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- 2023
18. Supplemental Table 1. Thirty-nine cell lines used in combination screen. from An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies
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Stuart D. Shumway, Andrew Bloecher, Theresa Zhang, Christopher Winter, Brian B. Haines, Razvan Cristescu, William Arthur, Andrey Loboda, Serguei Lejnine, Astrid Kral, Jing Li, Yaping Liu, Brian Roberts, Melissa Chenard, Igor Feldman, Yair Benita, and Jennifer O'Neil
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RAS mutation/signature does not predict response to mTOR/Wee1 combination.
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- 2023
19. Supplementary Methods, Tables 1 - 4, Figure Legends from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
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José Baselga, Scot Ebbinghaus, Yang Song, Ann Leighton-Swayze, Richard A. Klinghoffer, Jason Frazier, Youyuan Xu, Sharda Jha, Christopher G. Winter, Theresa Zhang, Brian B. Haines, Desamparados Roda, Irene Braña, Mark N. Stein, Andrés Cervantes, Johanna C. Bendell, Sriram Sathyanarayanan, and Serena Di Cosimo
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Supplementary Table 1. Hits from the dalotuzumab enhancer screen. Supplementary Table 2. Patient and disease characteristics. Supplementary Table 3. Summary of dose-limiting toxicities. Supplementary Table 4. Summary of clinical efficacy in breast cancer patients.
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- 2023
20. Supplementary Figure 1 from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
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José Baselga, Scot Ebbinghaus, Yang Song, Ann Leighton-Swayze, Richard A. Klinghoffer, Jason Frazier, Youyuan Xu, Sharda Jha, Christopher G. Winter, Theresa Zhang, Brian B. Haines, Desamparados Roda, Irene Braña, Mark N. Stein, Andrés Cervantes, Johanna C. Bendell, Sriram Sathyanarayanan, and Serena Di Cosimo
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Supplementary Figure 1. Treatment and pharmacodynamic assessment schedules.
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- 2023
21. Data from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
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José Baselga, Scot Ebbinghaus, Yang Song, Ann Leighton-Swayze, Richard A. Klinghoffer, Jason Frazier, Youyuan Xu, Sharda Jha, Christopher G. Winter, Theresa Zhang, Brian B. Haines, Desamparados Roda, Irene Braña, Mark N. Stein, Andrés Cervantes, Johanna C. Bendell, Sriram Sathyanarayanan, and Serena Di Cosimo
- Abstract
Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.Experimental Design:In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity.Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379). Clin Cancer Res; 21(1); 49–59. ©2014 AACR.
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- 2023
22. Supplementary Figure 3 from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
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José Baselga, Scot Ebbinghaus, Yang Song, Ann Leighton-Swayze, Richard A. Klinghoffer, Jason Frazier, Youyuan Xu, Sharda Jha, Christopher G. Winter, Theresa Zhang, Brian B. Haines, Desamparados Roda, Irene Braña, Mark N. Stein, Andrés Cervantes, Johanna C. Bendell, Sriram Sathyanarayanan, and Serena Di Cosimo
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Supplementary Figure 3. Change in Ki67 levels with ridaforolimus and dalotuzumab combination therapy
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- 2023
23. Supplementary Figure 2 from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
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José Baselga, Scot Ebbinghaus, Yang Song, Ann Leighton-Swayze, Richard A. Klinghoffer, Jason Frazier, Youyuan Xu, Sharda Jha, Christopher G. Winter, Theresa Zhang, Brian B. Haines, Desamparados Roda, Irene Braña, Mark N. Stein, Andrés Cervantes, Johanna C. Bendell, Sriram Sathyanarayanan, and Serena Di Cosimo
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Supplementary Figure 2. Combination therapy with ridaforolimus and dalotuzumab potentiates PI3K pathway inhibition and blocks cancer cell proliferation
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- 2023
24. Supplementary Figure 4 from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
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José Baselga, Scot Ebbinghaus, Yang Song, Ann Leighton-Swayze, Richard A. Klinghoffer, Jason Frazier, Youyuan Xu, Sharda Jha, Christopher G. Winter, Theresa Zhang, Brian B. Haines, Desamparados Roda, Irene Braña, Mark N. Stein, Andrés Cervantes, Johanna C. Bendell, Sriram Sathyanarayanan, and Serena Di Cosimo
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Supplementary Figure 4. Responder biomarker hypothesis for ridaforolimus and dalotuzumab?based therapy
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- 2023
25. Abstract 3452: TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical glioblastoma models
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Minjie Zhang, Alice Tsai, Kevin M. Cottrell, Brian B. Haines, Erik Wilker, Heather DiBenedetto, Ron Weitzman, Alan Huang, Charles B. Davis, John P. Maxwell, and Kimberly J. Briggs
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Cancer Research ,Oncology - Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive primary malignant brain tumors in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) on standard of care therapies, which include surgery, radiotherapy, and the alkylating agent temozolomide. Therefore, developing new treatments for GBM is an urgent unmet medical need. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that inhibits PRMT5 activity selectively in MTAP-null cells leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors are homozygous null for MTAP [1, 2]. In preclinical in vitro studies, the antiproliferation activity of TNG908 was 15 times more potent in MTAP-null cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is not a substrate for P-glycoprotein nor Breast Cancer Resistant Protein efflux transporters, attributes which are favorable for crossing the blood-brain barrier. TNG908 demonstrated in vivo brain penetration in multiple preclinical studies, including non-human primates and mice, suggesting that TNG908 may fulfill the significant unmet need in the treatment of GBM. Pharmacodynamic activity of TNG908 to inhibit PRMT5 was demonstrated by decreased SDMA-modified protein levels in a dose-dependent manner in a GBM xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite reduced Kpuu in rodents compared to primates, oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant small molecule PRMT5 inhibitor that is selective for MTAP-null tumor cells with good drug-like properties and strong antitumor activity in preclinical models of GBM. As such, TNG908 may provide a novel treatment strategy for MTAP-deleted GBM patients. *MZ and AT contributed equally to the work. Reference: 1.Cerami et al., Cell, 2013. 2.Gao et al., Sci Signal, 2013 Citation Format: Minjie Zhang, Alice Tsai, Kevin M. Cottrell, Brian B. Haines, Erik Wilker, Heather DiBenedetto, Ron Weitzman, Alan Huang, Charles B. Davis, John P. Maxwell, Kimberly J. Briggs. TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical glioblastoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3452.
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- 2023
26. Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability
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Damian Deavall, Jeffrey Bryant, Agnieszka Denslow, James B. Rottman, Peter Grzesik, Jennifer S. Lee, Brian B. Haines, Terry Farkaly, Daniel Wambua, Prajna Behara, Jacqueline Hewett, Finer Mitchell H, Lorena Lerner, Judith Jacques, Joseph C. Glorioso, Caitlin Goshert, Christophe Quéva, Edward M. Kennedy, and Ana De Almeida
- Subjects
0301 basic medicine ,Cancer Research ,Small interfering RNA ,viruses ,Biology ,medicine.disease_cause ,lcsh:RC254-282 ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Interferon ,medicine ,cancer ,Pharmacology (medical) ,Vector (molecular biology) ,Virotherapy ,oncolytic virus ,microRNA attenuation ,interferon ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,HSV-1 ,Oncolytic virus ,030104 developmental biology ,Herpes simplex virus ,Oncology ,Viral replication ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Original Article ,virotherapy ,medicine.drug - Abstract
Development of next-generation oncolytic viruses requires the design of vectors that are potently oncolytic, immunogenic in human tumors, and well tolerated in patients. Starting with a joint-region deleted herpes simplex virus 1 (HSV-1) to create large transgene capability, we retained a single copy of the ICP34.5 gene, introduced mutations in UL37 to inhibit retrograde axonal transport, and inserted cell-type-specific microRNA (miRNA) target cassettes in HSV-1 genes essential for replication or neurovirulence. Ten miRNA candidates highly expressed in normal tissues and with low or absent expression in malignancies were selected from a comprehensive profile of 800 miRNAs with an emphasis on protection of the nervous system. Among the genes essential for viral replication identified using a small interfering RNA (siRNA) screen, we selected ICP4, ICP27, and UL8 for miRNA attenuation where a single miRNA is sufficient to potently attenuate viral replication. Additionally, a neuron-specific miRNA target cassette was introduced to control ICP34.5 expression. This vector is resistant to type I interferon compared to ICP34.5-deleted oncolytic HSVs, and in cancer cell lines, the oncolytic activity of the modified vector is equivalent to its parental virus. In vivo, this vector potently inhibits tumor growth while being well tolerated, even at high intravenous doses, compared to parental wild-type HSV-1., Graphical Abstract, Next-generation oncolytic viral immunotherapy is designed to promote greater oncolytic potency, be highly immunogenic in human tumors, and have an improved tolerability profile among patients. This article describes the design of a highly engineered novel oncolytic HSV-1 vector, ONCR-159, demonstrates its broad therapeutic index, and confirms its potent antitumor activity.
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- 2020
27. Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer
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Ana De Almeida, Judy Jacques, Jacqueline Hewett, Mitchel H. Finer, Amal Rahmeh, Edward M. Kennedy, Lorena Lerner, Jennifer Lee, Danielle Douglas, Brian B. Haines, Lauren Herschelman, Sonia Feau, Lingxin Kong, Matt Scott, Melissa Hayes, Christophe Quéva, Sanmit Adhikari, Jessica Deterling, Jacob Spinale, Jeffrey Bryant, Agnieszka Denslow, Elizabeth McMichael, and Ted Ashburn
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Text mining ,biology ,business.industry ,viruses ,medicine.medical_treatment ,Cancer research ,medicine ,Cancer ,RNA virus ,Immunotherapy ,biology.organism_classification ,medicine.disease ,business - Abstract
Oncolytic viruses (OVs) are an emerging therapeutic approach for the treatment of cancer. Clinical benefit has been demonstrated for intratumoral administration, but the therapeutic effectiveness of intravenous delivery has been limited by neutralizing antibody responses against the virus. To circumvent this limitation, we developed Synthetic RNA viruses, a novel approach for intravenous and repeated administration of OVs, consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21 (CVA21), we demonstrate vRNA delivery, viral replication, spread, and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promoted immune cell infiltration and enhanced anti-tumor activity in combination with anti-PD-1 checkpoint inhibitor. Altogether, the Synthetic RNA virus platform provides an innovative approach that enables repeat intravenous administration of viral immunotherapy.
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- 2021
28. Abstract 383: ONCR-021 as a systemic intravenous synthetic RNA virus immunotherapy for the repeat treatment of cancer
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Jeffrey Bryant, Agnieszka Denslow, Jacqueline Hewett, Lingxin Cong, Ana De Almeida, Jennifer Lee, Judy Jacques, Sonia Feau, Daniel. Wambua, Adrienne Yanez, Pam Shou-Ping Wang, Jessica Deterling, Matthew Scott, Jason Auer, Brian B. Haines, Christophe Quéva, Lorena Lerner, and Edward M. Kennedy
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Cancer Research ,Oncology - Abstract
Oncolytic viruses (OV) have shown great potential to improve clinical outcomes when dosed intratumorally, however, their therapeutic efficacy when intravenously administered is likely limited by the rapid emergence of neutralizing antibodies. To overcome this limitation, we developed Synthetic RNA viruses consisting of a replication competent viral genomic RNA (vRNA) encapsulated within a lipid nanoparticle (LNP) for IV administration. Upon dosing and delivery of this infectious RNA payload, the vRNA initiates viral replication and virus production in neoplastic cells leading to oncolysis and tumor destruction. This formulation enables repeat intravenous dosing of a replication competent oncolytic virotherapy even in presence of circulating neutralizing antibody to the virus. Here we present ONCR-021, an LNP formulation of Coxsackievirus A21 (CVA21) vRNA. ONCR-021 vRNA encodes a novel ICAM1-dependent strain of CVA21 that results in greater in vitro and in vivo oncolysis compared to the previously described CVA21 Kuykendall strain. ONCR-021 is broadly oncolytic in cancer cell lines in vitro and is intended for clinical development in NSCLC, RCC, and HCC based upon the viral tropism. IV-administration of ONCR-021 vRNA results in rapid initiation of viral replication, oncolysis, and potent anti-tumor efficacy, even in the presence of circulating CVA21 neutralizing antibodies. This efficacy is principally driven by CVA21 amplification in situ after delivery to tumor cells and we demonstrate viral replication, virion production and spread within the tumor after dosing. We also observe only modest and transient production of CVA21 in healthy tissues of transgenic mice expressing the CVA21 entry receptor human ICAM1. Consistent with these findings, high doses levels of ONCR-021 were well-tolerated in this model. Altogether, these preclinical data support the development of ONCR-021, a novel synthetic oncolytic virus designed to overcome the challenges of repeat intravenous administration of viral immunotherapy for the treatment of disseminated cancers. Citation Format: Jeffrey Bryant, Agnieszka Denslow, Jacqueline Hewett, Lingxin Cong, Ana De Almeida, Jennifer Lee, Judy Jacques, Sonia Feau, Daniel. Wambua, Adrienne Yanez, Pam Shou-Ping Wang, Jessica Deterling, Matthew Scott, Jason Auer, Brian B. Haines, Christophe Quéva, Lorena Lerner, Edward M. Kennedy. ONCR-021 as a systemic intravenous synthetic RNA virus immunotherapy for the repeat treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 383.
- Published
- 2022
29. Combination of EP
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Yun, Wang, Long, Cui, Peter, Georgiev, Latika, Singh, Yanyan, Zheng, Ying, Yu, Jeff, Grein, Chunsheng, Zhang, Eric S, Muise, David L, Sloman, Heidi, Ferguson, Hongshi, Yu, Cristina St, Pierre, Pranal J, Dakle, Vincenzo, Pucci, James, Baker, Andrey, Loboda, Doug, Linn, Christopher, Brynczka, Doug, Wilson, Brian B, Haines, Brian, Long, Richard, Wnek, Svetlana, Sadekova, Michael, Rosenzweig, Andrew, Haidle, Yongxin, Han, and Sheila H, Ranganath
- Subjects
lymphocytes ,Macrophages ,CD8-Positive T-Lymphocytes ,pge2 ,Dinoprostone ,Mice ,ep4 antagonism ,Cyclooxygenase 2 ,myeloid cells ,Animals ,lipids (amino acids, peptides, and proteins) ,Immunotherapy ,Receptors, Prostaglandin E, EP4 Subtype ,Research Article ,Original Research - Abstract
Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2–mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.
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- 2021
30. Combination of EP4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells
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Latika Singh, Pranal J Dakle, Eric S. Muise, Heidi Ferguson, Cristina St. Pierre, Yanyan Zheng, James Baker, Chunsheng Zhang, Brian Long, Hongshi Yu, Brian B. Haines, Christopher Brynczka, Doug Linn, Vincenzo Pucci, Michael Rosenzweig, Jeff Grein, Sheila Ranganath, Andrew M. Haidle, Richard Wnek, Peter Georgiev, Svetlana Sadekova, Yongxin Han, Ying Yu, Long Cui, Andrey Loboda, Doug Wilson, Yun Wang, and David L. Sloman
- Subjects
lymphocytes ,0301 basic medicine ,Myeloid ,medicine.medical_treatment ,Immunology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,ep4 antagonism ,Interferon ,medicine ,Immunology and Allergy ,RC254-282 ,Tumor microenvironment ,Chemistry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Interleukin ,Immunotherapy ,pge2 ,RC581-607 ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,myeloid cells ,030220 oncology & carcinogenesis ,Cancer research ,lipids (amino acids, peptides, and proteins) ,Tumor necrosis factor alpha ,immunotherapy ,Immunologic diseases. Allergy ,CD8 ,medicine.drug - Abstract
Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2–mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.
- Published
- 2021
31. High Levels of Expression of P-glycoprotein/Multidrug Resistance Protein Result in Resistance to Vintafolide
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Kristen L. Picard, Razvan Cristescu, Jennifer O'Neil, Theresa Zhang, Joseph A. Reddy, Melissa Nelson, Marilynn Vetzel, Amy D. Guertin, Andrey Loboda, Serguei Lejnine, Marlene C. Hinton, Emmett V. Schmidt, Alexander Stoeck, Ryan Dorton, Alicia Bloomfield, Isabelle Dussault, Christopher P. Leamon, Michael Nebozhyn, and Brian B. Haines
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0301 basic medicine ,Cancer Research ,ATP Binding Cassette Transporter, Subfamily B ,Cell ,Gene Expression ,Antineoplastic Agents ,Pharmacology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Folic Acid ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Cluster Analysis ,Humans ,RNA, Messenger ,Vinca Alkaloids ,Cell Proliferation ,Platinum ,P-glycoprotein ,Vintafolide ,Dose-Response Relationship, Drug ,biology ,Cell growth ,Gene Expression Profiling ,Folate Receptors, GPI-Anchored ,Computational Biology ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Folate receptor ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Female - Abstract
Targeting surface receptors overexpressed on cancer cells is one way to specifically treat cancer versus normal cells. Vintafolide (EC145), which consists of folate linked to a cytotoxic small molecule, desacetylvinblastine hydrazide (DAVLBH), takes advantage of the overexpression of folate receptor (FR) on cancer cells. Once bound to FR, vintafolide enters the cell by endocytosis, and the reducing environment of the endosome cleaves the linker, releasing DAVLBH to destabilize microtubules. Vintafolide has shown efficacy and improved tolerability compared with DAVLBH in FR-positive preclinical models. As the first FR-targeting drug to reach the clinic, vintafolide has achieved favorable responses in phase II clinical trials in FR-positive ovarian and lung cancer. However, some FR-positive patients in these clinical trials do not respond to vintafolide. We sought to identify potential biomarkers of resistance to aid in the future development of this and other FR-targeting drugs. Here, we confirm that high P-glycoprotein (P-gp) expression was the strongest predictor of resistance to DAVLBH in a panel of 359 cancer cell lines. Furthermore, targeted delivery of DAVLBH via the FR, as in vintafolide, fails to overcome P-gp–mediated efflux of DAVLBH in both in vitro and in vivo preclinical models. Therefore, we suggest that patients whose tumors express high levels of P-gp be excluded from future clinical trials for vintafolide as well as other FR-targeted therapeutics bearing a P-gp substrate. Mol Cancer Ther; 15(8); 1998–2008. ©2016 AACR.
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- 2016
32. Abstract 4572: mONCR-177 oncolytic virotherapy stimulates anti-tumor and anti-viral immunogenicity
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Christophe Quéva, Brian B. Haines, Edward M. Kennedy, Jacqueline Hewett, Melissa Hayes, Sonia Feau, Daniel Wambua, Terry Farkaly, Jacob Spinale, Lingxin Kong, Jennifer Lee, Lorena Lerner, Agnieszka Denslow, and Peter Grzesik
- Subjects
Antitumor activity ,Cancer Research ,Oncology ,business.industry ,Immunogenicity ,Cancer research ,Medicine ,business ,Oncolytic virus - Abstract
Oncolytic viruses represent a promising class of therapeutic agents for the treatment of cancers that poorly respond to immune checkpoint inhibitors. Oncorus is developing ONCR-177, an oncolytic herpes simplex virus engineered for potent oncolysis and stimulation of antitumor immunity. ONCR-177 is replication competent in tumor cells, but its replication and neuropathic activities are attenuated in healthy cells using microRNA-dependent degradation of viral transcripts and by mutations in UL37 that prevent retrograde transport in neurons. In addition, ONCR-177 encodes five immune-stimulatory transgenes: IL-12, CCL4, FLT3LG, a PD-1 humanized antagonist VHH nanobody, and a CTLA4 blocking monoclonal antibody. Transgenes were chosen to efficiently recruit effector T (CD8 and CD4 Th1), NK, and classical dendritic cells to the tumor, and to counter upregulation of immune checkpoints. The individual and collective mechanisms of action of the transgenes are designed to augment local and distant innate and adaptive anti-tumor immune responses. Tumor-specific response was evaluated using mONCR-177, a mouse functional surrogate for ONCR-177, that is built on the same base vector ONCR-159 but expresses the immune transgenes suitable for murine studies. In a CT26 bilateral colon carcinoma tumor model and a MC38 colon adenocarcinoma model, immune responses elicited by intratumoral injection of mONCR-177 and ONCR-159 were compared. Intratumoral T cell responses were evaluated for a tumor-associated antigen (TAA) and an HSV specific antigen in the MC38 model. In the CT26 tumor model, treatment with mONCR-177 resulted in greater immune infiltration with a higher activation status and an improved CD8:Treg ratio. Treatment with mONCR-177 elicited significantly more tumor antigen specific IFNγ and TNFα producing, intratumoral CD8T cells. The increase in anti-tumor response with mONCR-177 treatment was further evidenced by the increase in polyfunctional CD8 T cells producing IFNγ, TNFα, and/or IL-2 in response to TAA stimulation. In the MC38 tumor model, treatment with mONCR-177 resulted in greater immune infiltration in both the injected and non-injected tumor. The CD8:Treg ratio was improved and PD-1 expression was decreased. Tumor antigen specific cytokine production was higher with mONCR-177 treatment. Additionally, a significant increase in HSV-specific polyfunctional CD8+ T cells was observed. mONCR-177 effectively stimulates an intratumoral immune response to both tumor and viral antigens. Treatment results in increased infiltrating immune cells, activation, and polyfunctional CD8+ T cells. These results highlight the dual modality mechanism of action of mONCR-177 treatment through direct tumor cell killing and immune stimulation through the antiviral response, and their enhancement by the immune stimulatory transgenes. Citation Format: Melissa Hayes, Agnieszka Denslow, Jacqueline Hewett, Daniel Wambua, Lingxin Kong, Jacob Spinale, Peter Grzesik, Jennifer Lee, Terry Farkaly, Edward M. Kennedy, Lorena Lerner, Christophe Queva, Brian Haines, Sonia Feau. mONCR-177 oncolytic virotherapy stimulates anti-tumor and anti-viral immunogenicity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4572.
- Published
- 2020
33. Abstract B23: microRNA attenuated oHSV-1 armed with multiple immunomodulatory payloads mediates robust and selective antitumor immune response in preclinical tumor models
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Jennifer S. Lee, Agnieszka Denslow, Brian B. Haines, Christophe Quéva, Michael Ball, Lorenz Ponce, Caroline Webb, Jacqueline Gursha, Daniel Wambua, Cecilia Kwong, Finer Mitchell H, Michael Paglia, Prajna Behera, Judith Jacques, Lorena Lerner, Allison Colthart, Lingxin Kong, Peter Grzesik, Terry Farkaly, Laura Viggiano Salta, Edward M. Kennedy, and Caity Montagna
- Subjects
Cancer Research ,business.industry ,medicine.medical_treatment ,Immunology ,Antigen presentation ,Immunotherapy ,medicine.disease_cause ,Immune checkpoint ,Oncolytic virus ,Herpes simplex virus ,Immune system ,Viral replication ,Interferon ,Cancer research ,Medicine ,business ,medicine.drug - Abstract
Although oncolytic viruses have shown clinical efficacy for local treatment of cancerous tumors, the ability to induce immune-mediated regression to visceral lesions is not robust. Immune checkpoint modulation has been efficacious in a fraction of cancers associated with an inflamed microenvironment but is associated with toxicity due to nonspecific T-cell activation. Therefore, combining these two strategies has the exciting potential to be an effective cancer therapy. Oncolytic virus can be genetically modified to decrease pathogenicity to normal cells and to increase their lytic potential and ability to stimulate antitumor immunity, thus improving the risk-benefit ratio for cancer patients. Oncorus oHSV (ONCR) are novel oncolytic herpes simplex virus type-1 vectors developed for the treatment of solid tumors. ONCR utilizes a unique conditional-lethal strategy in which tissue-specific miRs binding sites are inserted into early genes essential for viral replication and in the neurovirulence gene ICP34.5. This strategy curtails viral replication in normal cells, including neurons, and limits the expression of g34.5 to tumor cells, thus promoting potent viral replication in presence of type I interferon. Fifteen immunostimulatory transgenes and combination thereof were systematically evaluated in dual flank syngeneic mouse tumor models to test both for oncolysis and abscopal efficacy on the contralateral noninjected tumor. Among the selected transgenes, IL-12 was found to elicit the most potent efficacy on the ipsilateral and contralateral tumors. We demonstrated that the replication of ONCR and the expression of IL-12 was limited to the injected tumors. By contrast, induction of systemic immunity as assessed by IFNg production in contralateral tumors and in plasma was observed. ONCR expressing IL-12 elicited efficacy in multiple subcutaneous and metastatic models. Additional payloads designed to stimulate antigen presentation, recruitment of immune cells and inhibition of tumor immune suppression were identified as further enhancing IL-12 activity. Data supporting the selection of a suite of payloads cloned into a single ONCR vector will be presented. ONCR represents a new class of oncolytic virus that promote antitumor responses through a multiprong mechanism of action dependent on selective tumor cell killing, the induction of systemic antitumor immunity and reversion of immune suppression. Citation Format: Lorena Lerner, Edward M. Kennedy, Terry Farkaly, Allison Colthart, Caity Montagna, Prajna Behera, Judith Jacques, Peter Grzesik, Jennifer Lee, Agnieszka Denslow, Jacqueline Gursha, Brian Haines, Michael Ball, Daniel Wambua, Cecilia Kwong, Lingxin Kong, Michael Paglia, Laura Viggiano Salta, Lorenz Ponce, Caroline Webb, Mitchell Finer, Christophe Quéva. microRNA attenuated oHSV-1 armed with multiple immunomodulatory payloads mediates robust and selective antitumor immune response in preclinical tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B23.
- Published
- 2020
34. Abstract B74: Dual mechanism of ONCR-177 enhances antitumor immunogenicity
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Christophe Quéva, Jacob Spinale, Lingxin Kong, Prajna Behera, Jennifer S. Lee, Terry Farkaly, Lorena Lerner, Agnieska Denslow, Sonia Feau, Melissa Hayes, Jacqueline Gurshaw, Peter Grzesik, Edward M. Kennedy, Brian B. Haines, Daniel Wambua, and Shreeya Khatiwada
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Cancer Research ,Antigen processing ,medicine.medical_treatment ,Immunogenicity ,Immunology ,Immunotherapy ,Biology ,Acquired immune system ,Oncolytic virus ,Immune system ,Antigen ,Cancer research ,medicine ,Tumor necrosis factor alpha - Abstract
Oncolytic viruses represent a new class of therapeutic agents for the treatment of cancers that poorly respond to immune checkpoint inhibitors. Oncorus is developing ONCR-177, an oncolytic herpes simplex virus engineered for enhanced oncolysis and antitumor immunity. ONCR-177 is replication competent in tumor cells, but its replication and neuropathic activities are attenuated in healthy cells using miRNA-dependent degradation of viral transcripts and by mutations in UL37 that prevent retrograde transport in neurons. Efficacy is enhanced by a gain of function in the fusogenic glycoprotein B to enhance viral entry and inactivation of US12 to restore antigen processing. ONCR-177 is armed with five immunostimulatory transgenes: IL-12, CCL4, FLT3LG, a PD-1 humanized antagonist VHH nanobody, and the CTLA4 blocking monoclonal antibody ipilimumab. The antitumor effect of ONCR-177 utilizes two distinct modalities of immune stimulation. First, ONCR-177 is specific for tumor cells where infection and replication result in direct tumor cell killing. Second, lysis of tumor cells and expression of ONCR-177 immune payloads stimulate the immune environment through multiple mechanisms: innate signaling through production of PAMP/DAMP signals, immune cell recruitment, exposure of tumor-specific antigens, and activation of the adaptive immune response. Tumor-specific immunogenicity was evaluated using mONCR-171, a mouse functional surrogate for ONCR-177, that is built on the same base vector ONCR-159 but expresses the immune transgenes suitable for murine studies. In a CT26 bilateral colon carcinoma tumor model, immune responses elicited by intratumoral injection of mONCR-171 and ONCR-159 were compared. Intratumoral T cells were evaluated for effector phenotype and function in response to a tumor-associated antigen. We observed a shift toward enhanced activation in the mONCR-171 treatment group. Treatment with mONCR-171 resulted in more tumor-associated CD8+ T cells, higher activation, and more effector cells. This group also had lower PD-1 expression, fewer Treg cells, and a favorable CD8:Treg ratio. The tumor-specific response was assessed using the CT26 tumor-associated antigen AH1, a peptide derived from envelope glycoprotein 70 (gp70) of endogenous murine leukemia virus (MuLV). Treatment with mONCR-171 elicited significantly more IFNγ and TNFα producing, intratumoral CD8+ T cells, producing significantly higher levels of IFNγ. The increase in antitumor immunogenicity with mONCR-171 treatment was further evidenced by the increase in polyfunctional CD8+ T cells, producing IFNγ, TNFα, and/or IL-2 in response to antigen stimulation. These results highlight the dual modality mechanism of action of mONCR-171 treatment though the direct tumor cell killing and immune stimulation through the antiviral response and their enhancement by the immune stimulatory transgenes. Citation Format: Melissa Hayes, Agnieska Denslow, Jacqueline Gurshaw, Daniel Wambua, Shreeya Khatiwada, Lingxin Kong, Jacob Spinale, Prajna Behera, Peter Grzesik, Jennifer Lee, Terry Farkaly, Edward Kennedy, Lorena Lerner, Christophe Quéva, Brian Haines, Sonia Feau. Dual mechanism of ONCR-177 enhances antitumor immunogenicity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B74.
- Published
- 2020
35. Identification of the transgenic integration site in 2C T cell receptor transgenic mice
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Brian B. Haines, Andreas Luch, Chae-Yeon Son, and Chun Jeih Ryu
- Subjects
0301 basic medicine ,Genetically modified mouse ,Transgene ,T cell ,Receptors, Antigen, T-Cell ,Gene Expression ,Mice, Transgenic ,Biology ,Polymerase Chain Reaction ,Chromosomes ,03 medical and health sciences ,Genetics ,medicine ,Cytotoxic T cell ,Animals ,Transgenes ,Southern blot ,T-cell receptor ,Promoter ,Molecular biology ,Mice, Inbred C57BL ,Allelic exclusion ,Blotting, Southern ,030104 developmental biology ,medicine.anatomical_structure ,Animal Science and Zoology ,Agronomy and Crop Science ,Biotechnology - Abstract
2C T cell receptor (TCR) transgenic mice have been long used to study the molecular basis of TCR binding to peptide/major compatibility complexes and the cytotoxicity mechanism of cytotoxic T lymphocytes (CTLs). To study the role of variable gene promoters in allelic exclusion, we previously constructed mutant mice in which the Vβ13 promoter was deleted (P13 mice). Introduction of 2C transgene into P13 mice accelerated the onset of systemic CD8 T cell lymphoma between 14 and 27 weeks of age, although parental P13 mice appeared to be normal. This observation suggests that the lymphoma development may be linked to features of 2C transgene. To identify the integration site of 2C transgene, Southern blotting identified a 2C-specific DNA fragment by 3′ region probe of 2C TCR α transgene, and digestion-circularization-polymerase chain reaction (DC-PCR) amplified the 2C-specific DNA fragment with inverse primers specific to the southern probe. Sequence analysis revealed that DC-PCR product contained the probe sequences and the junction sequences of integration site, indicating that 2C TCR α transgene is integrated into chromosome 1. Further genomic analysis revealed cytosolic phospholipase A2 group IVA (cPLA2) as the nearest gene to the integration site. cPLA2 expression was upregulated in the normal thymi and T cell lymphomas from 2C transgenic mice, although it was not altered in the lymph nodes of 2C transgenic mice. The result is the first report demonstrating the integration site of 2C TCR transgene, and will facilitate the proper use of 2C transgenic mice in studies of CTLs.
- Published
- 2018
36. Abstract 940: Development of ONCR-177, an miR-attenuated oncolytic HSV-1 designed to potently activate systemic antitumor immunity
- Author
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Peter Grzesik, Caitlin Goshert, Prajna Behera, Jennifer S. Lee, Brian B. Haines, Cecilia Kwong, Allison Colthart, Lingxin Kong, Michael Ball, Terry Farkaly, Jacqueline Gursha, Christophe Quéva, Edward M. Kennedy, Agnieszka Denslow, Daniel Wambua, and Lorena Lerner
- Subjects
Cancer Research ,business.industry ,medicine.medical_treatment ,T cell ,Immune checkpoint ,Virus ,Oncolytic virus ,Immune system ,Cytokine ,medicine.anatomical_structure ,Oncology ,Immunity ,Cancer research ,Medicine ,business ,CD8 - Abstract
ONCR-177 is a highly modified recombinant oncolytic Herpes Simplex Virus (oHSV) designed to be a safe and efficacious therapy for the treatment of solid tumor indications. Complementary safety mechanisms, such as tissue-specific miR attenuation of essential viral genes and UL37 mutation, were introduced to reduce replication, neuropathic activity, and latency in normal cells, while preserving oncolytic ability in tumor cells. In addition, ONCR-177 is armed with five transgenes: the NK and T cell activating cytokine IL-12, the chemokines CCL4 and FLT3LG (extracellular domain) to allow for expansion and recruitment of classical dendritic cells, and antagonists to the clinically validated immune checkpoint targets PD-1 and CTLA-4 to counter T cell exhaustion. Therefore, ONCR-177 is proposed to have a dual mechanism of action whereby the miR attenuation strategy allows for selective oncolysis of tumors cells and the transgenes mediate potent stimulation of systemic anti-tumor immunity. Since human IL-12 and the anti-CTLA-4 antagonist do not cross-react with the mouse targets, most nonclinical pharmacology studies were conducted with the mouse surrogate mONCR-171, which expresses within the same base vector as ONCR-177 the mouse equivalent to the ONCR-177 transgenes. Intra-tumoral administration of mONCR-171 in the oHSV-sensitive A20 BALB/c lymphoma bilateral tumor model resulted in response rates (partial and complete tumor regressions) of 100% and 80%, respectively, on the injected (ipsilateral) and distant (contralateral) tumor. mONCR-171 was also highly efficacious in the B16F10 melanoma model, an oHSV-resistant C57BL/6 based tumor model engineered to be permissive to oHSV by introduction of Nectin-1, and in the oHSV-resistant MC38 C57BL/6 colon carcinoma model. Abscopal anti-tumor activity could not be explained by propagation of the virus since viral DNA and transgenes were only detectable in the injected tumor. Rather, mONCR-171 treatment resulted in increased numbers of activated NK cells, CD8 and CD4 T cells, and classical dendritic cells. The proportion of Tregs decreased, resulting in large CD8/Treg ratios. These changes in immune contexture occurred in both the ipsilateral and contralateral tumor and were more pronounced with mONCR-171 treatment compared to the base vector without transgenes, indicating that the observed abscopal effects were due to the elicitation of systemic anti-tumor immunity mediated in part by the transgenes. These encouraging preclinical data warrant the clinical investigation of ONCR-177 in patients with metastatic cancer. Citation Format: Brian B. Haines, Agnieszka Denslow, Michael S. Ball, Jacqueline Gursha, Daniel Wambua, Cecilia Kwong, Lingxin Kong, Prajna Behera, Peter Grzesik, Caitlin Goshert, Allison Colthart, Jennifer S. Lee, Terry Farkaly, Edward M. Kennedy, Lorena Lerner, Christophe Queva. Development of ONCR-177, an miR-attenuated oncolytic HSV-1 designed to potently activate systemic antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 940.
- Published
- 2019
37. Abstract 1452: Development of ONCR-148, a miR-attenuated oncolytic HSV-1 designed to potently activate antitumor T cell response
- Author
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Agnieszka Denslow, Brian B. Haines, Michael S. Ball, Jacqueline Gursha, Daniel Wambua, Cecilia Kwong, Lingxin Kong, Allison Colthart, Prajna Behera, Peter Grzesik, Jennifer Lee, Terry Farkaly, Caitlin Goshert, Edward M. Kennedy, Lorena Lerner, and Christophe Quéva
- Subjects
Cancer Research ,Oncology - Abstract
Oncolytic viruses, through cancer cell-selective lysis and accompanying release of danger signals that promote immune activation, have demonstrated antitumor efficacy in monotherapy of metastatic melanoma and have shown promising activity in combination with checkpoint inhibitors. We present here the activity of ONCR-148, a recombinant oncolytic Herpes Simplex Virus (oHSV) designed to be a safe and efficacious therapy for the treatment of solid tumors. Neuron-specific miR attenuation of ICP4 gene inhibits viral replication in neurons while preserving its potent oncolytic activity in tumor cells. The antitumor potency of the virus is enhanced by incorporating in its genome a transgene expressing fibroblast activation protein (FAP)- and CD3- bispecific antibody that recruits and re-directs the cytolytic activity of T cells toward FAP-expressing stromal cells. FAP is a cell-surface serine protease that is almost exclusively found in fibroblasts within tumor stroma. However, systemic administration of a FAP-CD3 bispecific antibody was not tolerated due to the toxicity toward FAP-expressing bone marrow mesenchymal cells (Tran et al., 2013. J.Exp.Med, 210(6), 1125-1135). Thus, the local intra-tumoral delivery of FAP-CD3 is an attractive approach to promote tumor lysis and T cell activation against cancerous lesions. To test the in vivo activity of ONCR-148, as FAP is poorly expressed in syngeneic mouse tumor models, we developed a bilateral mouse FAP-expressing MC38 syngeneic colon carcinoma model (MC38-FAP), allowing to test local antitumor activity in oHSV-injected tumors and abscopal efficacy mediated by immune cells in the non-injected tumors. Intra-tumoral administration of ONCR-148 in the MC38-FAP model resulted in tumor growth inhibition of 60% (p Citation Format: Agnieszka Denslow, Brian B. Haines, Michael S. Ball, Jacqueline Gursha, Daniel Wambua, Cecilia Kwong, Lingxin Kong, Allison Colthart, Prajna Behera, Peter Grzesik, Jennifer Lee, Terry Farkaly, Caitlin Goshert, Edward M. Kennedy, Lorena Lerner, Christophe Quéva. Development of ONCR-148, a miR-attenuated oncolytic HSV-1 designed to potently activate antitumor T cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1452.
- Published
- 2019
38. Abstract 4773: Development of ONCR-NEP, a lipid nanoparticle delivered oncolytic virus capable of robust in situ amplification resulting in tumor lysis and regression
- Author
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Terry Farkaly, Lingxin Kong, Jennifer Lee, Judy Jacques, Jacqueline Gursha, Brian B. Haines, Edward M. Kennedy, Finer Mitchell H, Christophe Quéva, Agnieszka Denslow, Lorena Lerner, Prajna Behara, and Peter Grzesik
- Subjects
Cancer Research ,Expression vector ,Oncology ,Viral replication ,In vivo ,Sense (molecular biology) ,Cancer research ,Vector (molecular biology) ,Transfection ,Biology ,Virus ,Oncolytic virus - Abstract
Oncolytic viruses (OV) have shown clinical efficacy for treatment of malignancies when administered intratumorally. Attempts to use OV for systemic treatment of cancer have shown very limited success due to the presence of neutralizing antibodies. Development of an intravenously delivered oncolytic viral therapy that maintains its potency and effectiveness in the presence of neutralizing antibodies is greatly needed for patients with visceral lesions that are metastatic and difficult to inject. Therefore, the OV field is moving toward the design of vector platforms that can be used for systemic therapy to take full advantage of the oncolytic activity and the induction of anti-tumor immunity. Oncorus is developing a new strategy for systemic delivery of OV genomes by using tumor targeted nanoparticles, designed to be immunologically inert systemically, but can initiate a local robust intratumoral oncolytic virus infection. The Nanoparticle Encapsulated Polynucleotide (NEP) platform is designed for systemic delivery of replication competent OV genomes encoded by a plasmid DNA loaded into tumor-homing nanoparticles. To initiate viral replication intratumorally from a plasmid DNA we engineered a mammalian mRNA cassette that codes for an infectious +sense picornaviral RNA. This RNA is liberated from the larger capped and polyadenylated mammalian transcript by combination of ribozymes and siRNA cleavage, enabling rapid expression of viral proteins and viral replication. We selected Seneca Valley Virus (SVV) as our first candidate virus for the NEP platform. SVV is a potent oncolytic virus in neuroendocrine tumors previously evaluated in clinical trial after IV administration and well tolerated in the patients. The robust initiation of SVV replication from the pDNA expression construct results in cellular lysis in permissive cells when transfected in vitro. In vivo, intratumoral injection of a lipid based formulated SVV plasmid resulted in robust viral replication and dramatic tumor growth inhibition in multiple tumor models. This viral construct has also been modified to express immunomodulatory payloads to enhance the adaptive immune response by recruitment of immune effector cells. Finally, we have enabled miRNA attenuation of his construct to add a genetic tissue selectivity switch for safety, and we have shown that both miR-1 and miR-122 effectively and specifically attenuate viral replication. To enable ONCR-NEP therapy for intravenously administration, we have begun developing a lipid nanoparticle formulation with an active tumor targeting moiety. We have obtained lipid nanoparticle formulations with favorable physical and functional characteristics that are effective both in vitro and in vivo. We show here for the first time the development of a synthetic virus, a breakthrough therapeutic technology that is highly effective in vivo. Citation Format: Edward M. Kennedy, Jennifer S. Lee, Judy Jacques, Terry Farkaly, Prajna Behara, Peter Grzesik, Brian B. Haines, Agnieszka Denslow, Jacqueline Gursha, Lingxin Kong, Mitchell Finer, Christophe Quéva, Lorena Lerner. Development of ONCR-NEP, a lipid nanoparticle delivered oncolytic virus capable of robust in situ amplification resulting in tumor lysis and regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4773.
- Published
- 2019
39. Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors
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Minilik Angagaw, Kaiko Kunii, Leigh Zawel, Marlene C. Hinton, Chris Winter, Weisheng Zhang, Christopher Ware, Clay L. Efferson, Cloud P. Paweletz, Stephen Fawell, Jennifer Tammam, Brian B. Haines, Pradip K. Majumder, Theresa Zhang, Jonathan D. Cheng, Sriram Sathyanarayanan, Heike Keilhack, Joe Zhu, and Gary Gilliland
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Cancer Research ,biology ,business.industry ,RPTOR ,Cancer ,medicine.disease ,Ridaforolimus ,chemistry.chemical_compound ,Prostate cancer ,chemistry ,Oncology ,Immunology ,biology.protein ,Cancer research ,medicine ,PTEN ,Tensin ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
Activation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer. Pathway bifurcation of AKT and mTOR was noted in both mouse and human prostate tumors. We demonstrated for the first time that cotargeting mTOR and AKT with ridaforolimus/MK-8669 and M1K-2206, respectively, delivers additive antitumor effects in vivo when compared to single agents. Our preclinical data suggest that the combination of AKT and mTOR inhibitors might be more effective in treating prostate cancer patients than current treatment regimens or either treatment alone.
- Published
- 2012
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40. Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer
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Marc A. Becker, Sean C. Harrington, S. John Weroha, Paul Haluska, Brian B. Haines, Sriram Sathyanarayanan, Xiaonan Hou, and Piyawan Tienchaianada
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0301 basic medicine ,Cancer Research ,mTOR inhibitor ,Apoptosis ,Breast neoplasms/drug therapy ,mTORC1 ,Receptor tyrosine kinase ,Receptor, IGF Type 1 ,Mice ,Drug resistance, Neoplasm ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin receptor substrate ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,Medicine ,Phosphorylation ,Aromatase ,Mice, Inbred BALB C ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,TOR Serine-Threonine Kinases ,Antibodies, Monoclonal ,Drug Synergism ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Female ,Signal Transduction ,Research Article ,Neoplasms, Hormone-Dependent ,Aromatase inhibitors/therapeutic use ,Blotting, Western ,Mice, Nude ,Breast Neoplasms ,Antibodies, Monoclonal, Humanized ,Real-Time Polymerase Chain Reaction ,Ridaforolimus ,03 medical and health sciences ,Antigens, CD ,Disease models, Animal ,Genetics ,Animals ,Humans ,RNA, Messenger ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Sirolimus ,business.industry ,Xenograft Model Antitumor Assays ,Receptor, Insulin ,Insulin receptor ,030104 developmental biology ,chemistry ,biology.protein ,Cancer research ,business ,Proto-Oncogene Proteins c-akt ,Estrogen receptor alpha - Abstract
Background Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option. Methods Using hormone-sensitive breast cancer cells stably transfected with the aromatase gene (MCF-7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; “MK-0646”; anti-IGF-1R antibody), ridaforolimus (RIDA; “MK-8669”; mTORC1 small molecule inhibitor) and letrozole (“LET”, aromatase inhibitor). Results With the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK-0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach. Conclusion These data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK-8669 as an efficacious anti-tumor strategy for ER-positive breast tumors. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2847-3) contains supplementary material, which is available to authorized users.
- Published
- 2016
41. T cell activation and anti-tumor efficacy of anti-LAG-3 antibodies is independent of LAG-3 – MHCII blocking capacity
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Wendy M. Blumenschein, Rene De Waal Malefyt, Saso Cemerski, Heather Hirsch, Linda Liang, Jason Laskey, Maribel Beaumont, Jeanine D. Mattson, Brian B. Haines, Melissa Chenard, Shuxia Zhao, Edward Hsieh, Rinkan Shukla, Long Cui, and Laurence Fayadat-Dilman
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Pharmacology ,Antitumor activity ,Cancer Research ,Tumor microenvironment ,biology ,T cell ,Immunology ,Streptamer ,Inhibitory postsynaptic potential ,medicine.anatomical_structure ,Oncology ,Poster Presentation ,biology.protein ,Cancer research ,medicine ,Molecular Medicine ,Immunology and Allergy ,Cytotoxic T cell ,Antibody ,Homeostasis - Abstract
Meeting abstracts LAG-3 has been shown to act as an inhibitory molecule involved in the regulation of T cell activation, proliferation and homeostasis. Exhausted T cell populations that evolve in the tumor microenvironment or during chronic viral infections show coordinated expression of LAG-3 and
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- 2015
42. An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies
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Serguei Lejnine, Brian B. Haines, Razvan Cristescu, Igor Feldman, Theresa Zhang, Melissa Chenard, Andrew Bloecher, Andrey Loboda, Astrid M. Kral, Jennifer O'Neil, William Arthur, Stuart D. Shumway, Brian S. Roberts, Yair Benita, Christopher Winter, Yaping Liu, and Jing Li
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0301 basic medicine ,Drug ,Cancer Research ,Cell Survival ,media_common.quotation_subject ,Pyrimidinones ,Pharmacology ,Ridaforolimus ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Random Allocation ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,media_common ,Cell Proliferation ,Sirolimus ,biology ,Cell growth ,Cancer ,Drug Synergism ,Neoplasms, Experimental ,medicine.disease ,Xenograft Model Antitumor Assays ,High-Throughput Screening Assays ,Wee1 ,030104 developmental biology ,Pyrimidines ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Pyrazoles ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic drug combinations can convert weakly efficacious monotherapies into regimens that produce robust antitumor activity. This can be explained in part through pathway interdependencies that are critical for cancer cell proliferation and survival. However, identification of the various interdependencies is difficult due to the complex molecular circuitry that underlies tumor development and progression. Here, we present a high-throughput platform that allows for an unbiased identification of synergistic and efficacious drug combinations. In a screen of 22,737 experiments of 583 doublet combinations in 39 diverse cancer cell lines using a 4 by 4 dosing regimen, both well-known and novel synergistic and efficacious combinations were identified. Here, we present an example of one such novel combination, a Wee1 inhibitor (AZD1775) and an mTOR inhibitor (ridaforolimus), and demonstrate that the combination potently and synergistically inhibits cancer cell growth in vitro and in vivo. This approach has identified novel combinations that would be difficult to reliably predict based purely on our current understanding of cancer cell biology. Mol Cancer Ther; 15(6); 1155–62. ©2016 AACR.
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- 2015
43. Recombination Activating Genes (RAG) in Lymphoma Development
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Jianzhu Chen, Chun Jeih Ryu, and Brian B. Haines
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Lymphoma ,Genes, RAG-1 ,Apoptosis ,Mice, Transgenic ,Context (language use) ,Biology ,medicine.disease_cause ,Mice ,medicine ,Animals ,Lymphocytes ,Enhancer ,Molecular Biology ,Gene ,Genetics ,Mutation ,Cell Cycle ,T-cell receptor ,Cell Biology ,Genes, p53 ,medicine.disease ,Genes, bcl-2 ,Cell biology ,DNA-Binding Proteins ,Regulatory sequence ,Genes, T-Cell Receptor beta ,Signal transduction ,Signal Transduction ,Developmental Biology - Abstract
The recombination activating genes (RAG) play a central role in the generation of a diverse immune repertoire by mediating DNA recombination events at antigen receptor loci in developing B and T lymphocytes. However, inappropriate RAG activity throughout the genome has been implicated in a large variety of human and mouse lymphomas. Mechanisms by which RAG can provoke or perpetuate lymphoma include deregulation of certain genes by translocation to antigen receptor regulatory regions, the formation of chimeric oncogenes, inactivation of tumor suppressor or micro-RNA loci, or activation of oncogenes. Here we present the T cell receptor enhancer (Ebeta) deficient mouse as a tractable in vivo model system to study the role of RAG activity in the context of lymphoma development, and contrast our system with those of others. We posit a general hypothesis that virtually any mutation that impairs early lymphocyte development at stages when RAG is expressed can constitute a pro-carcinogenic event. Our model system provides a means to assess the roles of RAG activity in human lymphoid malignancies.
- Published
- 2006
44. Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations
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Chun Jeih Ryu, Maria F. Fragoso, Sandy Chang, Dobrin Draganov, Hyo Jeong Hong, Jianzhu Chen, Alexei Protopopov, Sang Gi Paik, Ronald A. DePinho, Brian B. Haines, Andreas Luch, and Yun Hee Kang
- Subjects
Cancer Research ,Lymphoma ,DNA damage ,T cell ,T-Lymphocytes ,Apoptosis ,CELLCYCLE ,Thymus Gland ,Biology ,medicine.disease_cause ,Gene Rearrangement, T-Lymphocyte ,Chromosome aberration ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Sequence Deletion ,Chromosome Aberrations ,Mice, Knockout ,Mutation ,T-cell receptor ,Spectral Karyotyping ,Gene rearrangement ,Cell Biology ,Molecular biology ,DNA-Binding Proteins ,Thymocyte ,medicine.anatomical_structure ,Oncology ,Immunology ,Chromosomal region ,Genes, T-Cell Receptor beta ,Tumor Suppressor Protein p53 ,DNA Damage - Abstract
Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR beta gene enhancer (E beta) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the E beta mutation into p53-/- mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.
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- 2006
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- View/download PDF
45. Abstract 4714: Blockade of LAG-3 amplifies immune activation signatures and augments curative antitumor responses to anti-PD-1 therapy in immune competent mouse models of cancer
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Brian B. Haines, Sarah Javaid, Heather Hirsch, Saso Cemerski, Brian Long, Rene De Waal Malefyt, Michael Rosenzweig, Long Cui, Terri McClanahan, Shuli Zhang, and Manjiri Sathe
- Subjects
0301 basic medicine ,Cancer Research ,biology ,Combination therapy ,business.industry ,Pembrolizumab ,Major histocompatibility complex ,medicine.disease_cause ,Immune checkpoint ,Autoimmunity ,Immune tolerance ,03 medical and health sciences ,030104 developmental biology ,Immune system ,Oncology ,Immunology ,Blocking antibody ,biology.protein ,Medicine ,business - Abstract
MK-4280 is a humanized IgG4 monoclonal antibody (mAb) that binds to the immune checkpoint receptor Lymphocyte Activation Gene-3 (LAG-3) to block the interaction with its ligand, Major Histocompatibility Complex (MHC) Class II. LAG-3 is frequently co-expressed with other immune checkpoint receptors, most notably programmed cell death protein-1 (PD-1), on T cells with an exhausted phenotype. LAG-3 and PD-1 cooperate to regulate peripheral immune tolerance in healthy individuals, and, conversely, play critical roles in several diseases, including autoimmunity, graft rejection, viral infections, and cancer. Co-blockade of LAG-3 and PD-1 in immunocompetent mouse tumor models have demonstrated augmented anti-tumor activity over single agents. However, the molecular mechanisms behind these combination effects have not been fully investigated. Here, preclinical proof-of-biology studies are presented for co-targeting LAG-3 and PD-1 in cancer. c28G10-mG1-[D265A] (abbreviated 28G10-mG1) is a rat:mouse chimera that mimics MK-4280 by its ability to directly block the mouse LAG-3:MHC Class II interaction without initiating Fc-mediated effector functions. As a single agent, 28G10-mG1 demonstrated modest anti-tumor activity across several syngeneic mouse tumor models, despite evidence of systemic drug exposure and target engagement (as assessed by sLAG-3-mAb complex accumulation). The combination of 28G10-mG1 and the anti-mouse PD-1 blocking antibody mDX400 resulted in greater tumor growth inhibition and increased numbers of complete responses (CR) over mDX400 alone in the MBT-2 tumor model. Furthermore, animals that had achieved CR to combination therapy were subsequently protected from MBT-2 re-challenge, suggesting the establishment of immune memory. RT-qPCR analyses revealed up-regulation of immune-related genes, primarily at Day 4 in the blood and Day 8 in the tumor with mDX400, but not 28G10-mG1, treatment. However, when combined with mDX400, 28G10-mG1 further altered the expression of many immune-related genes that were perturbed by mDX400 single agent therapy. Genes unique to combination treatment were also observed. Significantly, immune pathway signatures associated with clinical efficacy to Keytruda were upregulated with combination therapy. Tumor transcriptome and network analysis by RNAseq revealed enrichment in several immune- and cytokine-related pathways with combination therapy compared to mDX400 single agent therapy. Taken together, these preclinical oncology studies support the concept of co-targeting LAG-3 to increase the therapeutic efficacy of PD-1 blockade. Clinical investigation of MK-4280 in combination with anti-PD-1 therapy (pembrolizumab/Keytruda) is ongoing. Citation Format: Brian B. Haines, Sarah Javaid, Long Cui, Heather Hirsch, Saso Cemerski, Terri McClanahan, Manjiri Sathe, Shuli Zhang, Michael Rosenzweig, Brian Long, Rene de Waal Malefyt. Blockade of LAG-3 amplifies immune activation signatures and augments curative antitumor responses to anti-PD-1 therapy in immune competent mouse models of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4714. doi:10.1158/1538-7445.AM2017-4714
- Published
- 2017
46. Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial
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Andrés Cervantes, Ann Leighton-Swayze, Richard A. Klinghoffer, José Baselga, Scot Ebbinghaus, Sriram Sathyanarayanan, Christopher Winter, Theresa Zhang, Irene Brana, Sharda Jha, Yang Song, Serena Di Cosimo, Johanna C. Bendell, Brian B. Haines, Desamparados Roda, Jason Frazier, Mark N. Stein, and Youyuan Xu
- Subjects
Adult ,Cancer Research ,Phases of clinical research ,Breast Neoplasms ,Pharmacology ,Antibodies, Monoclonal, Humanized ,Article ,Receptor, IGF Type 1 ,Ridaforolimus ,chemistry.chemical_compound ,Breast cancer ,In vivo ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,Insulin-like growth factor 1 receptor ,Aged ,Sirolimus ,Dalotuzumab ,business.industry ,TOR Serine-Threonine Kinases ,Antibodies, Monoclonal ,Receptors, Somatomedin ,Middle Aged ,medicine.disease ,Xenograft Model Antitumor Assays ,Oncology ,chemistry ,Monoclonal ,business ,Signal Transduction - Abstract
Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity. Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379). Clin Cancer Res; 21(1); 49–59. ©2014 AACR.
- Published
- 2014
47. Discovery of biomarkers predictive of GSI response in triple negative breast cancer and adenoid cystic carcinoma
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Alexander Stoeck, Michael J. Kluk, Gary Gilliland, Andrew S. Truong, Serguei Lejnine, Christopher Ware, Hongfang Wang, Li Pan, Stephen Fawell, John Maclean, Brian B. Haines, Theresa Zhang, Jason Laskey, X. Shirley Liu, Brandon E. Kremer, Chongzhi Zang, Bradley E. Bernstein, Jing Yuan, Philip W. Garrett-engele, Warren S. Pear, Jon C. Aster, Sriram Sathyanarayanan, Christopher A. Moskaluk, Leigh Zawel, and Birgit Knoechel
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Models, Molecular ,Adenoid cystic carcinoma ,Protein Conformation ,Genes, myc ,Antineoplastic Agents ,Apoptosis ,Triple Negative Breast Neoplasms ,Biology ,Article ,Cell Line, Tumor ,Thiadiazoles ,Carcinoma ,medicine ,Animals ,Humans ,Exome ,Protease Inhibitors ,Protein Interaction Domains and Motifs ,Triple-negative breast cancer ,Cellular Senescence ,Gene Rearrangement ,Receptors, Notch ,Cancer ,High-Throughput Nucleotide Sequencing ,Gene rearrangement ,medicine.disease ,Prognosis ,Primary tumor ,Carcinoma, Adenoid Cystic ,Xenograft Model Antitumor Assays ,Cyclic S-Oxides ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Treatment Outcome ,Oncology ,Drug Resistance, Neoplasm ,Mutation ,Cancer research ,Female ,Amyloid Precursor Protein Secretases ,Cell aging ,Biomarkers ,Signal Transduction - Abstract
Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD–low tumors without NOTCH1 mutations were resistant. Significance: NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies. Cancer Discov; 4(10); 1154–67. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 1103
- Published
- 2014
48. Divergent kinetics differentiate the mechanism of action of two HDAC inhibitors
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Brian B. Haines, Judith C. Fleming, Joon Jung, Paul Secrist, Hongmei Wang, Thomas A. Miller, Richard W. Heidebrecht, Paul Harrington, Joshua Close, Nicole Ozerova, John Maclean, Melissa Chenard, and Astrid M. Kral
- Subjects
Gene isoform ,Models, Molecular ,Conformational change ,Protein Conformation ,Cell ,Histone Deacetylase 2 ,Mice, Nude ,Antineoplastic Agents ,Histone Deacetylase 1 ,Biology ,Hydroxamic Acids ,Biochemistry ,Benzoates ,Substrate Specificity ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Fluorescent Dyes ,Vorinostat ,Mechanism (biology) ,Ligand binding assay ,HDAC1 ,Histone Deacetylase Inhibitors ,Kinetics ,Histone ,medicine.anatomical_structure ,Mechanism of action ,Xanthenes ,biology.protein ,Heterografts ,Female ,medicine.symptom ,Fluorescein-5-isothiocyanate ,Protein Binding - Abstract
Histone deacetylases (HDACs) play diverse roles in many diseases including cancer, sarcopenia, and Alzheimer’s. Different isoforms of HDACs appear to play disparate roles in the cell and are associated with specific diseases; as such, a substantial effort has been made to develop isoform-selective HDAC inhibitors. Our group focused on developing HDAC1/HDAC2-specific inhibitors as a cancer therapeutic. In the course of characterizing the mechanism of inhibition of a novel HDAC1/2-selective inhibitor, it was determined that it did not exhibit classical Michaelis–Menten kinetic behavior; this result is in contrast to the seminal HDAC inhibitor SAHA. Enzymatic assays, along with a newly developed binding assay, were used to determine the rates of binding and the affinities of both the HDAC1/2-selective inhibitor and SAHA. The mechanism of action studies identified a potential conformational change required for optimal binding by the selective inhibitor. A model of this putative conformational change is proposed.
- Published
- 2014
49. Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor
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Matthew G. Stanton, David J. Witter, Christopher Hamblett, Nicole Ozerova, Brian B. Haines, Richard E. Middleton, Judith C. Fleming, Phieng Siliphaivanh, Dawn Marie Mampreian Hoffman, Hongmei Wang, Alexander A. Szewczak, Jed L. Hubbs, Melissa Chenard, Astrid M. Kral, Bethany Hughes, Kevin J. Wilson, Paul Harrington, J. Paul Secrist, Richard W. Heidebrecht, Joey L. Methot, Thomas A. Miller, Jonathan C. Cruz, Andreas Harsch, and Candia M. Kenific
- Subjects
biology ,Histone deacetylase 2 ,medicine.drug_class ,Organic Chemistry ,Histone deacetylase inhibitor ,Pharmacology ,Biochemistry ,In vitro ,HDAC1 ,Histone ,In vivo ,Acetylation ,Drug Discovery ,Gene expression ,biology.protein ,medicine - Abstract
The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and gene expression changes were also observed in cell culture, and histone acetylation was observed in vivo beyond disappearance of drug from plasma. In vivo studies further demonstrated that continuous target inhibition was well tolerated and efficacious in tumor-bearing mice, leading to tumor growth inhibition with either once-daily or intermittent administration.
- Published
- 2014
50. T cell activation and anti-tumor efficacy of anti-Lag3 mAbs are independent of Lag-3–MHC Class II blocking capacity
- Author
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Edward Hsieh, Saso Cemerski, S. Zhao, Wendy M. Blumenschein, R. Shukla, R. De Waal Malefyt, Long Cui, Melissa Chenard, Brian B. Haines, Jason Laskey, Tatyana Churakova, Laurence Fayadat-Dilman, and Maribel Beaumont
- Subjects
Antitumor activity ,Cancer Research ,MHC class II ,LAG3 ,medicine.anatomical_structure ,Oncology ,biology ,Chemistry ,Blocking (radio) ,T cell ,biology.protein ,medicine ,Cancer research - Published
- 2016
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