Patrick Flannery
University of Colorado Denver
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Featured researches published by Patrick Flannery.
Oncology Reports | 2017
Patrick Flannery; John DeSisto; Vladimir Amani; Sujatha Venkataraman; Rakeb Lemma; Eric Prince; Andrew M. Donson; Erin E. Moroze; Lindsey M. Hoffman; Jean M. Mulcahy Levy; Nicholas K. Foreman; Rajeev Vibhakar; Adam Green
Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brain tumor. The mechanistic target of rapamycin (MTOR), a key oncogene, functions as two distinct signaling complexes, MTORC1 and MTORC2. We set out to determine the preclinical efficacy and mechanism of action of MTOR inhibitors in DIPG. We evaluated the MTORC1 inhibitor everolimus and the MTORC1/2 inhibitor AZD2014 in three patient-derived DIPG cell lines using cell culture models. We created dose-response curves for both compounds. We measured phenotypic effects on cell self-renewal, apoptosis, cell cycle, differentiation, senescence, and autophagy. We assessed the effects of each compound on the AKT pathway. Finally, we measured the efficacy of AZD2014 in combination with radiation therapy (RT) and a panel of FDA-approved chemotherapy drugs. While everolimus showed minimal antitumor efficacy, AZD2014 revealed IC50 levels of 410–552 nM and IC90 levels of 1.30–8.86 µM in the three cell lines. AZD2014 demonstrated increased inhibition of cell self-renewal compared to everolimus. AZD2014 decreased expression of phospho-AKT, while no such effect was noted with everolimus. Direct AKT inhibition showed similar efficacy to AZD2014, and induction of constitutive AKT activity rescued DIPG cells from the effects of AZD2014. AZD2014 exhibited synergistic relationships with both RT and various chemotherapy agents across classes, including the multikinase inhibitor ponatinib. MTORC1/2 inhibition shows antitumor activity in cell culture models of DIPG due to the effect of MTORC2 inhibition on AKT. This strategy should be further assessed for potential incorporation into combinatorial approaches to the treatment of DIPG.
Cancer Research | 2017
John DeSisto; Patrick Flannery; Trinayan Kashyap; Rakeb Lemma; Shelby Mestnik; Andrew L. Kung; Rajeev Vibhakar; Yosef Landesman; Adam Green
Background: Pediatric high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) account for the majority of pediatric brain tumor deaths and respond poorly to chemotherapy. Selinexor, a nuclear export inhibitor, is effective against HGG and DIPG in in vitro and in vivo models, but resistance to treatment develops. We previously identified the NF-κB pathway as a likely mediator of selinexor’s activity in these tumors. NF-κB transcriptional activity is regulated by an inhibitor, IKB-α, whose levels are in turn regulated by ubiquitination and proteasomal degradation. IKB-α is a client of exportin-1 (XPO1); its nuclear levels are increased by selinexor treatment, leading to inhibition of NF-κB. We subsequently identified proteasome inhibitors as potentially synergistic with selinexor in HGG and DIPG through a screen of all FDA-approved chemotherapy agents. Proteasome inhibition has also been shown to synergize with selinexor treatment in multiple myeloma and osteosarcoma. Methods: We treated HGG cell lines (BT245 and GBM1) and DIPG cell lines (DIPG4, DIPG7 and SF7761) for five days with selinexor in combination with each of three proteasome inhibitors, bortezomib, carfilzomib and marizomib, and assayed cell viability at the conclusion of treatment. In each experiment, cells were treated with selinexor, a proteasome inhibitor, and a combination of the two drugs at several constant ratios. IC50 values were computed for each drug acting alone, and the combination index (CI) of the two drugs acting together was computed using the Chou-Talalay method. We also treated SF7761 cells with a combination of radiation (8Gy), selinexor, and a proteasome inhibitor. Results: The proteasome inhibitors had widely varying IC50 values in the cell lines treated, ranging from 1nM to 5µM. The CI for the combination of selinexor and each proteasome inhibitor was consistently less than 1 (indicating a synergistic relationship) in the cell lines tested. We found that radiation and proteasome inhibition had an antagonistic relationship (CI>1), radiation and selinexor a synergistic relationship (CI Conclusions: Selinexor and proteasome inhibitors show promise as a combination therapy for HGG and DIPG. We are conducting in vivo experiments to further explore this combination for subsequent clinical trial use. Citation Format: John DeSisto, Patrick Flannery, Trinayan Kashyap, Rakeb Lemma, Shelby Mestnik, Andrew Kung, Rajeev Vibhakar, Yosef Landesman, Adam Green. Synergistic effects of the XPO1 inhibitor selinexor with proteasome inhibitors in pediatric high-grade glioma and diffuse intrinsic pontine glioma [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 1946. doi:10.1158/1538-7445.AM2017-1946
Neuro-oncology | 2018
John DeSisto; John T. Lucas; Andrew M. Donson; Bridget Sanford; Gang Wu; Gregory T. Armstrong; Michael A. Arnold; Smita Bhatia; Patrick Flannery; Rakeb Lemma; Lakotah Hardie; Lindsey M. Hoffman; Kathleen Dorris; Arthur K. Liu; Nicholas K. Foreman; Rajeev Vibhakar; Kenneth L. Jones; Sariah Allen; Suzanne J. Baker; Thomas E. Merchant; Brent A. Orr; Adam Green
Neuro-oncology | 2018
Adam Green; Patrick Flannery; Todd C. Hankinson; Brent O’Neill; John DeSisto; Rakeb Lemma; Lindsey M. Hoffman; Jean M. Mulcahy Levy; Jennifer Raybin; Molly Hemenway; Carl Koschmann; Michael H. Handler; Nicholas K. Foreman; Rajeev Vibhakar; Michael F. Wempe; Kathleen Dorris
Neuro-oncology | 2018
Andrea Griesinger; Angela Pierce; Davis Witt; Patrick Flannery; Andrew M. Donson; Katherine Gowan; Todd C. Hankinson; Michael H. Handler; Kenneth L. Jones; Adam Green; Rajeev Vibhakar; Nicholas K. Foreman
Journal of Clinical Oncology | 2018
John T. Lucas; John DeSisto; Gang Wu; Andrew M. Donson; Suzanne J. Baker; Michael A. Arnold; Smita Bhatia; Patrick Flannery; Rakeb Lemma; Lakotah Hardie; Lindsey Marie Hoffman; Kathleen Doris; Arthur K. Liu; Nicholas K. Foreman; Rajeev Vibhakar; Sariah Allen; Thomas E. Merchant; Adam L. Green; Brent A. Orr
Neuro-oncology | 2017
Jean M. Mulcahy Levy; Bridget Sanford; Andrew Morin; Adam Green; Patrick Flannery; Kenneth L. Jones; Anurhada Banerjee; Kellie Nazemi; David Samuel; Lindsay Kilburn; David Solomon; Theodore Nicolaides
Neuro-oncology | 2017
Patrick Flannery; John DeSisto; Rakeb Lemma; Andrew M. Donson; Nicholas K. Foreman; Rajeev Vibhakar; Kenneth L. Jones; Adam L. Green
Neuro-oncology | 2017
John DeSisto; Andrew M. Donson; Patrick Flannery; Rakeb Lemma; Bridget Sanford; Nicholas K. Foreman; Rajeev Vibhakar; Kenneth L. Jones; Adam L. Green
Neuro-oncology | 2016
Patrick Flannery; John DeSisto; Vladimir Amani; Sujatha Venkataraman; Rajeev Vibhakar; Adam Green