Graham C. Fletcher
University Health Network
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Graham C. Fletcher.
Molecular Cancer Therapeutics | 2011
Graham C. Fletcher; Richard D. Brokx; Trisha Denny; Todd Hembrough; Stacy M. Plum; William E. Fogler; Carolyn Sidor; Mark R. Bray
ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 values ranging from 0.025 to 0.7 μmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinum-resistant ovarian cancer. Mol Cancer Ther; 10(1); 126–37. ©2010 AACR.
Clinical Cancer Research | 2011
Jennifer R. Diamond; Bruno R. Bastos; Ryan J. Hansen; Daniel L. Gustafson; S. Gail Eckhardt; E. L. Kwak; Shuchi Sumant Pandya; Graham C. Fletcher; Todd M. Pitts; Gillian N. Kulikowski; Mark Morrow; Jamie Arnott; Mark R. Bray; Carolyn Sidor; Wells A. Messersmith; Geoffrey I. Shapiro
Purpose: ENMD-2076 is a unique orally bioavailable Aurora kinase and VEGFR inhibitor. The purpose of this phase 1 study of ENMD-2076 was to determine the MTD, pharmacokinetic, and pharmacodynamic profiles and preliminary antitumor activity. Experimental Design: Patients with refractory advanced solid malignancies were treated with ENMD-2076 orally with continuous once daily dosing. Doses from 60 to 200 mg/m2 were evaluated using a standard 3 (to 4) + 3 design. Pharmacokinetic parameters were studied on days 1, 28, and 30 to 35 of cycle 1. Expanded MTD cohorts included patients with ovarian cancer, colorectal cancer, and refractory solid tumors. Results: A total of 67 patients (46 F, 21M; ages 30–76) entered the study. Dose levels of 60, 80, 120, 200, and 160 mg/m2 were evaluated. Two patients experienced grade 3 hypertension at 200 mg/m2, and additional grade 3 neutropenia events limited tolerability at this dose. An intermediate dose of 160 mg/m2 was determined to be the MTD. The most common drug-related adverse events included hypertension, nausea/vomiting, and fatigue. The pharmacokinetics of ENMD-2076 were characterized by a rapid absorption phase (Tmax 3–7.8 hours), a t1/2 of 27.3 to 38.3 hours after a single dose, and dose proportional exposure. Decreased plasma sVEGFR2 was observed posttreatment. Two patients with platinum refractory/resistant ovarian cancer had RECIST partial responses. Conclusions: ENMD-2076 was well tolerated, had a linear pharmacokinetic profile, and showed promising antitumor activity, particularly in ovarian cancer. The recommended phase 2 dose of ENMD-2076 is 160 mg/m2 administered orally once daily with continuous dosing. Clin Cancer Res; 17(4); 849–60. ©2010 AACR.
Clinical Cancer Research | 2010
John J. Tentler; Erica L. Bradshaw-Pierce; Natalie J. Serkova; Kendra M. Hasebroock; Todd M. Pitts; Jennifer R. Diamond; Graham C. Fletcher; Mark R. Bray; S. Gail Eckhardt
Purpose: This in vivo study was designed to investigate the efficacy of ENMD-2076, a small-molecule kinase inhibitor with activity against the Aurora kinases A and B, and several other tyrosine kinases linked to cancer, including vascular endothelial growth factor receptor 2, cKit, and fibroblast growth factor receptor 1, against murine xenograft models of human colorectal cancer (CRC). Experimental Design: HT-29 CRC cell line xenografts were treated with either vehicle or ENMD-2076 (100 or 200 mg/kg) orally daily for 28 days. Tumor growth inhibition, dynamic contrast-enhanced magnetic resonance imaging, and 18FDG-positron emission tomography were conducted to assess the antiproliferative, antiangiogenic, and antimetabolic responses, respectively. Effects on proliferation were also analyzed by immunohistochemical methods. Additionally, three patient-derived xenografts from primary and metastatic sites were treated with ENMD-2076 (100 mg/kg) and assessed for tumor growth inhibition. Results: In the HT-29 xenograft model, ENMD-2076 induced initial tumor growth inhibition followed by regression. Treatment was associated with significant tumor blanching, indicating a loss of vascularity and substantial reductions in tumor vascular permeability and perfusion as measured by dynamic contrast-enhanced magnetic resonance imaging. Positron emission tomography scanning showed significant decreases in 18FDG uptake at days 3 and 21 of treatment, which was associated with a marked reduction in proliferation as assessed by Ki-67. All three of the patient-derived xenografts tested were sensitive to treatment with ENMD 2076 as measured by tumor growth inhibition. Conclusions: ENMD-2076 showed robust antitumor activity against cell line and patient-derived xenograft models of CRC that is detectable by functional imaging, supporting clinical investigation of this agent in CRC. Clin Cancer Res; 16(11); 2989–98. ©2010 AACR.
Clinical Cancer Research | 2013
Jennifer R. Diamond; S. Gail Eckhardt; Aik Choon Tan; Timothy P. Newton; Heather M. Selby; Kelsey L. Brunkow; Maria I. Kachaeva; Marileila Varella-Garcia; Todd M. Pitts; Mark R. Bray; Graham C. Fletcher; John J. Tentler
Purpose: The Aurora kinases are a family of conserved serine-threonine kinases with key roles in mitotic cell division. As with other promising anticancer targets, patient selection strategies to identify a responsive subtype will likely be required for successful clinical development of Aurora kinase inhibitors. The purpose of this study was to evaluate the antitumor activity of the Aurora and angiogenic kinase inhibitor ENMD-2076 against preclinical models of breast cancer with identification of candidate predictive biomarkers. Experimental Design: Twenty-nine breast cancer cell lines were exposed to ENMD-2076 and the effects on proliferation, apoptosis, and cell-cycle distribution were evaluated. In vitro activity was confirmed in MDA-MB-468 and MDA-MB-231 triple-negative breast cancer xenografts. Systematic gene expression analysis was used to identify up- and downregulated pathways in the sensitive and resistant cell lines, including within the triple-negative breast cancer subset. Results: ENMD-2076 showed antiproliferative activity against breast cancer cell lines, with more robust activity against cell lines lacking estrogen receptor expression and those without increased HER2 expression. Within the triple-negative breast cancer subset, cell lines with a p53 mutation and increased p53 expression were more sensitive to the cytotoxic and proapoptotic effects of ENMD-2076 exposure than cell lines with decreased p53 expression. Conclusions: ENMD-2076 exhibited robust anticancer activity against models of triple-negative breast cancer and the candidate predictive biomarkers identified in this study may be useful in selecting patients for Aurora kinase inhibitors in the future. Clin Cancer Res; 19(1); 291–303. ©2012 AACR.
European Journal of Cancer | 2013
Ursula A. Matulonis; Julie Lee; Brian Lasonde; William P. Tew; Afra Yehwalashet; Daniela Matei; Kian Behbakht; Jill Grothusen; Gini F. Fleming; Nita K. Lee; Jamie Arnott; Mark R. Bray; Graham C. Fletcher; Richard D. Brokx; Vincent Castonguay; Helen Mackay; Carolyn Sidor; Amit M. Oza
PURPOSE The purpose was to assess the activity and side effect profile of ENMD-2076, an oral anti-angiogenic and anti-proliferative kinase inhibitor, in platinum-resistant recurrent epithelial ovarian cancer (EOC), fallopian tube or peritoneal cancer. Archival tumour tissue was obtained for correlative analyses. EXPERIMENTAL DESIGN This was an open-label single-arm Phase II study of single agent ENMD-2076 taken daily orally (PO). The primary objective was to determine the progression free survival (PFS) rate at 6 months of ENMD-2076 in platinum-resistant cancer based on RECIST v1.1. Secondary objectives included response rate (RR), duration of response, overall survival (OS) and safety. An exploratory analysis of archival tissue for mitotic index and angiogenesis was conducted in an attempt to identify a sensitive or resistant patient phenotype. RESULTS 64 patients were enrolled, and the PFS rate at 6 months was 22% with a median time to progression of 3.6 months. The median number of prior regimens was 2. The most common adverse events were fatigue, hypertension and diarrhoea with the most common Grade 3/4 events being hypertension and fatigue. None of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples were predictive of greater benefit or resistance to ENMD-2076 treatment. CONCLUSIONS ENMD-2076 has activity in platinum-resistant ovarian cancer, and observed toxicities were similar to other PO kinase inhibitors. Additional studies with ENMD-2076 are warranted, especially in combination with active chemotherapeutic agents in platinum-resistant patients. Further work to determine appropriate biomarkers for ENMD-2076 should be incorporated into new clinical studies.
Journal of Medicinal Chemistry | 2015
Yong Liu; Yunhui Lang; Narendra Kumar B. Patel; Grace Ng; Radoslaw Laufer; Sze-Wan Li; Louise Edwards; Bryan T. Forrest; Peter Sampson; Miklos Feher; Fuqiang Ban; Donald E. Awrey; I. P. Beletskaya; Guodong Mao; Richard Hodgson; Olga Plotnikova; Wei Qiu; Nickolay Y. Chirgadze; Jacqueline M. Mason; Xin Wei; Dan Chi-Chia Lin; Yi Che; Reza Kiarash; Brian Madeira; Graham C. Fletcher; Tak W. Mak; Mark R. Bray; Henry W. Pauls
The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI50 < 0.1 μM), displayed low off-target activity (>500×), and microsomal stability (T(1/2) > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.
ACS Medicinal Chemistry Letters | 2016
Yong Liu; Radoslaw Laufer; Narendra Kumar B. Patel; Grace Ng; Peter Sampson; Sze-Wan Li; Yunhui Lang; Miklos Feher; Richard D. Brokx; I. P. Beletskaya; Richard Hodgson; Olga Plotnikova; Donald E. Awrey; Wei Qiu; Nickolay Y. Chirgadze; Jacqueline M. Mason; Xin Wei; Dan Chi-Chia Lin; Yi Che; Reza Kiarash; Graham C. Fletcher; Tak W. Mak; Mark R. Bray; Henry W. Pauls
This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K i = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.
Proceedings of the National Academy of Sciences of the United States of America | 2017
Jacqueline M. Mason; Xin Wei; Graham C. Fletcher; Reza Kiarash; Richard D. Brokx; Richard Hodgson; Irina Beletskaya; Mark R. Bray; Tak W. Mak
Significance At present, microtubule-targeting agents are the most important antimitotic drugs used in the clinic. However, there is an urgent need for the discovery of new approaches to more effectively target tumor cells with less toxicity. Emerging strategies for anticancer therapy include exploiting cell-cycle checkpoint vulnerabilities and genomic instability in cancer cells. The spindle assembly checkpoint (SAC) is important for cell survival, and its inactivation generates lethal genomic instability in cancer cells. Inhibition of SAC signaling through targeting of monopolar spindle 1 (Mps1) has provided an indication of the feasibility of such an approach. We report here the cellular and antitumor effects of CFI-402257, a potent and specific small-molecule inhibitor of Mps1. CFI-402257 is currently in a phase I clinical trial (ClinicalTrials.gov ID: NCT02792465). Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy. Here, we report the cellular and antitumor effects of CFI-402257, a potent (Mps1 Ki = 0.09 ± 0.02 nM; cellular Mps1 EC50 = 6.5 ± 0.5 nM), highly selective, and orally active small-molecule inhibitor of Mps1 that was identified through a drug-discovery program. Human cancer cells treated with CFI-402257 exhibit effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death. Oral administration of CFI-402257 in monotherapy or in combination with an anti-programmed cell death 1 (PD-1) antibody in mouse models of human cancer results in inhibition of tumor growth at doses that are well-tolerated. Our findings provide a rationale for the clinical evaluation of CFI-402257 in patients with solid tumors.
Bioorganic & Medicinal Chemistry Letters | 2016
Radoslaw Laufer; Sze-Wan Li; Yong Liu; Grace Ng; Yunhui Lang; Miklos Feher; Richard D. Brokx; Irina Beletskaya; Richard Hodgson; Guodong Mao; Olga Plotnikova; Donald E. Awrey; Jacqueline M. Mason; Xin Wei; Dan Chi-Chia Lin; Yi Che; Reza Kiarash; Brian Madeira; Graham C. Fletcher; Tak W. Mak; Mark R. Bray; Henry W. Pauls
TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0.8nM) and exceptional kinase selectivity. The SAR indicates a strong dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide moiety delineating the geometry for 1½ type kinase inhibitor. Molecular modeling indicates the extensive and optimal contacts, mediated through H-bonds and hydrophobic interactions, are responsible for the selectivity and potency of the inhibitors. The compounds demonstrate a strong anti-proliferative activity in a panel of human cancer cell lines (HCT116 GI50<15nM) and good rodent pharmacokinetics (oral %F 97%).
Cancer Research | 2016
Philippe L. Bedard; David W. Cescon; Graham C. Fletcher; Trish Denny; Richard D. Brokx; Peter Sampson; Mark R. Bray; Dennis J. Slamon; Tak W. Mak; Zev A. Wainberg
Background: CFI-400945 is a first-in-class, potent, selective, orally active inhibitor of Polo-like kinase 4 (PLK4) (Ki = 0.26 nM), a conserved master regulator of centriole duplication that is important for maintenance of genomic integrity. In preclinical studies, CFI-400945 demonstrated robust anti-tumor activity, including durable complete tumor regression, in a large number of patient-derived xenograft models from multiple tumor types (breast, ovarian, pancreas, prostate carcinomas; some derived from heavily pre-treated patients). The objectives of this first-in-human phase I trial are to establish safety, tolerability, pharmacokinetics, and recommended phase II dose (RP2D) of CFI-400945. Methods: Patients with advanced solid tumors age >18 years, with ECOG performance status of 0-1, adequate organ function and RECIST-measurable disease progressing on standard treatments are eligible. Dose escalation follows a standard 3+3 design, with a starting dose of 3mg once daily continuous oral dosing based upon preclinical data and a severely toxic dose to 10 percent (STD10) in rats of 3 mg/kg. The primary endpoint is the incidence of dose limiting toxicities (DLTs) during the first cycle. Safety assessments using CTCAE version 4.03 criteria are performed weekly during the first three cycles and then every two weeks. Response assessments are performed every two cycles. Results: From April/14 to December/15, 31 patients were enrolled across eight pre-defined dose levels (3, 6, 11, 16, 24, 32, 48 and 72 mg). No DLT events have been observed. Dose escalation at 96mg is currently ongoing. The most frequent treatment-related adverse events (trAEs) include fatigue (24%), diarrhea (17.2%), nausea (17.2%), decreased appetite (13.8%) and vomiting (6.9%). All trAEs were grade 1 or grade 2. Fifteen serious adverse events (SAEs) have occurred in 9 patients, all considered unrelated to CFI-400945 treatment. Preliminary PK results estimate a half-life of about 10 hours, with Cmax and AUC showing dose proportionality. Two patients enrolled at the 48 mg dose level have completed >6 cycles, including a patient with KRAS mutant colorectal cancer who achieved 24% reduction in target lesions and >50% reduction in serum CEA levels. Conclusions: CFI-400945 is well tolerated at doses up to 72mg with a favorable PK profile. Preliminary evidence of anti-tumor activity has been observed. Exploration of 96mg daily dosing is ongoing and once the RP2D has been established exploration of anti-tumor activity in biomarker-driven expansion arms of CFI-400945 in indications including advanced breast cancer is planned. Updated results of this ongoing trial will be presented at the meeting. Citation Format: Philippe L. Bedard, David W. Cescon, Graham Fletcher, Trish Denny, Richard Brokx, Peter Sampson, Mark R. Bray, Dennis J. Slamon, Tak W. Mak, Zev A. Wainberg. First-in-human phase I trial of the oral PLK4 inhibitor CFI-400945 in patients with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT066.