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Featured researches published by Fanying Meng.
Molecular Cancer Therapeutics | 2012
Fanying Meng; James W. Evans; Deepthi Bhupathi; Monica Banica; Leslie Lan; Gustavo Lorente; Jian-Xin Duan; Xiaohong Cai; Alexandra M. Mowday; Christopher P. Guise; Andrej Maroz; Robert F. Anderson; Adam V. Patterson; Gregory C. Stachelek; Peter M. Glazer; Mark D. Matteucci; Charles P. Hart
TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) of bromo-isophosphoramide mustard currently undergoing clinical evaluation. Here, we describe broad-spectrum activity, hypoxia-selective activation, and mechanism of action of TH-302. The concentration and time dependence of TH-302 activation was examined as a function of oxygen concentration, with reference to the prototypic HAP tirapazamine, and showed superior oxygen inhibition of cytotoxicity and much improved dose potency relative to tirapazamine. Enhanced TH-302 cytotoxicity under hypoxia was observed across 32 human cancer cell lines. One-electron reductive enzyme dependence was confirmed using cells overexpressing human NADPH:cytochrome P450 oxidoreductase and radiolytic reduction established the single-electron stoichiometry of TH-302 fragmentation (activation). Examining downstream effects of TH-302 activity, we observed hypoxia-dependent induction of γH2AX phosphorylation, DNA cross-linking, and cell-cycle arrest. We used Chinese hamster ovary cell–based DNA repair mutant cell lines and established that lines deficient in homology-dependent repair, but not lines deficient in base excision, nucleotide excision, or nonhomologous end-joining repair, exhibited marked sensitivity to TH-302 under hypoxia. Consistent with this finding, enhanced sensitivity to TH-302 was also observed in lines deficient in BRCA1, BRCA2, and FANCA. Finally, we characterized TH-302 activity in the three-dimensional tumor spheroid and multicellular layer models. TH-302 showed much enhanced potency in H460 spheroids compared with H460 monolayer cells under normoxia. Multicellular layers composed of mixtures of parental HCT116 cells and HCT116 cells engineered to express an oxygen-insensitive bacterial nitroreductase showed that TH-302 exhibits a significant bystander effect. Mol Cancer Ther; 11(3); 740–51. ©2011 AACR.
Cancer Biology & Therapy | 2015
Jessica Sun; Qian Liu; Dharmendra Ahluwalia; Wenwu Li; Fanying Meng; Yan Wang; Deepthi Bhupathi; Ayesha S. Ruprell; Charles P. Hart
Tumors often contain hypoxic regions resistant to chemo- and radiotherapy. TH-302 (T) is an investigational hypoxia-activated prodrug that selectively releases the DNA cross-linker bromo-isophosphoramide mustard under hypoxic conditions. This study evaluated the efficacy and safety profile of combining T with gemcitabine (G) and nab-paclitaxel (nP) in human pancreatic ductal adenocarcinoma (PDAC) xenograft models in mice. Antitumor activity of the G + nP + T triplet was assessed and compared with T-alone or the G + nP doublet in the Hs766t, MIA PaCa-2, PANC-1, and BxPC-3 PDAC xenograft models. Efficacy was assessed by tumor growth kinetic analysis. Body weight, blood cell counts, blood chemistry, and the von Frey neuropathy assay were analyzed to evaluate safety profiles. Pharmacodynamic changes after the treatment were determined by immunohistochemistry of cell proliferation, DNA damage, apoptosis, hypoxia, and tumor stroma density. The G + nP + T triplet exhibited enhanced efficacy compared with T-alone or the G + nP doublet. Compared with vehicle (V), G + nP induced body weight loss, reduced neutrophil and lymphocyte counts, increased the levels of liver function parameters, and induced neurotoxicity. However, when T was added to G + nP, there was no statistically increased impairment compared to G + nP. The triplet significantly increased DNA damage, apoptosis, and tumor necrosis. Furthermore, the triplet further inhibited cell proliferation and reduced stroma density and intratumoral hypoxia. The triplet combination of G + nP + T exhibited superior efficacy but additive toxicity was not evident compared to the G + nP doublet in this study. This study provides a translational rationale for combining G, nP, and T in the clinical setting to assess efficacy and safety. A Phase I clinical trial of the triplet combination is currently underway (NCT02047500).
Cancer Chemotherapy and Pharmacology | 2008
Fanying Meng; Xiaohong Cai; Jian-Xin Duan; Mark Matteucci; Charles P. Hart
PurposeSince anticancer agents that interfere with microtubule function are in widespread use and have a broad spectrum of activity against both hematological malignancies and solid tumors, there is an urgent need to develop novel tubulin inhibitors with broader activities and avoiding drug resistance.Methods and resultsIn this study, we describe the characterization of select lead compounds from a novel class of indazole-based tubulin inhibitors. Three lead compounds, TH-337, TH-482 and TH-494, exhibit potent antiproliferative activity against cell lines derived from human pancreatic carcinoma, human breast adenocarcinoma and human colorectal adenocarcinoma cells. The three compounds were also tested for cytotoxicity against a panel of clinically relevant drug resistant cancer cell lines that either overexpress the drug resistance pumps MDR-1, MRP-1 and BCRP-1 or have altered Topoisomerase II activity. TH-482 and -494 retained cytotoxic activities against all of the resistant cell lines tested; however, TH-337 exhibited decreased cytotoxicity in the cell line overexpressing BCRP-1, indicating that TH-337 is a substrate of that pump. We show that TH-482’s antiproliferative activity is due to cell cycle arrest at the G2/M phase. We demonstrate that TH-482 binds specifically to the colchicine site of tubulin and that it inhibits tubulin polymerization in vitro in a concentration-dependent manner. The in vitro anti-vascular activities of TH-482 were assessed using the HUVEC-C cell line. TH-482 inhibits in vitro neovessel formation and disrupts pre-established vessels using HUVEC-C cells. TH-482 also increases permeability of vascular endothelial cells in a concentration- and time-dependent manner.ConclusionsTH-482 demonstrates potent in vitro efficacy as a novel tubulin-targeted anti-proliferative and anti-vascular agent and notably is more potent in antiproliferative assays than the benchmark compound combretastatin A-4. These results identify TH-482 as a potent tubulin inhibitor, and support the investigation of its in vivo efficacy and pharmacokinetic properties as the prototype of a new class of anti-tubulin agents.
Journal of Medicinal Chemistry | 2011
Jian-Xin Duan; Xiaohong Cai; Fanying Meng; Jessica Sun; Qian Liu; Donald Jung; Hailong Jiao; Jackson V. Matteucci; Brian Jung; Deepthi Bhupathi; Dharmendra Ahluwalia; Heli Huang; Charles P. Hart; Mark Matteucci
14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.
BMC Cancer | 2015
Fanying Meng; Deepthi Bhupathi; Jessica Sun; Qian Liu; Dharmendra Ahluwalia; Yan Wang; Mark D. Matteucci; Charles P. Hart
BackgroundThe hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities.MethodsWe employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities.ResultsTH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination.ConclusionsTH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.
Molecular Cancer Therapeutics | 2009
Charles P. Hart; Andrew J. Armstrong; Elena G. Chiorean; Jessica Sun; Virginia K. Langmuir; Fanying Meng; Clarence Eng; Stewart Kroll; Mark D. Matteucci; John G. Curd
Hypoxia is a defining feature of solid tumors, including prostate cancer. Metastases also exhibit subregional hypoxia and micrometastases may be severely hypoxic. Hypoxic cells are known to be resistant to standard chemotherapies and thus play a role in treatment failure and disease relapse. TH‐302, a tumor‐selective hypoxia‐activated prodrug of the cytotoxic warhead bromo‐isophosphoramide mustard (Br‐IPM), is currently in clinical development for the treatment of advanced solid tumors. We explored the preclinical efficacy of TH‐302 in both in vitro and in vivo models of prostate cancer. Based on these translational results, we identified prostate cancer as an indication for further clinical investigations. Preclinically, TH‐302 demonstrated hypoxia‐selective cytotoxicity in the human prostate cancer cell lines PC‐3, LNCaP, and DU‐145. We explored in vivo prostate cancer efficacy in PC‐3 xenograft models that included (1) an ectopic subcutaneous model, (2) an orthotopic model, and (3) a model of bone and soft tissue prostate cancer metastases. TH‐302 demonstrated efficacy both as monotherapy and in combinations with taxanes in all three settings. The combination of TH‐302 and docetaxel in the disseminated prostate cancer metastases model demonstrated 100% complete responses in the 8 of 10 animals surviving to the end of the study at approximately 8 weeks. The TH‐302 Phase 1 dose escalation clinical trial established the monotherapy maximum tolerated dose (MTD) of TH‐302 dosed weekly for 3 weeks of a 4 week cycle at 575 mg/m2. Mucosal and skin toxicity were dose limiting, while hematologic toxicity was minimal. Evidence of anti‐tumor activity was observed including four RECIST responses in patients with small cell lung cancer and metastatic melanoma. In the ongoing Phase 1/2 combination therapy clinical trials of TH‐302, the MTD of TH‐302 was established at 340 mg/m2 when dosed at days 1 and 8 with docetaxel 75 mg/m2 on day 1 every 3 weeks. Neutropenia was dose‐limiting. In the first two patients with metastatic castration‐resistant prostate cancer (CRPC) treated with the combination of TH‐302 and docetaxel, PSA responses (a > 50% reduction from baseline) have been observed along with a marked reduction in cancer‐related pain in one of the patients. An additional 12 CRPC patients will be enrolled. These translational studies and early clinical findings indicate that the addition of TH‐302 to docetaxel may be a promising new treatment option for prostate cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B185.
Cancer Research | 2015
Jessica Sun; Fanying Meng; Qian Liu; Dharmendra Ahluwalia; Wenwu Li; Yan Wang; Deepthi Bhupathi; Charles P. Hart
Background: TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Checkpoint kinase 1 (Chk1) plays a key role in the activation of the DNA damage checkpoint in the cell cycle. We investigated the association between Chk1 inhibitor AZD7762′s-mediated modulation of select downstream pharmacodynamic (PD) biomarkers and potentiation of TH-302 efficacy in the HT29 xenograft model. Material and methods: HT29 ectopic human colorectal xenograft model was employed. Six animals per group were treated with Vehicle (V), TH-302 (T) at 150 mg/kg on Day 1, AZD7762 (A) at 25 mg/kg on Day 1 and 2, or T + A. Two dosing schedules were used in the combination: 1), A was given first, and 4 h and 24 h later, T and A was dosed, respectively (ATA); and 2), T was given first, and 4 h and 24 h later, A was dosed (TAA). The PD biomarkers were evaluated by immunohistochemistry (IHC) on the samples collected on Day 3. In a separate efficacy study, ten animals per group were treated with V, T at 100 mg/kg on Day 1, 4/wk x 2wks, A at 20 mg/kg on Day 1, 2, 4 and 5/wk x 2wks, ATA or TAA combination. Antitumor activity was assessed by tumor growth inhibition (TGI). Results: The biomarker study showed phosphorylated Chk1 (Ser345), γH2AX-positive cells (DNA damage), and Caspase-3 positive cells (apoptosis), were significantly increased in ATA, compared with V, A, T or TAA (p Conclusion: The results suggest that the Chk1 inhibitor A potentiates the efficacy of T in a dose schedule-dependent manner, consistent with dose schedule dependent modulations of PD biomarkers. The detailed mechanistic analysis indicates that the sensitization is due to both disruption of the Chk1 mediated DNA damage checkpoint of the cell cycle and the induction of apoptosis. These studies provide additional support to the preclinical translational rationale for combining TH-302 with Chk1 inhibitors in the clinical trial setting. Citation Format: Jessica D. Sun, Fanying Meng, Qian Liu, Dharmendra Ahluwalia, Wenwu Li, Yan Wang, Deepthi Bhupathi, Charles P. Hart. Association between Chk1 inhibitor AZD7762-mediated modulation of pharmacodynamic biomarkers and potentiation of hypoxia-activated prodrug TH-302 antitumor efficacy in a human tumor xenograft model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2424. doi:10.1158/1538-7445.AM2015-2424
Translational Oncology | 2018
Sushil Kumar; Jessica Sun; Libo Zhang; Reza Bayat Mokhtari; Bing Wu; Fanying Meng; Qian Liu; Deepthi Bhupathi; Yan Wang; Herman Yeger; Charles P. Hart; Sylvain Baruchel
Antiangiogenic therapy has shown promising results in preclinical and clinical trials. However, tumor cells acquire resistance to this therapy by gaining ability to survive and proliferate under hypoxia induced by antiangiogenic therapy. Combining antiangiogenic therapy with hypoxia-activated prodrugs can overcome this limitation. Here, we have tested the combination of antiangiogenic drug sunitinib in combination with hypoxia-activated prodrug evofosfamide in neuroblastoma. In vitro, neuroblastoma cell line SK-N-BE(2) was 40-folds sensitive to evofosfamide under hypoxia compared to normoxia. In IV metastatic model, evofosfamide significantly increased mice survival compared to the vehicle (P=.02). In SK-N-BE(2) subcutaneous xenograft model, we tested two different treatment regimens using 30 mg/kg sunitinib and 50 mg/kg evofosfamide. Here, sunitinib therapy when started along with evofosfamide treatment showed higher efficacy compared to single agents in subcutaneous SK-N-BE(2) xenograft model, whereas sunitinib when started 7 days after evofosfamide treatment did not have any advantage compared to treatment with either single agent. Immunofluorescence of tumor sections revealed higher number of apoptotic cells and hypoxic areas compared to either single agent when both treatments were started together. Treatment with 80 mg/kg sunitinib with 50 mg/kg evofosfamide was significantly superior to single agents in both xenograft and metastatic models. This study confirms the preclinical efficacy of sunitinib and evofosfamide in murine models of aggressive neuroblastoma. Sunitinib enhances the efficacy of evofosfamide by increasing hypoxic areas, and evofosfamide targets hypoxic tumor cells. Consequently, each drug enhances the activity of the other.
Cancer Research | 2016
Fanying Meng; Deepthi Bhupathi; Geraldine Chan; Charles P. Hart
Cisplatin is one of the most widely used anticancer agents for the treatment of an array of malignancies. Although multiple mechanisms are involved in cisplatin efficacy, the most prominent and best understood modes of action are the generation of DNA lesions and induction of apoptosis and mitochondrial reactive oxygen species (ROS)-dependent effects on mitochondrial integrity. However, intrinsic or acquired cisplatin resistance can become a limiting factor in cisplatin-based therapy. Evofosfamide is a hypoxia-activated prodrug that is reduced at its nitroimidazole group and preferentially under hypoxic conditions releases Br-IPM, a DNA cross-linker. Evofosfamide is currently being investigated in multiple clinical trials for the treatment of cancer including indications and settings where resistance to cisplatin is observed (e.g. second-line non-small cell lung cancer; NCT01403610). We have previously demonstrated both shared and distinct DNA repair pathways involved with evofosfamide and cisplatin DNA damage. In the current study, we have conducted comparative studies to identify any distinctions in the relative role of ROS underlying cell sensitivity to cisplatin and evofosfamide to help evaluate the potential of evofosfamide to treat cisplatin-resistant tumors. The cisplatin-sensitive cervical cancer cell line ME180, the intermediate cisplatin-resistant human ovarian cancer cell line SK-OV-3, and cisplatin-resistant human lung cancer cell line A549 were investigated with respect to their chemosensitivity to evofosfamide. Unlike cisplatin, evofosfamide exhibited similar potency across all three cell lines. Addition of the ROS scavenger N-acetyl-L-cysteine (NAC) reduced the potency of cisplatin- but not evofosfamide-mediated cytotoxicity, indicating ROS plays a role in cytotoxicity mediated by cisplatin, but not evofosfamide. ROS levels were investigated using the dye H2DCFDA. Cisplatin induced a concentration-dependent and NAC-inhibitable increase of cellular ROS in cisplatin-sensitive ME-180 cells but not in cisplatin-resistant A549 cells. In contrast, ROS levels were not affected by the addition of evofosfamide under normoxia and hypoxia in both ME180 and A549 cells. In order to ascertain whether mitochondrial pathway-mediated apoptosis was involved in cytotoxicity mediated by evofosfamide and cisplatin, mitochondrial membrane depolarization was investigated with the dye JC-1. Cisplatin induced a concentration-dependent JC-1 polarization and these effects were abolished by NAC. In contrast, evofosfamide did not affect mitochondrial membrane potential. In conclusion, this data demonstrates that ROS is an essential factor in cisplatin-mediated cytotoxicity, but not in evofosfamide-mediated cytotoxicity. Citation Format: Fanying Meng, Deepthi Bhupathi, Geraldine Chan, Charles P. Hart. Distinct roles of intracellular ROS in cisplatin and evofosfamide cytotoxicity. [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 2803.
Cancer Research | 2016
Jian-Xin Duan; Zhong Wang; Qing Li; Yeyu Cao; Ping He; Fanying Meng; Changhua Zhou; Yanhong Wang; Gavin Jiagui Qu; Henry Li; Jiang Li; Meng Yang; Hui Qi; Don Jung; Mei Song; Mark Matteucci
Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the reduction of a diverse group of substrates, including prostaglandin (PG) D2 and PGH2. It has been reported that AKR1C3 is overexpressed in the majority of hepatocellular carcinomas (HCC) with 58% of HCC patient surgical tumor samples having strong expression of the enzyme1. Tumors overexpressing AKR1C3 can be resistant to radiation therapy2 and chemotherapies3. AKR1C3 is also expressed in normal tissues,but its expression is much lower than in HCC tissue1. HCC is the sixth most common cause of cancer. It has very poor prognosis, and is the second leading cause of cancer death in all cancers. Treatment options for late stage liver cancer are very limited, with Sorafenib, a multi-tyrosine kinase inhibitor, being the only approved drug with limited efficacy. More effective therapies are urgently needed. TH3424 is a prodrug which selectively releases a DNA alkylating agent upon exposure to activated AKR1C3. In vitro cell proliferation tests with TH3424 in several HCC cell lines showed that it is very potent (IC50 ≤ 10 nM with 2 hour exposure) in killing cancer cells with high levels of AKR1C3, but less active (IC50 ≥ 10 μM) in killing cells with low or no AKR1C3 reductase. The activity of TH3424 correlates with the expression level of AKR1C3 as the potency of TH3424 is inhibited when used with a specific AKR1C3 inhibitor:4 (IC50: 4 nM vs 6.3 μM with SN33638) in a non-small cell lung cancer cell line (H460). In vivo orthotopic and patient derived disease (PDX) liver cancer model studies have shown promising efficacy with TH3424 being administer weekly with doses as low as 1.5mg/kg. TH3424 showed better efficacy than Sorafenib in an orthotopic HepG2 mouse model. Three of 8 mice treated with TH3424 at 2.5 mg/kg, Q7Dx3, and 8 of 8 mice treated with TH3424 at 5 mg/kg, Q7Dx3 were tumor free at day 35. Reference:1: Guise C. P.; Abbattista M. R.; Singleton R. S.; Holford S. D.; Connolly J.; Dachs G. U.; Fox S. B.; Rollock R.; Harvey J.; Guiford P.; Daňate F.; Wilson W. R.; and Patterson A. V.; Cancer Res.70(4), 2010, 1573 2: Xiong W.; Zhao J.; Yu H.; Li X.; Sun S.; Li Y.; Xia Q.; Zhang C.; He Q.; Gao X.; Zhang L.; Zhou D.; Plos One, V. 9 (11), 2014, e111911 3: Liu C.; Lou W.; Zhu Y.; Yang J.; Nadiminty N.; Gaikwad N.; Evans C.; Gao A.; Cancer Res.; 2015, 75(7), 1413 4: Flanagan J. U.; Atwell G. J.; Heinrich D. M.; Brooke D. G.; Silva S.; Rigoreau L. J. M.; Trivier E.; Turnbull A. P.; Raynham T.; Jamieson S. M. F.; Denny W. A.; Bioorg. Med. Chem.; 22(2014); 967 Citation Format: Jianxin Duan, Zhong Wang, Qing Li, Yeyu Cao, Ping He, Fanying Meng, Changhua Zhou, Yanhong Wang, Gavin Qu, Henry Li, Jiang Li, Meng Yang, Hui Qi, Don Jung, Mei Song, Mark Matteucci. In vitro and in vivo antitumor activity of TH3424: Preclinical rationale for a highly selective AKR1C3 prodrug for treating hepatocellular carcinomas. [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 1369.