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  • American Association for Cancer Research (AACR)  (12)
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  • 1
    Online Resource
    Online Resource
    Abstract 3371: Preclinical disposition and pharmacokinetics of volitinib, a novel selective cMet inhibitor .
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3371-3371
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3371-3371
    Abstract: Volitinib is a novel selective cMet inhibitor. This study is to evaluate its preclinical ADME/PK profile. Volitinib has high membrane permeability (Papp (A & gt;B) 28×10−6 cm/s) without efflux transport across Caco-2 cell monolayer and exhibits negligible P-gp inhibition (IC50 & gt; 17 μM). Metabolic stability of volitinib in liver microsomes and S9 fractions of rat, dog, monkey and human was evaluated. Five phase I metabolites were observed in liver microsomes and S9 fractions of different species, and three major metabolites resulted from demethylation (M1), hydroxylation (M2) and mono-oxygenation (M3) were found to be mediated by multiple enzymes, including CYP450s and aldehyde oxidase. Rat was the most similar species to human in terms of the in vitro metabolism and metabolite profile. Metabolism is the main route of elimination for volitinib in rat due to the fact that the fecal, urinary and biliary excretion of the parent volitinib accounted for & lt;2% of the dose. The total of 16 phase I metabolites and 8 phase II metabolites were identified in plasma and excreta of rat. M22, a sulfate conjugate of a monooxidized metabolite M5, dominated with the abundance in all tested matrices. Demethylation to M2 excreted in urine was also an important elimination pathway in rat. Volitinib showed no significant reversible or mechanism-based CYP inhibition in human liver microsomes, and no induction of CYP1A2 and CYP3A4 in human hepatocytes. Volitinib had moderate plasma protein binding rate (60%∼70% in rat, dog, and human; 40% in mouse; 80% in monkey) and exhibited wide distribution to different organs in rat, with high exposures in liver and kidney, very low in brain, spinal cord and testis comparing to the plasma level. In PK studies in mouse, rat and dog, Volitinib showed the rapid oral absorption (Tmax & lt;2.5 h) with high exposures and the acceptable bioavailability at 27.2%, 42.6% and 86.3%, respectively. The in vivo clearance (CL) was 11.0, 11.8 and 3.5 mL/min/kg in mouse, rat and dog, respectively, revealing a low extraction ratio. The volume of distribution in steady state (Vss) was 0.4, 1.4 and 1.4 L/kg in those species, respectively, indicating a moderate to low distribution pattern. Volitinib also displayed linear pharmacokinetics (PK) in the dose ranges of 1 to 25 mg/kg in rat and 2 to 10 mg/kg in dog. Food hardly affected its PK profile in dog. In contrast, volitinib in monkey showed a notably high extraction ratio (CL=17.2 mL/min/kg) consistent with the in vitro metabolism result. Considering the rapid absorption of volitinib (Tmax=1.9 h) and moderately low distribution (Vss=0.7 L/kg), the poor oral bioavailability (1.9%) of volitinib in monkey is considered to be the result of excessive first-pass extraction. Overall, volitinib exhibited favorable preclinical PK/ADME properties. Citation Format: Yi Gu, Yang Sai, Jian Wang, Sumei Xia, Guanglin Wang, Yuansheng Zhao, Li Zhang, Wenqing Yang, Guangxiu Dai, Weihan Zhang, Qisun Gong, Zhenping Tian, Weiguo Su. Preclinical disposition and pharmacokinetics of volitinib, a novel selective cMet inhibitor . [abstract] . In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3371. doi:10.1158/1538-7445.AM2013-3371
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3371
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
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    Abstract C160: HMPL-653, a highly potent and selective CSF-1R inhibitor, targeting both tumor cells and tumor microenvironment
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 12_Supplement ( 2023-12-01), p. C160-C160
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. C160-C160
    Abstract: Background: Colony stimulating factor 1 receptor (CSF-1R) and its ligand CSF-1 (CSF-1R/CSF-1) signaling regulates the function and survival of tumor-associated macrophages (TAM), which are involved in tumor progression and suppression of anti-tumor immunity. Moreover, activation of CSF-1R/CSF-1 axis including CSF-1 fusions or CSF-1R activating mutations has also been implicated in the pathogenesis of certain tumors such as tenosynovial giant cell tumor and histiocytic neoplasms. HMPL-653 is a highly potent and selective CSF-1R small molecule inhibitor, discovered and being currently developed in phase I clinical trial (NCT05277454) by HUTCHMED. Methods: The inhibition on CSF-1R kinase was determined using Z-LYTE™ kinase assay. The selectivity of HMPL-653 was assessed against a panel of 413 kinases by Eurofins. Cellular target inhibition on phosphorylation of CSF-1R (p-CSF-1R) was detected by ELISA. In vitro cell viability was measured by CCK-8 assay. Multiple CSF-1/CSF-1R driven tumor models in Nu/Nu nude mice were applied to determine the anti-tumor activity of HMPL-653 as a single agent. To demonstrate the immunoregulatory effect of HMPL-653, a murine tumor model, B16F10, was established in C57BL/6J mice, and the combination regimen, HMPL-653 plus PCP (poly (I:C)+CpG+anti-PD-1) was evaluated. Results: HMPL-653 strongly inhibited CSF-1R kinase with IC50 of 5 nM, showing & gt;7-fold potency than that of the approved CSF-1R inhibitor pexidartinib (IC50=39 nM). And the selectivity profiling in 413 kinase panels revealed that HMPL-653 was highly potent only against CSF-1R, indicating a lower off-target risk than paxidatinib reported. HMPL-653 potently inhibited CSF-1 stimulated p-CSF-1R in THP-1 cells with IC50 of 5 nM. In CSF-1/CSF-1R-dependent cell lines, M-NFS-60 (mouse myelogenous leukemia) and three cell lines stably expressed BCR-CSF-1R or CSF-1R mutations (Ba/F3-BCR-CSF-1R, Ba/F3-CSF-1RW450-E456del, and Ba/F3-CSF-1RY546-K551del), HMPL-653 significantly down regulated p-CSF-1R and its downstream signaling p-ERK and p-AKT. As a consequence, HMPL-653 robustly inhibited the cell viability of above cell models (IC50s: 3~40 nM). Besides the direct anti-tumor effect, HMPL-653 also demonstrated strong inhibition on macrophage survival and M2 macrophage polarization, indicating a potential effect on targeting tumor microenvironment. In vivo, oral administration of HMPL-653 induced remarkable and dose-dependent anti-tumor efficacies in M-NFS-60 ascites model and subcutaneous tumor models harboring above mentioned CSF-1R alterations. And the PK/PD analysis revealed that the anti-tumor effect correlated well with p-CSF-1R inhibition. Moreover, HMPL-653 significantly improved the anti-tumor activity of PCP regimen in B16F10 model by reducing TAMs including M2 macrophages and increasing the ratio of M1/M2 macrophages. Conclusion: HMPL-653 is a highly potent and selective CSF-1R small molecule inhibitor which targets both CSF-1/CSF-1R-dependent tumors and tumor associated macrophages, warranting further clinical evaluation. Citation Format: Jia Hu, Liang Ge, Hui Zhang, An Jiang, Juntao Yu, Weifang Xue, Jian Wang, Yang Sai, Na Yang, Weiguo Qing, Yongxin Ren, Michael Shi, Weiguo Su. HMPL-653, a highly potent and selective CSF-1R inhibitor, targeting both tumor cells and tumor microenvironment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C160.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-23-C160
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 16 ( 2019-08-15), p. 4924-4932
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 16 ( 2019-08-15), p. 4924-4932
    Abstract: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). Patients and Methods: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, Cmax was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. Conclusions: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-1189
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
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  • 4
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    Abstract A094: Preclinical characterization of HMPL-415, a second-generation SHP2 inhibitor
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 12_Supplement ( 2023-12-01), p. A094-A094
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. A094-A094
    Abstract: Background: Oncogenic activation of the RAS/MAPK signaling pathway is one of the leading causes for driving a variety of cancers. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) functions downstream of multiple RTKs, and integrates growth factor signals to promote RAS activation, making it an attractive drug target for cancers harboring oncogenic alterations in RAS/MAPK pathway. Herein, we present the preclinical characterization of HMPL-415, a highly potent, selective and non-competitive SHP2 inhibitor, discovered and being currently developed in phase I clinical trial (NCT05886374) by HUTCHMED. Methods: The inhibition of HMPL-415 on the full length and catalytic domain of SHP2 was detected by a biochemical DIFMUP pseudosubstracte-fluorgenic assay. For selectivity, HMPL-415 was assessed against a panel of 413 kinases and 21 phosphatases by Eurofins. The modulation of HMPL-415 on RAS/MAPK signaling cascades was evaluated by western blot. In vitro anti-proliferation activity was measured by CellTiter-Glo luminescent assay. Multiple human xenograft tumors with RAS/MAPK pathway activation were applied in immune-deficient mice to investigate the anti-tumor activity of HMPL-415. Results: In vitro, HMPL-415 displayed higher potency in enzyme (5 fold) and cellular target inhibition ( & gt; 20 fold) compared to first-generation SHP inhibitor TNO155. It strongly inhibited full length of human SHP2 with an IC50 of 0.4 nM, while had no inhibitory activity up to 10 µM against the catalytic domain of SHP2. In NCI-H358 (KrasG12C), NCI-H508 (class Ⅲ BRAFG596R), and NCI-H1838 (NF1N184fs) cells, HMPL-415 inhibited p-ERK with IC50s of 1~3 nM, and significantly suppressed downstream molecules p-RSK and p-S6. Through inhibition of RAS/MAPK signaling pathway, HMPL-415 robustly inhibited cell proliferation in a panel of human cancer cell lines with KRAS G12C/V, BRAF class Ⅲ, NF1 loss of function (LOF), RTK mutations or KRAS amplification (median GI50 =1 nM) compared to cell lines harboring KRAS G12D, G13 or Q61 mutations (median GI50 & gt;1 µM), indicating a dependence on specific KRAS nucleotide-cycling for anti-tumor effect. Furthermore, the selectivity across panels of 413 kinases and 21 phosphatases revealed that HMPL-415 should have a low off-target risk. In vivo, oral administration of HMPL-415 showed prolonged and high tumor exposure and sustained inhibition on RAS/MAPK signaling after repeat dosing. In human xenograft models carrying KRAS, BRAF class Ⅲ, NF1LOF, and EGFR alterations, HMPL-415 dose-dependently induced tumor growth inhibition at continuous daily doses that were well tolerated. Tumor regression was observed in most tumor models tested at the dose of 3 mg/kg/day, which demonstrated much superior anti-tumor activity than that of TNO155 at 30 mg/kg/day. Conclusion: HMPL-415 is a highly potent, selective and non-competitive SHP2 inhibitor that demonstrates strong anti-tumor activity in vitro and in vivo, supporting further clinical evaluation. Citation Format: Jia Hu, Jun Ni, Zhihu Gao, Xiaoqing Liu, Hui Zhang, Pan Wang, Min Cheng, Guanglin Wang, Zeyu Zhong, Jian Wang, Yang Sai, Na Yang, Weiguo Qing, Yongxin Ren, Michael Shi, Weiguo Su. Preclinical characterization of HMPL-415, a second-generation SHP2 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A094.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-23-A094
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract 6321: HMPL-453, a highly selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays potent activity in FGFR-altered tumor models
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6321-6321
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6321-6321
    Abstract: Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate numerous cellular processes. Dysregulation of FGFR signaling due to receptor fusion, mutation or amplification is observed across multiple cancer types, making activated FGFRs an important therapeutic target. Herein, we present the preclinical characterization of HMPL-453, a highly potent and selective inhibitor of FGFR1, 2, and 3, discovered and being currently developed in phase II clinical trial (NCT04353375) by HUTCHMED. Methods: Kinase activity was measured by Transcreener™ Fluorescence Polarization assay or Z’-LYTE kinase assay. In vitro anti-proliferation activity was measured by CellTiter-Glo luminescent or CCK-8 assay. The effect of HMPL-453 on FGFR signaling pathway was detected by western blot. Multiple tumor models with FGFR alteration were applied in Nu/Nu nude mice to determine anti-tumor efficacy of 453 as a single agent. A model in immune-competent BALB/c mice inoculated with the constructed NIH/3T3 cells carrying FGFR2-AHCYL1 fusion was chosen to investigate the combination effect of HMPL-453 with anti-PD-1 antibody. Results: HMPL-453 potently inhibited the tyrosine kinase activities of recombinant FGFR 1, 2, and 3 in vitro (IC50 values of 6, 4, and 6 nM, respectively) with weaker activity against FGFR4 (IC50 = 425 nM). HMPL-453 selectively inhibited proliferation of tumor cell lines with dysregulated FGFR signaling (GI50s: 3~105 nM) compared with cell lines lacking FGFR aberrations (GI50s & gt; 1.5 µM). HMPL-453 demonstrated strong inhibition of phosphorylation of FGFR and downstream protein in tumor cell lines harboring FGFR2 fusion. Oral administration of HMPL-453 could induce time- and dose-dependent inhibition of phosphorylation of FGFR and resulted in remarkable and dose-dependent anti-tumor activity in multiple FGFR-altered tumor models. HMPL-453 at the dose of 50 mg/kg/day could induce tumor regression in most tumor models tested. Moreover, HMPL-453 significantly improved anti-tumor activity of anti-PD-1 antibody in a FGFR2 fusion model by priming the immune environment. Conclusion: HMPL-453 is a highly potent and selective inhibitor of FGFR 1, 2, and 3 with strong activity against FGFR-deregulated tumors in preclinical models, supporting continued investigation in patients with FGFR alterations (such as fusion and mutation) either as a single agent or in combination with PD-1 blockade. Citation Format: Jia Hu, Jun Ni, Longxian Jiao, Jinghong Zhou, Shiming Fan, Renxiang Tang, Wei Zhang, Xuelei Ge, Qihang Zhang, Juntao Yu, Ying Yu, Dongxia Shi, Min Cheng, Weifang Xue, Sumei Xia, Zeyu Zhong, Jian Wang, Yang Sai, Weiguo Qing, Guangxiu Dai, Yongxin Ren, Michael Shi, Weiguo Su. HMPL-453, a highly selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays potent activity in FGFR-altered tumor 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 6321.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6321
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract 1797: Preclinical evaluation of HM-018, a potent and selective JAK inhibitor in the treatment of myloproliferative disorders
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1797-1797
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1797-1797
    Abstract: JAK2 kinase mutation V617F is prevalent in myeloproliferative diseases (MPD), including polycythemia vera (PV, 81-99%), essential thrombocytosis (ET, 41-72%) and primary myelofibrosis (PMF, 39-57%). This point mutation constitutively activates the JAK kinase and leads to oncogenic potential of host cells, and thus making JAK2 a promising molecular target for MPD therapy. HM-018 is a small molecule inhibitor against JAK kinase and the compound's preclinical anti-MPD effects from signal transduction to biological consequences were investigated. HM-018 was found to inhibit JAK kinase 1, 2, 3 and TYK with IC50 of 0.010, 0.006, 0.040 and 0.047 μM, respectively. The compound demonstrated & gt;100 folds selectivity against a panel of 63 kinases. In accordance with enzymatic activity, HM-018 suppressed ligand dependent or constitutive JAK activation in multiple cell lines as evidenced by the decrease of STAT3/5 phosphorylation. As a result, JAK dependent cell proliferation was significantly inhibited by HM-018. EPO-mediated mouse PV model was utilized to evaluate the in vivo efficacy of the compound. HM-018 could shrink enlarged mouse spleen, a typical symptom of PV, in a dose dependent manner accompanied with decreased STAT5 phosphorylation both in animal spleen and in bone marrow after oral dosing for 7 days. To better mimic MPD development in a more clinically-relevant manner, JAK2-V617F-tranfected 32D cells were injected into mice intravenously, and it was observed that oral treatment of HM-018 not only prolonged the animal's life span, but also reduced MPD-related symptoms, such as spleen weight increase and organ invasion by malignant cells. Meanwhile, HM-018 exhibited a favorable pharmacokinetic profile and acceptable safety window in rats. Based on the preclinical data, HM-018 demonstrated anti-MPD potency both in vitro and in vivo, and the studies have provided rationale to further develop this compound as possible MPD therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1797. doi:1538-7445.AM2012-1797
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1797
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
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  • 7
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    Abstract 4499: HM5016699, a novel and selective PI3K/mTOR dual inhibitor
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4499-4499
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4499-4499
    Abstract: PI3KCA gene amplification and mutations have been identified in many types of tumors, suggesting the dysregulation of PI3K/AKT/mTOR axis plays pivotal roles in tumorigenesis and development. Reported here is the discovery of HM5016699 as a potent, reversible ATP-competitive PI3K/mTOR dual inhibitor for treatment of cancer. HM5016699 showed potent kinase inhibition with IC50 of 0.01, 0.206, 0.052, 0.051 and 0.059 µM on PI3Kα, β, γ, Δ and mTOR, respectively. It demonstrated high selectivity on PI3K family and mTOR over a panel of 274 kinases. Of the 67 tumor cell lines screened from lung, colon, breast, ovarian, and other tumor types, we found that the tumor cells with HER2 gene amplification or PTEN loss tended to be sensitive to HM5016699, while the tumor cells harboring PI3KCA mutations and wild type Ras/Raf were mostly sensitive to the compound. HM5016699 could also show p-Erk inhibition and apoptotic induction at higher concentrations in the tumor cells harboring Ras/Raf mutations, suggesting it might bring benefits to patients carrying Ras/Raf mutations in the clinic. Consistent with in vitro studies, HM5016699 exhibited dose dependent tumor growth inhibition on multiple human xenografts models. It was found that the tumors with PIK3CA mutation or PTEN deletion were highly sensitive to HM5016699 with ED50s ranging from 0.6 to 1.8 mg/kg in U87MG (pTEN null), SKOV3 (H1047) and H1975 (G118D), whereas in tumors with Ras/Raf mutations, such as DLD-1(G13D), A549 (G12S) and HT-29(V600E), its ED50s were from 3.0 to 15.0 mg/kg. The decreased phosphorylation of AKT and S6 was observed in the tumor xenograft tissues treated with HM5016699, which was well-correlated with compound exposure. Therefore, we concluded that HM5016699 demonstrated both in vitro and in vivo activity through acting on PI3K/mTOR pathway. HM5016699 exhibited a favorable pharmacokinetic profile and acceptable safety window in rats. The pre-clinical study results suggest that HM5016699 could be a promising anti-cancer agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4499. doi:10.1158/1538-7445.AM2011-4499
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-4499
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 8
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    Abstract 1808: HM-032, a novel PI3K/mTOR dual inhibitor, is active on K-Ras/Raf mutation tumors through up-regulation of Bim
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1808-1808
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1808-1808
    Abstract: PIK3CA gene amplification and mutations have been identified in many types of tumors, suggesting the deregulation of PI3K/AKT/mTOR axis plays pivotal roles in tumorigenesis and development. K-Ras/Raf mutation is recognized as one of the key drug resistant factors for tumors against TKIs. HM-032 was reported here as a potent, selective and reversible ATP-competitive PI3K/mTOR dual inhibitor with special apoptotic activity in tumor cells harboring K-Ras mutations. HM-032 showed potent kinase inhibition with IC50 of 0.0008, 0.002, 0.001, 0.002 and 0.001 µM on PI3Kα, β, δ, ≤ and mTOR, respectively. In human prostate PC3 cells, it inhibited p-AKTS473, p-S6 and p-4EPB1 with IC50s of 0.002, 0.015 and 0.056 μM. Of the 89 tumor cell lines from lung, colon, breast, ovarian, and other tumor types, it was found that tumor cells with HER2 gene amplification, or PIK3CA mutation were relatively more sensitive to HM-032. Attractively, HM-032 showed apoptotic induction activity in the tumor cells harboring Ras/Raf mutations through inhibiting p-Erk and increasing gene expression of pro-apoptotic protein Bim. This result suggested that HM-032 might bring benefits to patients carrying K-Ras/Raf mutations in the clinic. Consistent with in vitro studies, HM-032 exhibited significant tumor growth inhibition in a dose dependent manner on multiple human xenograft models, including breast tumor MDA-MB-361(PIK3CAE545K, Her2 amplification), lung tumors H460 (PIK3CAE545K, K-RasQ61H) and A549 (LKB1 del, K-RasG12S), and glioblastoma U87MG (PTEN del) after 3 weeks oral dosing. Correspondingly, decrease of p-AKT and p-S6 was observed in the tumor xenograft tissues upon treatment with HM-032. In addition, HM-032 exhibited unique in vivo PK properties characterized by low clearance and long t1/2, which supported the intermittent dosing schedule in xenograft models. Based on the pre-clinical study results, HM-032 is anticipated to be a promising agent against solid tumors including carrying Ras/Raf mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1808. doi:1538-7445.AM2012-1808
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1808
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
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  • 9
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    Abstract 2413: Phase I study of safety and pharmacokinetics of fruquintinib, a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with advanced solid tumors.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2413-2413
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2413-2413
    Abstract: Background: Fruquintinib is a novel oral small molecule compound discovered and developed by Hutchison MediPharma that selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has demonstrated potent inhibitory effects on multiple human tumor xenografts. This first-in-human study was conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs), safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of fruquintinib. Methods: This phase I study used a 3+3 design for dose-escalation of fruquintinib given once daily continuously (QD) or 3 weeks on and 1 week off in 28-day cycles in patients with solid tumors who had failed standard therapies. Endpoints included safety, PK, and preliminary efficacy measurements. Results: Forty patients were enrolled in 5 dose cohorts of 1-6 mg QD and 2 dose cohorts of 5mg and 6mg 3 wks on/1 wk off, with age 18-70 yr, 40% male, ECOG 0-1 and heavily pretreated cancers. Tumor types included CRC (12), breast (8), NSCLC (7), thyroid (3), gastric (2) and others (8). The most common adverse events (all grades) were hand-foot syndrome (HFS), elevation of serum thyroid stimulating hormone (TSH), stomatitis, hypertension, white blood cell decreased, proteinuria, hoarseness, fatigue, and diarrhea, each observed in ≥ 30% pts. Grade 3/4 AEs were relatively uncommon, with HFS and hypertension the only AEs occurred in ≥ 10% pts (15% for each). Only 6 pts terminated study treatment due to related AEs. 6 DLTs were observed: 2 grade 3 HFS both at 6mg, 1 grade 3 HFS and 1 grade 3 thrombocytopenia with subcutaneous bleeding at 5mg, 1 grade 3 hyperbilirubinemia at 4mg and 1 grade 3 fatigue at 6mg 3wks on/1 wk off. MTD was determined as 4mg QD or 6mg 3wks on/1 wk off. PK analysis showed good and rapid absorption followed by slow terminal elimination with a half-life of approximately 42 hours which was consistent across all dose groups. Both Cmax and AUC exhibited good dose proportionality over the studied dose range with low inter-patient variability following single and multiple doses. 34 patients were evaluable for tumor response, including 13 with confirmed partial response (PRs: 4 NSCLC, 3 CRC, 2 breast, 1 gastric, 1 pNET, 1 glandula submandibularis and 1 nasopharyngeal); and 15 with stable disease (SDs: 14 were 3-9 months). Conclusions: Fruquintinib was well tolerated at doses up to 4mg QD or 6mg 3wks on/1 wk off, and demonstrated excellent pharmacokinetic properties. Impressive clinical activity including durable PR and SD was observed in majority of patients with various heavily pre-treated advanced cancers. These promising results warrant further clinical development of fruquintinib. Citation Format: Jin Li, Junning Cao, Jian Zhang, Zhiyu Chen, Wei Peng, Songhua Fan, Charlie Qi, Yi Gu, Yang Sai, Hua Mu. Phase I study of safety and pharmacokinetics of fruquintinib, a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2413. doi:10.1158/1538-7445.AM2013-2413
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2413
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    Abstract 2204: A proteomic landscape of diffuse-type gastric cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2204-2204
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2204-2204
    Abstract: Gastric cancer is a heterogeneous disease characterized by poor clinical outcomes and limited targeted treatment options. Among them, diffuse-type gastric cancer (DGC) is the subtype with worst prognosis. Here we describe the first proteomic landscape of DGC. We carried out proteome profiling and targeted exome DNA sequencing of 84 DGC samples. We analyzed the 1,008 (168 x 6) raw files together for uniformed quality control and protein identification with 1% global protein false discovery rate (FDR), which resulted in the identification of 11,340 gene products (GPs). A SAM (significance analysis of microarray) analysis identified 1,641 proteins as differentially expressed between T (tumor) and N (nearby) with statistical significance (FDR q value & lt;0.01 by SAM and differential expression ratio & gt;0.5/ & lt; -0.5), including 1,211 up-regulated and 430 down-regulated GPs. Gene Ontology annotation indicated that tumor proteomes were significantly enriched in cell cycle, DNA replication, checkpoint, E2F, WNT, p53 signaling, epithelial mesenchymal transition (EMT), and inflammation/cytokine-receptor interaction pathways, and the proteomes of the nearby tissues are enriched in metabolism pathways, such as fatty acid metabolism, oxidative phosphorylation, and amino acid metabolism. Notably, many gastric makers (ANXA10, VSIG1, CLDN18, CTSE, TFF2, MUC5AC and MUC6) and signature proteins for stomach functions, including digestion, absorption, secretion, and stomach acid generation (PGC, GIF, GAST, and ATP4A), were lost in tumors. Based on proteome profiling alone, DGC can be subtyped into 3 major classes (PX1-3) that exhibit distinct proteome features and correlate with distinct clinical outcomes (Gehan-Breslow-Wilcoxon P = 0.024). PX1 exhibits proteome stability and the best overall survival; PX2 exhibits dysregulation in DNA replication and cell cycle, and is most sensitive to chemotherapy; PX3 features hyper-activated immune response and is not responsive to chemotherapy. We identified seven-marker proteins that can stratify DGC patients into these three subtypes, opening a door for proteome subtyping in clinical application and intervention. Furthermore, we nominated drug target candidates taking into consideration both the altered DGC proteome and association data with patients’ overall survival. This study revealed the altered signaling pathways in DGC and demonstrated the advantage of proteomic approach in molecular subtyping of cancer. Citation Format: Sai Ge, Xia Xia, Chen Ding, Bei Zhen, Quan Zhou, Jinwen Feng, Jiajia Yuan, Rui Chen, Yumei Li, Zhongqi Ge, Jiafu Ji, Lianhai Zhang, Jiayuan Wang, Zhongwu Li, Yumei Lai, Ying Hu, Yanyan Li, Yilin Li, Jing Gao, Lin Chen, Jianming Xu, Chunchao Zhang, Sung Yun Jung, Mingwei Liu, Lei Song, Wanlin Liu, Gaigai Guo, Tongqing Gong, Yin Huang, Yang Qiu, Tieliu Shi, Weimin Zhu, Yi Wang, Fuchu He, Lin Shen, Jun Qin, CNHPP. A proteomic landscape of diffuse-type gastric 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 2204. doi:10.1158/1538-7445.AM2017-2204
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-2204
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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