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  • American Association for Cancer Research (AACR)  (2)
  • 1
    Online Resource
    Online Resource
    Abstract 2524: Targeting microtubule-associated protein 4 with novel small molecule CH4938056 confers antitumor activity under quasi in vivo conditions and in xenograft models
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2524-2524
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2524-2524
    Abstract: Tumor microenvironment is a major factor influencing treatment resistance to conventional anticancer therapies. Indeed, under “quasi in vivo” conditions, with low oxygen (1%), low pH (6.5) and low glucose concentration (0.01%) to mimic the environments in grafted tumors in mice or in clinical tumors, anti-proliferative activities of some conventional anticancer agents were diminished. Here, we describe the small molecule CH4938056, which has a novel chemical structure and was identified through cell-based screening under the “quasi in vivo” conditions followed by chemical modification. Our initial phenotypic profiling revealed that CH4938056 specifically arrests cells at the M phase and that it overcomes multiple resistance mechanisms to conventional anticancer agents including over-expression of MDR1 and BCRP. Then, after designing and identifying a water-soluble phosphate prodrug which successfully converts to CH4938056 after injection, we demonstrated antitumor efficacy of CH4938056 in a HCT116 xenograft model and a MDR1-overexpressing cancer model. Chemo-proteomic studies and consequent biochemical analysis revealed that CH4938056 binds to microtubule-associated protein 4 (MAP4). Moreover, CH4938056 inhibited MAP4-dependent microtubule assembly in a cell free system. siRNA-mediated knockdown of MAP4 induced chromosomal misalignment in metaphase cells, which closely resembles the primary phenotype of the CH4938056-treated cells. Under the “quasi in vivo” conditions, MAP4 expression turned out to be down-regulated (since MAP4 transcription is known to be negatively regulated by p53 which is up-regulated under these conditions) and when we knocked down MAP4 with siRNA, cancer cells became sensitive to CH4938056, which altogether is consistent with the fact that CH4935056 has antitumor activity even under the “quasi in vivo” conditions. From these observations, we conclude that CH4938056 inhibits proliferation of cancer cells by targeting MAP4. Targeting MAP4 with CH4938056 offers a novel approach for the treatment of cancer, especially for patients resistant to conventional anticancer therapies. 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 2524. doi:10.1158/1538-7445.AM2011-2524
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2524
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Abstract LB-174: Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-174-LB-174
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-174-LB-174
    Abstract: Pancreatic cancer is one of the most challenging malignancies because of its dismal prognosis, largely unknown etiology, and absence of early detection method. Here we report the results of a meta-analysis of three genome-wide association studies (GWAS) involving 2039 pancreatic cancer cases and 32592 control subjects, which represent the largest sample size in the Japanese population. To complement the SNP-based GWAS, we performed a gene-based GWAS using MAGMA. Given the pleiotropic effects observed for the top variants, we performed a Mendelian randomization (MR) analysis to address the possible causal relationship between type-2 diabetes (T2D) and pancreatic cancer risk, using 82 T2D-related SNPs and 25 hemoglobin A1c (HbA1c)-related SNPs as instrumental variables. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P & lt;5.0×10-8), as well as 4 loci with suggestive evidence of association (P & lt;1.0×10-6) for pancreatic cancer. Of the identified risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (OR=1.46, 95%CI=1.29-1.66, P=4.28×10-9), an Asian-specific, non-synonymous variant of glycoprotein 2 (GP2) predicted to be highly deleterious. Additionally, gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified variants in the GP2 gene exhibited pleiotropic effects on multiple traits, including type 2 diabetes, Hemoglobin A1c (HbA1c) levels, and pancreatic cancer. MR analysis suggested that genetically increased HbA1c levels may be causally associated with increased pancreatic cancer risk. Further fine mapping and functional characterization are required to elucidate the effects of common GP2 gene variants on pancreatic cancer susceptibility. Moreover, our findings highlight genetic susceptibility factors shared between T2D and pancreatic cancer. Citation Format: Yingsong Lin, Masahiro Nakatochi, Hidemi Ito, Yoichiro Kamatani, Hiromi Sakamoto, Hiroshi Ishii, Naoki Sasahira, Makoto Ueno, Naoto Egawa, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Atsushi Shimizu, Takashi Kadowaki, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo. Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population [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 LB-174.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-LB-174
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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