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  • American Association for Cancer Research (AACR)  (3)
  • 1
    Online Resource
    Online Resource
    Stroma-Derived Matrix Metalloproteinase (MMP)-2 Promotes Membrane Type 1-MMP–Dependent Tumor Growth in Mice
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 9 ( 2007-05-01), p. 4311-4319
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 9 ( 2007-05-01), p. 4311-4319
    Abstract: Matrix metalloproteinase-2 (MMP-2) is a stroma-derived MMP belonging to the type IV collagenase family. It is believed to mediate tumor cell behavior by degrading deposits of type IV collagen, a major component of the basement membrane. The membrane type 1-MMP (MT1-MMP) is a highly potent activator of MMP-2 and is expressed in many tumor and stromal cells. However, the roles played by stromal MMP-2 in tumor progression in vivo remain poorly understood. We established a colon epithelial cell line from an Mt1-mmp−/− mouse strain and transfected these cells with an inducible expression system for MT1-MMP (MT1rev cells). Following s.c. implantation into Mmp-2+/+ mice and induction of MT1-MMP expression, MT1rev cells grew rapidly, whereas they grew very slowly in Mmp-2−/− mice, even in the presence of MT1-MMP. This MT1-MMP–dependent tumor growth of MT1rev cells was enhanced in Mmp-2−/− mice as long as MMP-2 was supplied via transfection or coimplantation of MMP-2–positive fibroblasts. MT1rev cells cultured in vitro in a three-dimensional collagen gel matrix also required the MT1-MMP/MMP-2 axis for rapid proliferation. MT1rev cells deposit type IV collagen primarily at the cell-collagen interface, and these deposits seem scarce at sites of invasion and proliferation. These data suggest that cooperation between stroma-derived MMP-2 and tumor-derived MT1-MMP may play a role in tumor invasion and proliferation via remodeling of the tumor-associated basement membrane. To our knowledge, this is the first study demonstrating that MT1-MMP–dependent tumor growth in vivo requires stromal-derived MMP-2. It also suggests that MMP-2 represents a potential target for tumor therapeutics. [Cancer Res 2007;67(9):4311–9]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-4761
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    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
    HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E -mutant High-grade Glioma
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 11 ( 2022-06-01), p. 2425-2439
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 11 ( 2022-06-01), p. 2425-2439
    Abstract: Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E-mutant high-grade gliomas (HGG); however, the therapeutic effect is limited by the emergence of drug resistance. Experimental Design: We established multiple paired BRAFV600E-mutant HGG patient-derived xenograft models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment-resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo. Results: We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the reactivation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E-mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3β (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular targeted therapy. Conclusions: The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E-mutant HGG.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-3622
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    Abstract 2863: Preclinical evaluation of astatine-211-conjugated anti-tissue factor antibody
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2863-2863
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2863-2863
    Abstract: It has been well-known that tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is overexpressed in various cancers including gastric cancer, pancreatic cancer and malignant gliomas. So far, we produced anti-TF monoclonal antibodies for targeting overexpressed TF in tumor site. Moreover, among them, we found that the clone 1084 possessed deep penetration property leading to more homogenous distribution in tumor than others. Currently, we are focusing on developing clone 1084 antibody armed with alpha emitters for cancer treatment, because alpha-particles are characterized by higher liner energy transfer (LET) and shorter range in tissue than other types of radiation, resulting in efficient deoxyribonucleic acid (DNA) double-strand breaks in cancer cells and minor effects on normal cells adjacent to tumor. In this study, we synthesized astatine-211, one of the most promising alpha-particle emitters, in the 209Bi(α,2n)211At reaction using the RIKEN Azimuthally Varying Field (AVF) cyclotron and labeled humanized clone 1084 with this radionuclide. First, we chemically attached a linker containing organic tin compound to the antibody and then labeled the liker-antibody complex with astatine-211 via a halogen-exchange reaction. Thin-layer chromatography (TLC) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies showed that we successfully labeled the antibody with astatine-211 and purified the radioactive antibody. We evaluated binding activity and in vitro cytocidal effect of the radioactive antibody by flow cytometry and water-soluble tetrazolium salt (WST-8) assay, respectively. The radioactive antibody specifically bound to TF expressed on cell membrane of gastric cancer cells and showed potent cell killing activity depending on TF expression of the cancer cells. Single photon emission computed tomography/computed tomography (SPECT/CT) study revealed that astatine-211 alone selectively accumulated in stomach and thyroid such as radioactive iodine. On the other hand, radioactive antibody showed similar pharmacokinetics to the naked 1084 antibody. Moreover, we confirmed in vivo anti-tumor effects of the radioactive antibody in a TF-overexpressing gastric cancer xenograft model. In conclusion, we successfully created astatine-211-conjugated anti-TF antibody and confirmed its anti-tumor effects. Citation Format: Hiroki Takashima, Yoshikatsu Koga, Kazunobu Onuki, Shino Manabe, Ryo Tsumura, Takahiro Anzai, Nozomi Iwata, Masahiro Yasunaga, Wang Yang, Takuya Yokokita, Yukiko Komori, Daiki Mori, Hiromitsu Haba, Hirofumi Fujii, Yasuhiro Matsumura. Preclinical evaluation of astatine-211-conjugated anti-tissue factor antibody [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2863.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2863
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    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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