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  • American Association for Cancer Research (AACR)  (3)
  • 2015-2019  (3)
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  • American Association for Cancer Research (AACR)  (3)
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  • 2015-2019  (3)
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Subjects(RVK)
  • 1
    Online Resource
    Online Resource
    A Clinically Applicable Gene-Expression Classifier Reveals Intrinsic and Extrinsic Contributions to Consensus Molecular Subtypes in Primary and Metastatic Colon Cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 14 ( 2019-07-15), p. 4431-4442
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 14 ( 2019-07-15), p. 4431-4442
    Abstract: Four consensus molecular subtypes (CMS1–4) of colorectal cancer were identified in primary tumors and found to be associated with distinctive biological features and clinical outcomes. Given that distant metastasis largely accounts for colorectal cancer–related mortality, we examined the molecular and clinical attributes of CMS in metastatic colorectal cancer (mCRC). Experimental Design: We developed a colorectal cancer–focused NanoString-based CMS classifier that is ideally suited to interrogate archival tissues. We successfully used this panel in the CMS classification of formalin-fixed paraffin-embedded (FFPE) tissues from mCRC cohorts, one of which is composed of paired primary tumors and metastases. Finally, we developed novel mouse implantation models to enable modeling of colorectal cancer in vivo at relevant sites. Results: Using our classifier, we find that the biological hallmarks of mCRC, including CMS, are in general highly similar to those observed in nonmetastatic early-stage disease. Importantly, our data demonstrate that CMS1 has the worst outcome in relapsed disease, compared with other CMS. Assigning CMS to primary tumors and their matched metastases reveals mostly concordant subtypes between primary and metastasis. Molecular analysis of matched discordant pairs reveals differences in stromal composition at each site. The development of two novel in vivo orthotopic implantation models further reinforces the notion that extrinsic factors may impact on CMS identification in matched primary and metastatic colorectal cancer. Conclusions: We describe the utility of a NanoString panel for CMS classification of FFPE clinical samples. Our work reveals the impact of intrinsic and extrinsic factors on colorectal cancer heterogeneity during disease progression.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-3032
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 3 ( 2015-03-01), p. 633-641
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 3 ( 2015-03-01), p. 633-641
    Abstract: Basal cell carcinoma (BCC) is the most commonly diagnosed cancer. While most BCCs are amenable to surgery, some tumors can reach a more advanced stage or metastasize, and become ineligible for surgical resection or radiotherapy. Abnormal activation of the Hedgehog (Hh) pathway is a key driver in BCC pathophysiology. Consequently, inhibitors of the Hh pathway have been developed. Molecules that inhibit the receptor protein Smoothened (SMO) are the most advanced in clinical development. Vismodegib is the first-in-class SMO inhibitor and has been approved in a number of countries for the treatment of metastatic or locally advanced BCC. Several molecules have demonstrated antitumoral activity, but treatment may be limited in duration by a number of side effects, and it is not yet established whether these agents are truly curative or whether continued treatment will be required. Resistance to SMO inhibition has been reported in the clinic for which incidence and mechanisms must be elucidated to inform future therapeutic strategies. Intermittent dosing regimens to improve tolerability, as well as neoadjuvant use of Hh pathway inhibitors, are currently under investigation. Here, we review the most recent outcomes obtained with Hh inhibitors under clinical investigation in BCC. Mol Cancer Ther; 14(3); 633–41. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-14-0703
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract LB-136: Characterization of residual Basal Cell Carcinoma after vismodegib treatment
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. LB-136-LB-136
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. LB-136-LB-136
    Abstract: We have generated a mouse model of Superficial Basal Cell Carcinoma (BCC) to study the effect of the Smoothened inhibitor vismodegib in vivo. Despite the potency of vimodegib in blocking Hedgehog (Hh) signaling and efficacy in treatment of BCC, residual disease persists in the mouse model. To better understand the Biology of BCC and the potential mechanisms maintaining BCC during treatment, we profiled isolated untreated as well as residual tumors. We found that treated tumors change their transcriptional program to resemble the cells of skin and hair follicle structures like the Interfollicular Epidermis (IFE) and Isthmus, both of which harbor stem cell compartments. Consistent with these findings, residual disease lacks expression of epidermal differentiation markers and initiates growth upon cessation of treatment. While Wnt signaling is clearly required for BCC initiation in mouse models, we show that Wnt signaling is down-regulated in untreated full-blown disease and subsequently strongly induced in the treated tumors. We hypothesize that re-initiation of the Wnt pathway maintains BCC and study the effect of blocking both Wnt and Hh pathways with combined treatment of vismodegib and Wnt inhibitors. Citation Format: Brian Biehs, Gerrit J. Dijkgraaf, Bruno Alicke, Franklin Peale, Stephen E. Gould, Frederic J. de Sauvage. Characterization of residual Basal Cell Carcinoma after vismodegib treatment [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 LB-136. doi:10.1158/1538-7445.AM2017-LB-136
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-LB-136
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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