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  • American Association for Cancer Research (AACR)  (61)
  • 1
    Online Resource
    Online Resource
    Abstract 3128: mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumors
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3128-3128
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3128-3128
    Abstract: Recently, novel small molecules targeting the mammalian target of rapamycin (mTOR) have been successfully tested for the treatment of endocrine neoplasias. Since these drugs will certainly be used as routine therapeutics in the near future, it is surprising that information on the exact expression patterns of mTOR and its downstream target 4EBP1 in endocrine tumors is still lacking. We investigated expression of mTOR and total as well as phosphorylated 4EBP4 in specimen of endocrine tumors by immunohistochemistry and correlated our findings with clinicopathologic variables and patient prognosis. We found that 61 (61.6%), 92 (92.2%), 79 (79.8%) and 69 (69.7%) out of 99 neuroendocrine foregut and midgut tumors were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1) and nuclear phospho-4EBP1, respectively. mTOR, 4EBP1 and p-4EBP1 (either cytoplasmic or nuclear) expression was higher in foregut tumors than in midgut tumors. Expression of mTOR was higher in foregut tumors with distant metastases (p=0.035) when compared to their locally restricted counterparts. 4EBP1 as well as p-4EBP1 (either cytoplasmic or nuclear) expression was associated with higher Ki-67 positivity and thereby proliferative activity. mTOR expression and activity as measured by phosphorylation of its downstream target 4EBP1 vary considerably in dependence of tumor location and metastatic status. We hypothesize that differences in mTOR expression patterns and/or activity might predict response to mTOR inhibitors which should be taken into account when future clinical trials with these substances are being planned. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3128.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3128
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 2
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    Abstract 1624: SIRT1 overexpression in pancreatic adenocarcinomas correlates with shortened patient survival and small molecule inhibition as well as target knockdown of SIRT1 induces growth arrest and apoptosis in pancreatic cancer cells
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1624-1624
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1624-1624
    Abstract: Aims: Several lines of evidence indicate that the nuclear enzyme SIRT1 belonging to the class III histone deacetylases is implicated in the initiation and progression of various malignancies. SIRT1 exerts its function by regulating deacetylation of histone and non-histone substrates leading to transcriptional repression of tumor suppressor genes. Recently, SIRT1 gained attraction as druggable target. Since chemotherapeutic treatment options are still very limited in pancreatic cancer we aimed at investigating the potential of SIRT1 in this regard by evaluating the effects of SIRT1 inhibition in vitro and SIRT1 expression in vivo. Methods: Employing immunohistochemistry SIRT1 expression was analyzed in a large cohort of pancreatic ductal adenocarcinomas and subsequently correlated with clinicopathological data and patient survival. Furthermore, we investigated the impact of SIRT1-specific small molecule inhibition and target knock down as well as combinatorial regimens including conventional chemotherapy and small molecule inhibitors directed against the EGFR in pancreatic cancer cell culture models. Using the xCELLigence system, cellular events were measured quantitatively in real time and corroborated by secondary conventional readouts including FACS analysis. Results: We found nuclear SIRT1 expression in 36 (27.9%) of 129 pancreatic carcinomas. SIRT1 expression was significantly higher in poorly differentiated carcinomas (p=0.002). SIRT1 expression was positively correlated with the expression of conventional HDACs suggesting a shared regulation. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p=0.002) and multivariate (HR 1.65, p=0.045) analysis under inclusion of WHO stage and grade. Small molecule inhibition and target knockdown of SIRT1 lead to a rapid growth arrest and influenced cell viability. This effect was even more pronounced in combinatorial regimens with Gefitinib, but not in combination with Gemcitabine. Conclusions: SIRT1 is shown to be an independent prognostic biomarker for pancreatic adenocarcinomas. Moreover our data suggest that SIRT1 plays an important functional role in pancreatic cancer cell growth, which can be levered out by combinatory small molecule inhibition. 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 1624. doi:10.1158/1538-7445.AM2011-1624
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1624
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
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  • 3
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    Abstract 2391: HPV status predicts therapy response in patients with locally advanced HNSCC receiving cetuximab-based radioimmunotherapy.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2391-2391
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2391-2391
    Abstract: HPV+ HNSCC show better therapy responses and improved survival when compared to HPV- HNSCC. No data exist on the prognostic value of HPV and combined HPV/EGFR status in patients with locally advanced HNSCC (LAHNSCC) treated with radiotherapy and cetuximab. The HPV status defined by p16INK4A immunohistochemistry and PCR-based chip analysis was assessed in a clinically well-characterized cohort of patients with LAHNSCC. Outcome was estimated using Kaplan-Meier analysis. Additionally, the EGFR expression levels and the effect of radioimmunotherapy in HPV+ and HPV- HNSCC cell lines were determined. 34% of the cases were p16INK4A/HPV positive. p16INK4A significantly correlated with male sex, younger patients and oropharnygeal localization and was a powerful predictor of OS (p=0.001) and PFS (p≤0.001). The HRs for HPV+ tumors were 0.17 (95%CI: 0.056-0.524, p=0.002) for OS and 0.12 (95%CI: 0.033-0.438, p=0.001) for PFS. P16INK4A correlated well with the HPV status (p≤0.001). The HPV+ UD-SCC2 cells had higher EGFR levels when compared to HPV- FaDu cells and the efficacy of combined radioimmunotherapy was stronger. This is the first study that demonstrates the prognostic value of HPV in patients with LAHNSCC receiving cetuximab-based radioimmunotherapy. Citation Format: Albrecht Stenzinger, Janina Wolf, Alexandra Jensen, Volker Endris, Manfred Dietel, Wilko Weichert. HPV status predicts therapy response in patients with locally advanced HNSCC receiving cetuximab-based radioimmunotherapy. [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 2391. doi:10.1158/1538-7445.AM2013-2391
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2391
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
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    Abstract B50: A patient-derived renal cell carcinoma model as a platform for the identification of novel diagnostic markers and therapeutic targets
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 19_Supplement ( 2013-10-01), p. B50-B50
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 19_Supplement ( 2013-10-01), p. B50-B50
    Abstract: Clear-cell renal cell carcinoma (ccRCC) is highly resistant to conventional therapies and to date effective treatment is restricted to surgical resection. Pre-clinical in vitro and in vivo models, which accurately mimic this disease, are critical for the development of novel effective therapies. Previous attempts to culture ccRCC cells have been proven difficult and thus, only few ccRCC cell lines are currently available. In addition long-term culturing often causes loss of primary tumor characteristics including tumor heterogeneity. This might explain why in contrast to other tumor entities, tumor-initiating cell (TIC) subpopulations have so far not been reported for ccRCC. TICs have been associated with tumor progression, metastasis and drug-resistance. Consequently these cells have also been named cancer stem cells (CSCs). Furthermore, distinct combinations of genetic and epigenetic alterations result in profound inter-patient heterogeneity and can in part promote TIC activity. Therefore, the development and characterization of clinically relevant patient derived ccRCC-models would provide an experimental basis to study the complex mechanisms leading to and maintaining ccRCCs. Hence, we established a patient-derived serum-free spheroid culture system that can be used to propagate primary ccRCC cells. These ccRCC cells retain their tumor-initiating potential and mimic the human malignancy upon orthotopic injection into immunodeficient mice. They not only mirror the histological properties but also the molecular features of the parental tumor. Moreover, these cells show the capacity to form de novo metastasis in lungs, which is the most common metastatic site for ccRCC in patients. The established ccRCC cultures were then used as a screening platform for the identification of surface proteins, which are heterogeneously expressed among tumor cells. Functional in vitro and in vivo assays showed that subpopulations defined by expression of these markers also displayed distinct functional characteristics including TIC activity. Gene Set Enrichment Analysis (GSEA) revealed differences in the signaling networks active in these sub-populations. In addition, molecular and cellular assays addressed the significance of these pathways for the maintenance of ccRCC malignancy. Currently the identified surface markers and underlying pathways are validated as potential novel diagnostic and therapeutic targets. Therefore, our novel patient-derived serum-free spheroid culture system serves as a platform to expand patient derived ccRCCs. It further allows the analysis and characterization of different subpopulations, which may ultimately contribute to the understanding of the molecular basis underlying progression, therapy-resistance and metastasis of this disease. Citation Format: Teresa Rigo-Watermeier, Corinna Klein, Vanessa Vogel, Christian Eisen, Thomas Hoefner, Wilko Weichert, Sascha Pahernik, Markus Hohenfellner, Martin R. Sprick, Andreas Trumpp. A patient-derived renal cell carcinoma model as a platform for the identification of novel diagnostic markers and therapeutic targets. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B50.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.FBCR13-B50
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
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    Abstract 3057: Unstable phenotype of human colon cancer tumor initiating cells
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3057-3057
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3057-3057
    Abstract: We have previously shown that long term progression of human colorectal cancer in serial xenotransplantation is driven by a small sub-fraction of all tumor initiating cells (TIC). These long-term TIC (LT-TIC) self-renew extensively in vivo and are exclusively able to seed metastases in distant organs. Defined phenotypic surface markers of LT-TIC would be crucial to develop effective antibody-based targeting strategies. However, it remains elusive whether a fixed phenotype of long-term TIC is associated with their tumorigenicity thereby allowing prospective isolation of this most relevant cancer cell fraction. To address this question, three dimensional spheroid cultures in serum free medium supplemented with FGF and EGF were generated from primary human colon cancer specimens to enrich for TIC. To calculate the frequency of TIC in spheroid cultures, cells were transplanted in limiting dilution into cohorts of Nod/SCID-IL2RG-/- (NSG) mice. TIC frequency varied from 1 in 22 to 1 in 2x104 spheroid cells, depending on the respective patient sample. When the spheroid cells were transferred to culture conditions that favor their differentiation (gelatin coated plates in the presence of serum and withdrawal of cytokines) the phenotype changed dramatically. The primary colon cancer cells did no longer grow as spheroids but formed an adherent cell layer and up-regulated the colon epithelial differentiation markers CDX2, DEFA5, KRT80, Muc20 and TFF2. In addition, CD133, a widely used marker to enrich for TICs in various solid cancers, was strongly down-regulated upon serum treatment. Strikingly, when xenotransplantated into NSG mice, cells cultured under spheroid and differentiation conditions equally formed serially transplantable tumors, demonstrating that tumor initiating and self-renewal capacity of TIC was not restricted to phenotypically immature spheroid cells. Moreover, CD133 expression did not predict successful tumor formation in vivo. Sorted CD133+ and CD133- cells from 3 individual patients formed tumors with equal efficiency and regenerated both, CD133+ and CD133- cells in vivo. Importantly, clonal analyses of individual lentivirally marked TIC clones cultured under either culture condition revealed no systematic differences in TIC frequency, demonstrating that phenotypic differentiation does not lead to quantitative elimination of TIC clones. Our results demonstrate that phenotypic differentiation does not eliminate the tumor-initiating potential of human colorectal TIC. Moreover, expression of CD133 does not predict their tumor forming and self-renewal potential. This pronounced phenotypic plasticity of human colon cancer TIC poses a grave challenge for surface-targeted elimination of TIC in colorectal cancer. Citation Format: Taronish D. Dubash, Christopher M. Hoffmann, Felix Oppel, Klara Giessler, Sarah Bergmann, Sebastian M. Dieter, Wilko Weichert, Martin Schneider, Manfred Schmidt, Christof von Kalle, Hanno Glimm, Claudia R. Ball. Unstable phenotype of human colon cancer tumor initiating cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3057. doi:10.1158/1538-7445.AM2014-3057
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-3057
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 6
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    Abstract P6-01-24: Long-term outcome data using Endopredict® as risk stratification and chemotherapy decision biomarker in hormone receptor positive, HER2-negative early breast cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P6-01-24-P6-01-24
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P6-01-24-P6-01-24
    Abstract: Background: The Endopredict test is used for estimating risk of distant recurrence for women presenting with early-stage breast cancer with a positive estrogen receptor (ER) and negative human epidermal growth factor receptor 2 (HER2) status. The current ASCO Guideline Update on biomarkers confirms the value of the Endopredict test to guide decisions of adjuvant endocrine and chemotherapy. This study shows prospective long-term outcome data of early breast cancer patients whose chemotherapy decision was guided by the Endopredict test result (EPclin). Methods: ER-positive and HER2-negative early breast cancer patients with 0-3 positive lymph nodes treated between March 2012 and March 2015 were included in this single institution study. The Endopredict® test was carried out on all tumour samples. Demographic, clinical and pathological data were assessed for each patient at baseline. Treatment compliance, local recurrence, distant metastases and survival was evaluated. Risk estimates were obtained by the Kaplan-Meier method and cumulative risk functions in case of competing risks. Group comparisons were performed by Cox proportional hazards regression models and quantified through hazard ratios. Median Follow-Up was estimated by the inverse Kaplan-Meier method. Exploratory hypothesis testing was conducted at two-sided 5% significance levels. Results: In a cohort of 368 consecutive cases the median follow-up time was 8.2 years. Endopredict allocated 238 pts (64%) in the EPclin low risk and 130 pts (34%) in the EPclin high risk group. The 5-year distant metastasis free survival (DMFS) in the EPclin low risk group was 96.6% (95% CI 0.943-0.989) and 85.5% (95% CI 0.796-0.920) in the EPclin high risk group. With a hazard ratio (HR) of 2.21 (95% CI: 1.27-3.88; p=0.005) the risk for distant metastasis in EPclin high risk patients was more than two-fold higher in comparison with EPclin low risk patients. 87 pts. (66.9%) of the EPclin high risk group underwent chemotherapy (compliant), whereas 43 pts (33.1 %) opposed the recommended chemotherapy (non-compliant). Kaplan-Meier plots in the EPclin high risk subgroups compliant vs non-compliant showed a significant disease-free survival (DFS) benefit towards the patients following the chemotherapy recommendation (HR 0.46; 95%CI 0.23-0.95; p=0.036). The 5-year DFS for the high risk compliant subgroup was 89.1% (95% CI: 0.827-0.961) vs. the high risk non-compliant subgroup with 68.9% (95% CI: 0.562-0.845). Regarding the subgroups pre- and postmenopausal, patients with a EPclin high risk test result were at significant higher risk of experiencing distant metastases than patients with a EPclin low risk test result in both subgroups (premenopausal: HR 3.55; 95%CI 1.17-12.32; p=0.025; postmenopausal: HR 1.19; 95%CI 0.99-3.7; p=0.054). We analyzed the EPclin categorization in context of the ki67 subtypes luminal A (low; 0-10%) and luminal B (high; 25-100%). The EPclin-based risk stratification was significantly associated with improved DFS in both ki67 subtypes (ki67 low: HR 4; 95%CI 1.25-12.04; p=0.021 and ki67 high: HR 3.77; 95%CI 1.19-18.93; p=0.022). 33.3% (21 pts) of all tumor samples classified as luminal B (63 pts), were reclassified towards the low risk group via Endopredict, sparing chemotherapy recommendation. Contrary 19.2% (14 pts) of all luminal A (73 pts) were categorized to high risk EPclin. Conclusion: These first long term prospective outcome data confirm, that Endopredict can guide decisions on adjuvant chemotherapy in early ER positive, HER2 negative breast cancer. Pts categorized as EPclin high risk benefitted from an adjuvant chemotherapy. Our results show that Endopredict risk stratification is also applicable in premenopausal women. Furthermore the Endopredict test showed a better classification accuracy in comparison to ki67 subtypes, resulting in a more precise estimation of prognosis. Citation Format: Evelyn Klein, Adriana Josipovic, Aurelia Noske, Sophie Anders, Carolin Mogler, Wilko Weichert, Alexander Hapfelmeier, Marion Kiechle, Johannes Ettl. Long-term outcome data using Endopredict® as risk stratification and chemotherapy decision biomarker in hormone receptor positive, HER2-negative early breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-24.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P6-01-24
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    Abstract PD9-07: Mdm2 gene amplification in estrogen receptor-positive breast cancer cells is associated with enhanced solid tumor growth and pronounced metastatic potential in humanized tumor mice (HTM) and a poor outcome of patients with luminal breast cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD9-07-PD9-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD9-07-PD9-07
    Abstract: Background: Luminal, i.e., estrogen receptor (ER)-positive breast cancer (BC) is a heterogeneous disease in terms of tumor progression, therapy response, and relapse. Additional biomarkers with a prognostic and predictive impact would facilitate advanced patient stratification and can reveal advanced therapeutic options for individual patients suffering from luminal BC subtype. First objective of this study was the hypothesis driven validation and identification of biomarkers associated with successful engraftment, augmented tumor growth, and enhanced metastasis upon xenotransplantation into HTM and non-humanized tumor mice. Second objective was the retrospective validation and correlation of aforementioned markers with clinical outcomes (disease free-survival [DFS] and overall survival [OS] ) of luminal BC patients after neoadjuvant chemotherapy within the GeparTrio trial. Methods: Immunodeficient NSG mice with and without immunological humanization were transplanted with primary, ER-positive BC tissues and cells. Engraftment rates, tumor progression, and metastasis were monitored as a function of marker expression and genomic alterations, considered to be associated with tumor cell stemness and tumor initiating capacity. Functional assays were applied to demonstrate the impact of identified markers on tumor cell viability, growth and migration in-vitro. Dual color fluorescence-in-situ-hybridization to monitor mdm2 gene and the cen12 region was applied to 502 pretherapeutic ER-positive tissue specimens of BC patients treated with anthracycline/taxane based neoadjuvant chemotherapy within the GeparTrio trial. Mdm2 gene expression was analyzed in the entire luminal BC cohort as well as in luminal-A and luminal-B samples classified based on a Ki-67 cut-off of 20% (St. Gallen guideline). Associations with survival outcomes were studied by Cox regression models. Results: We observed an elevated CD44 and c-MET expression in metastatic cells compared to the primarily growing xenotransplantants. Moreover, we found mdm2 gene amplification was associated with tumor growth and pronounced metastatic potential in NSG mice. Functional assays unveiled a reduced viability, proliferation, and migration capacity of inherently mdm2 positive breast cancer cells upon mdm2 knock-down or anti-mdm2 targeting. Validation of mdm2 gain in luminal BC cohort within the GeparTrio trial revealed a significant association of mdm2 amplification with worse DFS (HR=1.80 [95%CI 1.16-2.79] , log rank p=0.008) and OS (HR=1.75 [95%CI 1.00-3.05], log-rank p=0.047). This association was even stronger in luminal-A BC: DFS (HR=2.56 [95%CI 1.40-4.71] , log rank p=0.002 and OS (HR=3.27 [95%CI 1.51-7.09], log-rank p=0.001). Conclusions: Mdm2 gene amplification facilitates ER-positive BC engraftment and progression in a preclinical in-vivo xenograft humanized NSG mouse model. Targeting mdm2 in-vitro reduced malignant cell propagation and growth. In addition, an increased mdm2 gene dose is strongly associated with an unfavorable outcome of luminal BC. Prospective studies are required to verify the suitability of mdm2 for advanced luminal BC stratification and therapeutic targeting. Citation Format: Anja Kathrin Wege, Valentina Vladimirova, Christine Solbach, Eva-Maria Rom-Jurek, Jens-Uwe Blohmer, Paul Jank, Bruno Sinn, Andreas Trumpp, Elisabetta Marangoni, Knut Engels, Wilko Weichert, Nicole Pfarr, Christoph Irlbeck, Bernhard Polzer, Olaf Ortmann, Marion van Mackelenbergh, Carsten Denkert, Sibylle Loibl, Gero Brockhoff. Mdm2 gene amplification in estrogen receptor-positive breast cancer cells is associated with enhanced solid tumor growth and pronounced metastatic potential in humanized tumor mice (HTM) and a poor outcome of patients with luminal breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-PD9-07
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
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    Abstract PO-070: Longitudinal precision oncology platform to identify chemotherapy-induced vulnerabilities in pancreatic cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 22_Supplement ( 2021-11-15), p. PO-070-PO-070
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    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 22_Supplement ( 2021-11-15), p. PO-070-PO-070
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with poor survival rates as almost all patients develop resistance towards chemotherapy and molecular-informed targeted therapies are reserved to a few. Here, we aim to establish a longitudinal precision oncology platform with a multi-dimensional characterization of PDAC biopsies including genomic, transcriptomic as well as functional analyses to identify and exploit treatment-induced vulnerabilities. In order to investigate adaptive processes of tumors under treatment we aimed to generate PDAC patient-derived organoids (PDOs) and 2D cell lines before and after chemotherapy. Therefore, we enrolled a patient with borderline resectable PDAC who received neoadjuvant FOLFIRINOX. Endoscopic fine needle (pre-FFX) and surgical biopsies (post-FFX) were used to generate PDOs and 2D cells. Whole exome sequencing (WES) and RNA sequencing data of the pre-FFX and post-FFX organoids were compared in order to evaluate the genetic landscape and PDAC subtypes. 2D cells were subjected to an unbiased automated drug screening of 415 compounds to investigate FFX-induced vulnerabilities. Top targets were validated manually in the 2D cells and organoids. Although transcriptional subtyping classified both PDOs as classical PDAC, gene set enrichment analysis (GSEA) revealed a reduced pathway activation linked to the basal-like phenotype such as KRAS signaling in the post-FFX organoids. WES did not show major differences in the genetic landscape of the tumor pre- and post-FFX induction suggesting a plasticity process rather than a clonal selection during chemotherapy. Importantly, post-FFX cells exhibited an increased sensitivity in the unbiased drug screening towards MEK and EGFR inhibition compared to pre-FFX cells. 2D cells and organoids were treated with different MEK inhibitors (MEKi) for validation and post-FFX cells showed a highly increased response compared to the treatment-naïve cells, as well. Interestingly, when placed into the context of a panel of 15 primary PDAC cell lines the pre-FFX cells cluster with highly MEKi resistant PDAC cells whereas post-FFX cells belong to the most sensitive cell lines. In sum, integrating functional layers into personalized medicine allowed us to identify chemotherapy-induced vulnerabilities as potent targeted therapy options in PDAC. Thus, this longitudinal precision oncology platform harbors a unique opportunity to understand adaptive processes in tumor evolution and/or treatment-imposed pressure in PDAC patients. Citation Format: Katja Peschke, Hannah Jakubowski, Arlett Schäfer, Carlo Maurer, Sebastian Lange, Felix Orben, Raquel Bernad, Felix Harder, Matthias Eiber, Rupert Öllinger, Melissa Schlitter, Wilko Weichert, Veit Phillip, Christoph Schlag, Roland Schmid, Rickmer Braren, Bo Kong, Ekin Demir, Helmut Friess, Roland Rad, Dieter Saur, Günter Schneider, Maximilian Reichert. Longitudinal precision oncology platform to identify chemotherapy-induced vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-070.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA21-PO-070
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 9
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    Abstract 468: Clinical relevance of comprehensive genomic analysis in advanced-stage cancers and rare malignancies: Results from the MASTER trial of the German Cancer Consortium
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 468-468
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 468-468
    Abstract: Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on high-resolution molecular diagnostics. The value of comprehensive molecular profiling based on whole-exome/genome sequencing (WES/WGS) and global RNA sequencing to guide therapeutic decisions in individual patients remains to be established. We report the results of MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a multicenter registry trial for prospective, biology-driven stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors conducted under the auspices of NCT Heidelberg/Dresden and the German Cancer Consortium (DKTK). Based on a standardized workflow for selection and consenting of patients, sample processing, WES/WGS and RNA sequencing, bioinformatic analysis, and technical validation of potentially actionable findings, we have analyzed more than 1300 poor-prognosis (median overall survival, 12 months) patients representing a broad spectrum of entities. Evaluation of the data by a cross-institutional molecular tumor board has allowed categorization into 7 different intervention baskets and formulation of evidence-based recommendations for clinical management in more than 80% of patients, which were implemented in approximately one third of cases. Overall response and disease control rates on molecularly guided treatment were significantly improved compared to prior systemic therapies, which translated into a progression-free survival (PFS) ratio of greater than 1.3 in more than 40% of cases. In 5% of patients, comprehensive genomic profiling allowed to refine the clinical diagnosis, as exemplified by several soft-tissue sarcomas not otherwise specified and carcinomas of unknown primary site that could be categorized based on their genotypes and subsequent histopathologic re-evaluation. Finally, systematic analysis of germline alterations revealed that 11% of patients had pathogenic (ACMG Class 4 or 5) variants in known tumor predisposition genes, and that 4% were carriers for autosomal recessive disorders. This prospective trial demonstrates that molecular profiling based on WES/WGS and RNA sequencing in a multi-institutional clinical setting is feasible, complements and advances routine molecular diagnostics, and creates clinically meaningful therapeutic opportunities in a significant proportion of patients. To improve clinical translation, the MASTER platform is now linked to a growing portfolio of cross-institutional basket trials. In the intermediate term, genomic profiling within MASTER will be integrated with additional layers of patient characterization and extended to additional treatment modalities (e.g. radiotherapy and surgical interventions). Citation Format: Peter Horak, Christoph Heining, Simon Kreutzfeldt, Christoph E. Heilig, Lino Möhrmann, Laura Gieldon, Martina Fröhlich, Sebastian Uhrig, Daniel Hübschmann, Katja Beck, Daniela Richter, Stephan Wolf, Katrin Pfütze, Christina Geörg, Bettina Meißburger, Frederick Klauschen, Sebastian Ochsenreither, Gunnar Folprecht, Jens Siveke, Sebastian Bauer, Thomas Kindler, Christian Brandts, Melanie Börries, Nikolas von Bubnoff, Karsten Spiekermann, Philipp J. Jost, Klaus Schulze-Osthoff, Michael Bitzer, Peter Schirmacher, Christof von Kalle, Richard Schlenk, Barbara Klink, Barbara Hutter, Wilko Weichert, Albrecht Stenzinger, Evelin Schröck, Benedikt Brors, Hanno Glimm, Stefan Fröhling. Clinical relevance of comprehensive genomic analysis in advanced-stage cancers and rare malignancies: Results from the MASTER trial of the German Cancer Consortium [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 468.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-468
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Class I Histone Deacetylase Expression Has Independent Prognostic Impact in Human Colorectal Cancer: Specific Role of Class I Histone Deacetylases In vitro and In vivo
    American Association for Cancer Research (AACR) ; 2008
    In:  Clinical Cancer Research Vol. 14, No. 6 ( 2008-03-15), p. 1669-1677
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 6 ( 2008-03-15), p. 1669-1677
    Abstract: Purpose: Recently, several studies reported a strong functional link between histone deacetylases (HDAC) and the development of tumors of the large intestine. However, despite the importance of these molecules, comparably little is known on expression patterns and functions of specific HDAC isoforms in colorectal cancer. Experimental Design: We characterized class I HDAC isoform expression patterns in a cohort of 140 colorectal carcinomas by immunohistochemistry. In addition, effects of HDAC inhibition by valproic acid and suberoylanilide hydroxamic acid, and specific HDAC isoform knockdown by short interfering RNA, were investigated in a cell culture model. Results: We found class I HDACs highly expressed in a subset of colorectal carcinomas with positivity for HDAC1 in 36.4%, HDAC2 in 57.9%, and HDAC3 in 72.9% of cases. Expression was significantly enhanced in strongly proliferating (P = 0.002), dedifferentiated (P = 0.022) tumors. High HDAC expression levels implicated significantly reduced patient survival (P = 0.001), with HDAC2 expression being an independent survival prognosticator (hazard ratio, 2.6; P = 0.03). Short interfering RNA–based inhibition of HDAC1 and HDAC2 but not HDAC3 suppressed growth of colon cancer cells in vitro, although to a lesser extent than chemical HDAC inhibitors did. Conclusions: The strong prognostic impact of HDAC isoforms in colorectal cancer, the interactions of HDACs with tumor cell proliferation and differentiation in vivo, and our finding that HDACs are differentially expressed in colorectal tumors suggest that the evaluation of HDAC expression in clinical trials for HDAC inhibitors might help to identify a patient subgroup who will exceptionally profit from such a treatment.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-07-0990
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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