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Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC.
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| Zeitschriftentitel: | Journal of Clinical Oncology |
|---|---|
| Personen und Körperschaften: | , , , , , , |
| In: | Journal of Clinical Oncology, 37, 2019, 15_suppl, S. 6031-6031 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Clinical Oncology (ASCO)
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| Schlagwörter: |
| author_facet |
Klinghammer, Konrad Friedrich Politz, Oliver Eder, Theresa Otto, Raik Raguse, Jan D Hoffmann, Jens Keilholz, Ulrich Klinghammer, Konrad Friedrich Politz, Oliver Eder, Theresa Otto, Raik Raguse, Jan D Hoffmann, Jens Keilholz, Ulrich |
|---|---|
| author |
Klinghammer, Konrad Friedrich Politz, Oliver Eder, Theresa Otto, Raik Raguse, Jan D Hoffmann, Jens Keilholz, Ulrich |
| spellingShingle |
Klinghammer, Konrad Friedrich Politz, Oliver Eder, Theresa Otto, Raik Raguse, Jan D Hoffmann, Jens Keilholz, Ulrich Journal of Clinical Oncology Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. Cancer Research Oncology |
| author_sort |
klinghammer, konrad friedrich |
| spelling |
Klinghammer, Konrad Friedrich Politz, Oliver Eder, Theresa Otto, Raik Raguse, Jan D Hoffmann, Jens Keilholz, Ulrich 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6031 <jats:p> 6031 </jats:p><jats:p> Background: Copanlisib is a highly selective, pan-class I PI3K inhibitor with preferential activity against the p110α and p110δ isoforms that lead to downregulation of PI3K signaling. Copanlisib has been approved for the treatment of follicular lymphoma in the US. Here, we explored the anti-tumor activity of copanlisib in head and neck squamous cell carcinoma (HNSCC), where Pi3K signaling has been defined as alternate signaling in cetuximab resistant tumors. Further, TCGA data show up to 56% of HNSCC display either amplification or mutational changes in the Pi3K pathway making Pi3K an attractive target. Methods: Using a mouse-clinical trial set-up we profiled 20 patient derived HNSCC xenograft models for their sensitivity to cetuximab or copanlisib as single agent as well as in combination. Models were selected from our HNSCC PDX platform based on Pi3K mutational status, with 6 models harboring hot spot mutations, HPV positivity (n=3) and/or cetuximab resistance based on previous drug screenings (n=12). Treatment response was defined as tumor regression, stabilization or progression expressed as relative tumor volume (RTV) after 3 weeks of treatment: RTV<0,7 responder, RTV>1,2 progressor. Results: Copanlisib single agent treatment resulted in moderate activity with 5 responders (25%). In cetuximab resistant tumors (n=12) combined treatment led to an improved tumor response in 75% (n=9) whereas 41% (n=5) resulted in tumor control. Pi3KCA mutation was not predictive for treatment response to either cetuximab or copanlisib. No PTEN mutation was detected in the selected cohort. Increased Pi3K signaling activity evaluated through gene expression profiling and computed with GSEA pathway analyses was positively correlated with response. Conclusions: The anti-tumor responses observed in monotherapy or in combination treatment support further investigation for the potential of PI3K inhibition in HNSCC with high expression of Pi3K pathway signature as a potential predictive biomarker. </jats:p> Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. Journal of Clinical Oncology |
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| title |
Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_unstemmed |
Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_full |
Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_fullStr |
Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_full_unstemmed |
Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_short |
Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_sort |
preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of hnscc. |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6031 |
| publishDate |
2019 |
| physical |
6031-6031 |
| description |
<jats:p> 6031 </jats:p><jats:p> Background: Copanlisib is a highly selective, pan-class I PI3K inhibitor with preferential activity against the p110α and p110δ isoforms that lead to downregulation of PI3K signaling. Copanlisib has been approved for the treatment of follicular lymphoma in the US. Here, we explored the anti-tumor activity of copanlisib in head and neck squamous cell carcinoma (HNSCC), where Pi3K signaling has been defined as alternate signaling in cetuximab resistant tumors. Further, TCGA data show up to 56% of HNSCC display either amplification or mutational changes in the Pi3K pathway making Pi3K an attractive target. Methods: Using a mouse-clinical trial set-up we profiled 20 patient derived HNSCC xenograft models for their sensitivity to cetuximab or copanlisib as single agent as well as in combination. Models were selected from our HNSCC PDX platform based on Pi3K mutational status, with 6 models harboring hot spot mutations, HPV positivity (n=3) and/or cetuximab resistance based on previous drug screenings (n=12). Treatment response was defined as tumor regression, stabilization or progression expressed as relative tumor volume (RTV) after 3 weeks of treatment: RTV<0,7 responder, RTV>1,2 progressor. Results: Copanlisib single agent treatment resulted in moderate activity with 5 responders (25%). In cetuximab resistant tumors (n=12) combined treatment led to an improved tumor response in 75% (n=9) whereas 41% (n=5) resulted in tumor control. Pi3KCA mutation was not predictive for treatment response to either cetuximab or copanlisib. No PTEN mutation was detected in the selected cohort. Increased Pi3K signaling activity evaluated through gene expression profiling and computed with GSEA pathway analyses was positively correlated with response. Conclusions: The anti-tumor responses observed in monotherapy or in combination treatment support further investigation for the potential of PI3K inhibition in HNSCC with high expression of Pi3K pathway signature as a potential predictive biomarker. </jats:p> |
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| author | Klinghammer, Konrad Friedrich, Politz, Oliver, Eder, Theresa, Otto, Raik, Raguse, Jan D, Hoffmann, Jens, Keilholz, Ulrich |
| author_facet | Klinghammer, Konrad Friedrich, Politz, Oliver, Eder, Theresa, Otto, Raik, Raguse, Jan D, Hoffmann, Jens, Keilholz, Ulrich, Klinghammer, Konrad Friedrich, Politz, Oliver, Eder, Theresa, Otto, Raik, Raguse, Jan D, Hoffmann, Jens, Keilholz, Ulrich |
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| description | <jats:p> 6031 </jats:p><jats:p> Background: Copanlisib is a highly selective, pan-class I PI3K inhibitor with preferential activity against the p110α and p110δ isoforms that lead to downregulation of PI3K signaling. Copanlisib has been approved for the treatment of follicular lymphoma in the US. Here, we explored the anti-tumor activity of copanlisib in head and neck squamous cell carcinoma (HNSCC), where Pi3K signaling has been defined as alternate signaling in cetuximab resistant tumors. Further, TCGA data show up to 56% of HNSCC display either amplification or mutational changes in the Pi3K pathway making Pi3K an attractive target. Methods: Using a mouse-clinical trial set-up we profiled 20 patient derived HNSCC xenograft models for their sensitivity to cetuximab or copanlisib as single agent as well as in combination. Models were selected from our HNSCC PDX platform based on Pi3K mutational status, with 6 models harboring hot spot mutations, HPV positivity (n=3) and/or cetuximab resistance based on previous drug screenings (n=12). Treatment response was defined as tumor regression, stabilization or progression expressed as relative tumor volume (RTV) after 3 weeks of treatment: RTV<0,7 responder, RTV>1,2 progressor. Results: Copanlisib single agent treatment resulted in moderate activity with 5 responders (25%). In cetuximab resistant tumors (n=12) combined treatment led to an improved tumor response in 75% (n=9) whereas 41% (n=5) resulted in tumor control. Pi3KCA mutation was not predictive for treatment response to either cetuximab or copanlisib. No PTEN mutation was detected in the selected cohort. Increased Pi3K signaling activity evaluated through gene expression profiling and computed with GSEA pathway analyses was positively correlated with response. Conclusions: The anti-tumor responses observed in monotherapy or in combination treatment support further investigation for the potential of PI3K inhibition in HNSCC with high expression of Pi3K pathway signature as a potential predictive biomarker. </jats:p> |
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| spelling | Klinghammer, Konrad Friedrich Politz, Oliver Eder, Theresa Otto, Raik Raguse, Jan D Hoffmann, Jens Keilholz, Ulrich 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6031 <jats:p> 6031 </jats:p><jats:p> Background: Copanlisib is a highly selective, pan-class I PI3K inhibitor with preferential activity against the p110α and p110δ isoforms that lead to downregulation of PI3K signaling. Copanlisib has been approved for the treatment of follicular lymphoma in the US. Here, we explored the anti-tumor activity of copanlisib in head and neck squamous cell carcinoma (HNSCC), where Pi3K signaling has been defined as alternate signaling in cetuximab resistant tumors. Further, TCGA data show up to 56% of HNSCC display either amplification or mutational changes in the Pi3K pathway making Pi3K an attractive target. Methods: Using a mouse-clinical trial set-up we profiled 20 patient derived HNSCC xenograft models for their sensitivity to cetuximab or copanlisib as single agent as well as in combination. Models were selected from our HNSCC PDX platform based on Pi3K mutational status, with 6 models harboring hot spot mutations, HPV positivity (n=3) and/or cetuximab resistance based on previous drug screenings (n=12). Treatment response was defined as tumor regression, stabilization or progression expressed as relative tumor volume (RTV) after 3 weeks of treatment: RTV<0,7 responder, RTV>1,2 progressor. Results: Copanlisib single agent treatment resulted in moderate activity with 5 responders (25%). In cetuximab resistant tumors (n=12) combined treatment led to an improved tumor response in 75% (n=9) whereas 41% (n=5) resulted in tumor control. Pi3KCA mutation was not predictive for treatment response to either cetuximab or copanlisib. No PTEN mutation was detected in the selected cohort. Increased Pi3K signaling activity evaluated through gene expression profiling and computed with GSEA pathway analyses was positively correlated with response. Conclusions: The anti-tumor responses observed in monotherapy or in combination treatment support further investigation for the potential of PI3K inhibition in HNSCC with high expression of Pi3K pathway signature as a potential predictive biomarker. </jats:p> Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. Journal of Clinical Oncology |
| spellingShingle | Klinghammer, Konrad Friedrich, Politz, Oliver, Eder, Theresa, Otto, Raik, Raguse, Jan D, Hoffmann, Jens, Keilholz, Ulrich, Journal of Clinical Oncology, Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC., Cancer Research, Oncology |
| title | Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_full | Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_fullStr | Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_full_unstemmed | Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_short | Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| title_sort | preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of hnscc. |
| title_unstemmed | Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC. |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6031 |