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Oncotarget: Combination of copanlisib with cetuximab improves tumor response


Oncotarget published "Combination of copanlisib with cetuximab improves tumor response in cetuximab-resistant patient-derived xenografts of head and neck cancer" which reported that HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target, particularly in cetuximab-resistant tumors.

Here, the authors explored the antitumor activity of the selective, pan-class I PI3K inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft models with known HPV and PI3K mutational status and available data on cetuximab sensitivity.

Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models, and the effect was particularly pronounced in cetuximab-resistant tumors.

While no correlation was observed between PI3K mutation status and response to either cetuximab or copanlisib, increased PI3K signaling activity evaluated through gene expression profiling showed a positive correlation with response to copanlisib.

Together, these data support further investigation of PI3K inhibition in HNSCC and suggests gene expression patterns associated with PI3K signaling as a potential biomarker for predicting treatment responses.

"These data support further investigation of PI3K inhibition in HNSCC and suggests gene expression patterns associated with PI3K signaling"

Dr. Konrad Klinghammer from The Charité – Universitätsmedizin Berlin said, "Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common type of cancer with 0.65 million new cases and 0.33 million deaths annually worldwide."

Upregulated PI3K/AKT/mTOR signaling has also been shown to increase resistance to radiotherapy and cytostatic drugs, and PI3K has been defined as an alternate signaling pathway in cetuximab-resistant HNSCC.

Accordingly, based on the cancer genome atlas data, up to 56% of HNSCC display either amplification or mutational changes in the PI3K pathway, and according to the head and neck cancer tissue array data, the PI3K/AKT/mTOR pathway is upregulated in over 90% in both HPV-positive and negative HNSCCs.

Upregulated PI3K/AKT/mTOR signaling, the occurrence of mutational changes in the PI3K pathway, and emerging clinical data from trials with PI3K inhibitors make PI3K an attractive target for cancer therapy, particularly in patients with recurrent/metastatic HNSCC.

Figure 4: Gene set enrichment plot of the EGFR and PI3K-AKT-mTOR signaling pathways for the copanlisib and cetuximab cohorts. (A) Cetuximab-responsive cohort (labeled as “REST’ on the plot) presented with a differentially stronger activity of EGFR signaling (MSigDB id M563) compared to the cetuximab-resistant HNSCC samples (p = 0.040; false discovery rate, q = 0.022). (B) Copanlisib-responsive cohort (labeled as “Intermediate’ on the plot) was found to harbor a differentially stronger activity of PI3K-AKT-mTOR pathway (MSigDB id M5923) compared to the copanlisib-resistant HNSCC samples (p = 0.03; q = 0.067).

Copanlisib is a highly selective, pan-class I PI3K inhibitor with preferential activity against the p110α and p110Δ isoforms that lead to the downregulation of PI3K signaling.

To this end, a panel of altogether 33 HPV-positive or negative HNSCC PDX models were selected based on PI3KCA mutation status and cetuximab sensitivity to evaluate the efficacy of copanlisib given as monotherapy and in combination with cetuximab, and furthermore, the capacity of copanlisib to overcome resistance to cetuximab.

The Klinghammer Research Team concluded in their Oncotarget Research Paperwe demonstrated an improved tumor control by combining copanlisib with cetuximab using 33 patient-derived xenograft models and thereby establishing a preclinical rationale for the evaluation of this combination therapy in a clinical setting. A phase Ib/II study of copanlisib in combination with cetuximab in HNSCC patients harboring a PI3KCA mutation/amplification and/or a PTEN loss is currently ongoing.

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DOI - https://doi.org/10.18632/oncotarget.27763

Full text - https://www.oncotarget.com/article/27763/text/

Correspondence to - Konrad Klinghammer - konrad.klinghammer@charite.de

Keywords - cetuximab, copanlisib, head and neck squamous cell carcinoma, HPV, patient-derived xenograft model

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