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|Ref Type||Journal Article|
|Authors||Sommer A, Kopitz C, Schatz CA, Nising CF, Mahlert C, Lerchen HG, Stelte-Ludwig B, Hammer S, Greven S, Schuhmacher J, Braun M, Zierz R, Wittemer-Rump S, Harrenga A, Dittmer F, Reetz F, Apeler H, Jautelat R, Huynh H, Ziegelbauer K, Kreft B|
|Title||Preclinical Efficacy of the Auristatin-Based Antibody-Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors.|
|Abstract Text||The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric, and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody-drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which binds to the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a noncleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nanomolar to subnanomolar range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro Pharmacokinetic analyses in mice bearing FGFR2-positive NCI-H716 tumors indicated that the toxophore metabolite of FGFR2-ADC was enriched more than 30-fold in tumors compared with healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line-based or patient-derived xenograft models of human gastric or breast cancer. Furthermore, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients and a phase I study (NCT02368951) has been initiated. Cancer Res; 76(21); 6331-9. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Aprutumab ixadotin||BAY1187982|FGFR2-ADC||FGFR2 Antibody 3||Aprutumab ixadotin (BAY1187982) is a monoclonal FGFR2 antibody in conjugation with a derivative of auristatin, which may target FGFR2-expressing tumor cells for cytotoxicity (PMID: 27543601).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR2 dec exp||breast cancer||resistant||Aprutumab ixadotin||Preclinical - Cell culture||Actionable||In a preclinical study, Aprutumab ixadotin (BAY1187982) did not inhibit growth of breast cancer cells with very low Fgfr2 expression level in culture (PMID: 27543601).||27543601|
|FGFR2 positive||breast cancer||sensitive||Aprutumab ixadotin||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, Aprutumab ixadotin (BAY1187982) inhibited survival of Fgfr2 positive breast cancer cell lines in culture, and suppressed tumor growth in both cell line and patient-derived xenograft models (PMID: 27543601).||27543601|
|FGFR2 amp||ovarian cancer||sensitive||Aprutumab ixadotin||Preclinical - Pdx||Actionable||In a preclinical study, Aprutumab ixadotin (BAY1187982) inhibited tumor growth in patient-derived xenograft models of FGFR2 amplified ovarian cancer (PMID: 27543601).||27543601|
|FGFR2 positive||stomach cancer||sensitive||Aprutumab ixadotin||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, Aprutumab ixadotin (BAY1187982) inhibited survival of gastric cancer cell lines with elevated Fgfr2 expression level in culture, and suppressed tumor growth in cell line or patient-derived xenograft models (PMID: 27543601).||27543601|
|FGFR2 positive||Advanced Solid Tumor||sensitive||Aprutumab ixadotin||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, sensitivity to Aprutumab ixadotin (BAY1187982) positively correlated with Fgfr2 expression level in a variety of cancer cell lines in culture, and in cell line or patient-derived xenograft models (PMID: 27543601).||27543601|
|FGFR2 over exp||colorectal cancer||sensitive||Aprutumab ixadotin||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Aprutumab ixadotin (BAY1187982) inhibited survival of colorectal cancer cells with over expressing Fgfr2 in culture, and suppressed tumor growth in cell line xenograft models (PMID: 27543601).||27543601|