TY - JOUR
T1 - Dasatinib, paclitaxel, and carboplatin in women with advanced-stage or recurrent endometrial cancer
T2 - A pilot clinical and translational study
AU - Coleman, Robert L.
AU - Hu, Wei
AU - Soliman, Pamela
AU - Nick, Alpa
AU - Ramirez, Pedro T.
AU - Westin, Shannon N.
AU - Garcia, Michael E.
AU - Zhu, Zhifei
AU - Palancia, Julieta
AU - Fellman, Bryan M.
AU - Yuan, Ying
AU - Ram, Prahlad
AU - Bischoff, Farideh
AU - Schmeler, Kathleen
AU - Bodurka, Diane
AU - Meyer, Larissa A.
AU - Sood, Anil K.
N1 - Funding Information:
We thank Scientific Publications, Research Medical Library at MD Anderson Cancer Center for editing our manuscript and the RPPA Core for RPPA analysis. Financial support was provided by the NIH under award numbers P50 CA098258 and P50 CA217685, the Frank McGraw Memorial Chair in Cancer Research, and the American Cancer Society Research Professor Award (to AKS). RLC is supported by the Ann Rife Cox Chair in Gynecology. SNW was supported by the Andrew Sabin Family Fellowship. LAM was supported by the NIH under award number K07CA201013 .
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/4
Y1 - 2021/4
N2 - Purpose: To evaluate the effect of dasatinib therapy on EphA2 signaling in cancers of women with measurable (biopsy amenable) advanced-stage, chemo-naïve primary or recurrent endometrial cancer. Preliminary efficacy was also assessed. Patients and methods: We performed a pilot study of single-agent dasatinib lead-in, followed by triplet dasatinib, paclitaxel, and carboplatin. We measured the downstream effectors of EphA2 signaling in pre- and post-dasatinib treatment biopsy tissue samples; we also determined the severity of adverse events and patients' progression-free survival and overall survival durations. Results: Eighteen patients were recruited and given dasatinib (150 mg orally daily for 14 days), followed by paclitaxel, carboplatin and dasatinib (daily) for six cycles (21-day cycles). Seventeen patients were evaluable for toxicity and 11 patients for response. A reverse phase protein array and proximity ligation assay revealed that CRAF/BRAF dimerization, caveolin-1 level, and Notch pathway signaling were predictive of response and resistance to dasatinib. Overall, the objective response rate was 45% (95% CI: 17%–77%), with median progression-free survival duration of 10.5 months and median overall survival duration of 30.4 months. The most common grade 3 or 4 adverse events were neutropenia (76%), thrombocytopenia (53%), anemia (53%), and fatigue (12%). Conclusions: Caveolin-1 expression, in combination with CRAF/BRAF heterodimerization, is associated with resistance to EphA2 targeting by dasatinib. The triplet combination showed interesting clinical activity in endometrial cancer with acceptable toxicity. Pretreatment with dasatinib may accentuate combination therapy toxicity.
AB - Purpose: To evaluate the effect of dasatinib therapy on EphA2 signaling in cancers of women with measurable (biopsy amenable) advanced-stage, chemo-naïve primary or recurrent endometrial cancer. Preliminary efficacy was also assessed. Patients and methods: We performed a pilot study of single-agent dasatinib lead-in, followed by triplet dasatinib, paclitaxel, and carboplatin. We measured the downstream effectors of EphA2 signaling in pre- and post-dasatinib treatment biopsy tissue samples; we also determined the severity of adverse events and patients' progression-free survival and overall survival durations. Results: Eighteen patients were recruited and given dasatinib (150 mg orally daily for 14 days), followed by paclitaxel, carboplatin and dasatinib (daily) for six cycles (21-day cycles). Seventeen patients were evaluable for toxicity and 11 patients for response. A reverse phase protein array and proximity ligation assay revealed that CRAF/BRAF dimerization, caveolin-1 level, and Notch pathway signaling were predictive of response and resistance to dasatinib. Overall, the objective response rate was 45% (95% CI: 17%–77%), with median progression-free survival duration of 10.5 months and median overall survival duration of 30.4 months. The most common grade 3 or 4 adverse events were neutropenia (76%), thrombocytopenia (53%), anemia (53%), and fatigue (12%). Conclusions: Caveolin-1 expression, in combination with CRAF/BRAF heterodimerization, is associated with resistance to EphA2 targeting by dasatinib. The triplet combination showed interesting clinical activity in endometrial cancer with acceptable toxicity. Pretreatment with dasatinib may accentuate combination therapy toxicity.
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U2 - 10.1016/j.ygyno.2021.01.022
DO - 10.1016/j.ygyno.2021.01.022
M3 - Article
C2 - 33551196
AN - SCOPUS:85100442658
SN - 0090-8258
VL - 161
SP - 104
EP - 112
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 1
ER -