Phase II evaluation of dasatinib in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study☆
Highlights
► No objective responses with 7 of 34 patients had PFS ≥ 6 months. ► The agent was well tolerated with the major toxicities being grade 3 nausea/emesis, pain and pulmonary. ► No detectable relationships between clinical outcome and biomarkers.
Introduction
Despite initially high remission rates, at least 75% of women diagnosed with advanced stage epithelial ovarian carcinoma (EOC) will relapse and ultimately die of their disease [1]. Treatment of these patients once they develop recurrent disease remains a major problem. The need for new therapeutic strategies is evident. The SRC family of kinases (SFK) is a nine member group of membrane associated non-receptor tyrosine kinases that are involved in a variety of cellular signaling pathways [2]. The SFK is involved in the oncogenesis of numerous tumors including ovarian cancer. SRC regulates many intracellular signaling pathways responsible for various important tumor cell functions such as proliferation, motility and invasion, angiogenesis, and survival. SRC has been found to be overexpressed in a majority of late stage ovarian tumors and cell lines [3].
SRC is a component of signaling pathways downstream of many growth factor receptors, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and MNNG transforming gene product (c-MET) [4]. Increased resistance to traditional chemotherapy is modulated by SRC through increased activity of RAS and AKT [5]. Inhibition of SRC enhanced the activity of cytotoxic agents, including cisplatin, gemcitabine, and paclitaxel through the activation of caspase-3 in preclinical models [5], [6], [7]. In addition, tumor growth was blunted when human ovarian cancer cells carrying an antisense SRC construct were implanted into mice bearing these xenografts [8].
VEGF is an important growth factor for ovarian cancer cells [9]. VEGF was significantly down-regulated by SRC inhibition and microvessel density was reduced [10]. Anti-VEGF therapy has demonstrated activity in patients with recurrent and primary disease [11], [12]. VEGF stimulation of its receptor increased tyrosine phosphorylation of focal adhesion kinase, p130 CAS and paxillin [13]. Increased activity of these mediators leads to an increased epithelial-to-mesenchymal transition (EMT), a crucial step to enhancing the metastatic potential of these cancer cells [14]. SRC is a key intermediate in the EMT process [15], [16]. In addition, caveolin-1 expression indirectly promotes cell–cell adhesion in ovarian cancer cells [17], [18]. SRC interferes with caveolin function also promoting EMT and encouraging tumor spread.
Dasatinib is a potent oral inhibitor of breakpoint cluster region–Abelson fusion protein (BCR-ABL), c-KIT, ephrin type-A receptor 2 (EPHA2), c-FMS, and SFK [19], [20]. These kinases are implicated in oncogenic process and maintaining the metastatic phenotype of many cancers. Dasatinib's mechanism of action depends on it successfully competing for the ATP binding site contained in the kinase domain. The agent is widely approved for chronic myelogenous leukemia and Ph + acute lymphoblastic leukemia and is now under investigation for treating various solid tumors [21].
Based on these observations, the evaluation of dasatinib in patients with recurrent EOC was undertaken by the Gynecologic Oncology Group (GOG). Translational research (TR) objectives were included to explore the association between biomarkers and patient outcome. Biomarkers included cell-free DNA (cfDNA), circulating tumor cells (CTCs), circulating endothelial cells (CECs), circulating endothelial precursors (CEPs), and seven plasma biomarkers relevant to dasatinib treatment (EGF and its soluble receptor [sEGFR], VEGF and its soluble receptors [sVEGFR1, sVEGFR2, sVEGFR3], and insulin like growth factor binding protein 2 [IGFBP2]).
Section snippets
Eligibility
Eligible patients had a histologically confirmed diagnosis of EOC or primary peritoneal carcinoma, measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) [22], a GOG performance status of 0–2, and adequate bone marrow (absolute neutrophil count ≥ 1500/μL, platelet count ≥ 100,000/μL), renal (serum creatinine ≤ 1.5 × the upper limit of normal), and hepatic function (total bilirubin ≤ 1.5 × the upper limit of normal, and transaminases and alkaline phosphatase ≤ 2.5 ×
Patients and eligibility
Thirty-five patients were enrolled. One patient was deemed ineligible because inadequate data were available. Patient characteristics are listed in Table 1. A majority of patients (58.8%) received two prior regimens. All patients had performance status of 0 or 1.
Treatment and response
Patients received a median of two cycles (range, 1–12) of protocol therapy. Of 23 patients who received two or more cycles, 15 were escalated to 140 mg of dasatinib daily (70 mg bid) and 2 were reduced to 70 mg daily.
There were no
Discussion
Dasatinib was well tolerated but had minimal activity in patients with recurrent ovarian or primary peritoneal carcinoma. With SRC reported to be overexpressed in approximately 90% of ovarian cancers [3], no prescreening was performed to determine eligibility.
SRC occupies a strategic position in many cell signaling pathways affecting cell proliferation, growth, and survival [4]. It has an important role in mediating the epithelial-to-mesenchymal transition enhancing the metastatic potential of
Conflict of interest
The co-authors have no conflicts of interest to declare.
Acknowledgments
The authors thank De-Yu Shen in the Department of Gynecologic Oncology and Reproductive Medicine at MD Anderson Cancer Center for performing the quantitative PCR, the GOG Tissue Bank for their assistance with the banking and distribution of specimens and Veridex for providing specimen collection kits. The authors acknowledge support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program (AKS).
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This study was supported, in part, by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517), R01 CA140323 (to AKG), P50 CA083639 (to AKS), P50 CA093638 (AKG and RJS), and CA006927 (RJS). AKG was also supported by the Chancellors Distinguished Chair in Biomedical Sciences Professorship, and AKS is also supported by the Betty Anne Asche Murray Distinguished Professorship. The following Gynecologic Oncology Group member institutions participated in this study: Abington Memorial Hospital, Walter Reed Army Medical Center, Colorado Gynecologic Oncology Group P.C., Milton S. Hershey Medical Center, University of North Carolina School of Medicine, Indiana University School of Medicine, Rush-Presbyterian-St. Luke's Medical Center, State University of New York at Stony Brook, Fox Chase Cancer Center, University of Oklahoma, University of Virginia Health Sciences Center, University of Wisconsin Hospital, Women and Infants Hospital, The Hospital of Central Connecticut, and Community Clinical Oncology Program.