A Phase I Trial of Dasatinib, an Src-Family Kinase Inhibitor, in Combination with Paclitaxel and Carboplatin in Patients with Advanced or Recurrent Ovarian Cancer

Secord, Angeles Alvarez; Teoh, Deanna K.; Barry, William T.; Yu, Miao; Broadwater, Gloria; Havrilesky, Laura J.; Lee, Paula S.; Berchuck, Andrew; Lancaster, Johnathan M.

doi:10.1158/1078-0432.ccr-12-0507

Cited by 59 publications

(40 citation statements)

References 21 publications

(31 reference statements)

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“…However, to date, there has been limited success in using dasatinib in the treatment of ovarian cancer patients. When dasatinib was assessed as a single-agent therapy in patients with relapsed epithelial ovarian cancer, minimal antitumor activity was observed, although we note there were only two patients with OCCC in this study, neither of which had known ARID1A status (50,51). In a recent phase I clinical trial using dasatinib in combination with standard cytotoxic chemotherapy (carboplatin and paclitaxel), the drug combination regime could be delivered safely and some evidence of clinical efficacy was achieved (50,51).…”

Section: Discussionmentioning

confidence: 77%

“…When dasatinib was assessed as a single-agent therapy in patients with relapsed epithelial ovarian cancer, minimal antitumor activity was observed, although we note there were only two patients with OCCC in this study, neither of which had known ARID1A status (50,51). In a recent phase I clinical trial using dasatinib in combination with standard cytotoxic chemotherapy (carboplatin and paclitaxel), the drug combination regime could be delivered safely and some evidence of clinical efficacy was achieved (50,51). Of course, neither of these trials were designed to test the hypothesis that ARID1A-mutant OCCC might respond to dasatinib therapy and based upon the work we describe in this manuscript, we believe that testing this hypothesis is warranted.…”

Section: Discussionmentioning

confidence: 79%

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Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

Miller

Brough

Bajrami

et al. 2016

Molecular Cancer Therapeutics

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New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G 1 -S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 79%

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

Miller

Brough

Bajrami

et al. 2016

Molecular Cancer Therapeutics

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“…5 Based on this data, we conducted a phase 1 trial of combination paclitaxel and carboplatin in women with advanced and recurrent epithelial ovarian, peritoneal, or tubal cancer. 9 We observed a response rate of 40% including 3 (15%) complete responses and 5 (25%) partial responses with stable disease in 10 (50%) patients. The combination demonstrated clinical activity based on the response rates and survival outcomes in this patient population that included women with platinum-resistant disease.…”

mentioning

confidence: 68%

Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

Secord

Teoh

Jia³

et al. 2014

Int J Gynecol Cancer

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Purpose To explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan and doxorubicin in ovarian cancer cells. Experimental Design Cells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein: IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pre- and post-treatment. Dose-response curves were constructed and the combination index (CI) for drug interaction was calculated. Results In the IGROV1 cells, dasatinib alone reduced pSRC/tSRC 71% and p-paxillin/t-paxillin ratios 77%. pSRC (3-33%, p=0.002-0.04) and p-paxicillin (6-19%; p=0.01-0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine or topotecan had a synergistic anti-proliferative effect (CI 0.49-0.68), while dasatinib combined with doxorubicin had an additive effect (CI 1.08). In SKOV3 cells, dasatinib resulted in less pronounced reductions of pSRC/tSRC (49%) and p-paxillin/t-paxillin (62%). pSRC (18%; p<0.001) and p-paxillin levels (18%; p=0.001; 9%; p=0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on proliferation of these cells (CI 1.49-2.27). Conclusion Dasatinib in combination with relapse chemotherapeutic agents appears to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy is warranted.

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“…Imatinib and dasatinib, selective inhibitors of PDGFR and C-KIT, were evaluated in small phases II trials in recurrent EOC without any improvement both in RR and in survival endpoints [110,111].…”

Section: Anti-angiogenetic Agents In Platinum-resistant Ovarian Cancermentioning

confidence: 99%

Target Therapy in Platinum-Refractory/Resistant Ovarian Cancer: From Preclinical Findings to Current Clinical Practice

Staropoli¹,

Botta²,

Ciliberto³

et al. 2013

JCT

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Epithelial ovarian cancer (EOC) is the sixth most common malignancy in women. Ovarian tumors consist of several clinical and pathological entities that share an anatomic site. The gold standard treatment, both in front-line and in adjuvant setting, is represented by carboplatin/paclitaxel combination. Conversely, the second-line treatment is not well defined. The response to platinum is the major prognostic factor for survival. In this review we discuss the current views on platinum-refractory/resistant patient treatment only, which includes patients progressing or relapsing within 6 months from the last platinum-based course. Concerning this subgroup, the activity of several conventional drugs was confirmed in different trials without a significant impact in terms of overall survival. In the last years particular emphasis was given to targeted anti-angiogenetic therapy which produced a survival improvement with an acceptable toxicity profile. New "ad hoc" approaches, with a major attention to outcome-predictive factors, are eagerly awaited.

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A Phase I Trial of Dasatinib, an Src-Family Kinase Inhibitor, in Combination with Paclitaxel and Carboplatin in Patients with Advanced or Recurrent Ovarian Cancer

Cited by 59 publications

References 21 publications

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

Target Therapy in Platinum-Refractory/Resistant Ovarian Cancer: From Preclinical Findings to Current Clinical Practice

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