A randomised, placebo-controlled trial of weekly paclitaxel and saracatinib (AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer

McNeish, Iain A.; Ledermann, JA; Webber, Lee; James, Lisa M.; Kaye, SB; Hall, Marcia; Hall, Geoff; Clamp, Andrew R.; Earl, Helena; Banerjee, Susana; Kristeleit, RS; Raja, Fharat; Feeney, Amanda; Lawrence, Cheryl; Dawson-Athey, Linda; Persic, Mojca; Khan, Iftekhar

doi:10.1093/annonc/mdu363

Cited by 74 publications

(71 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A phase II trial in 37 patients with previously-treated advanced nonsmall-cell lung cancer, however, showed some signal of benefit, with 2 of 31 evaluable patients having partial responses lasting 3.7 and 14.6 months, and 6 patients being progression free at 16 weeks (primary endpoint) [28]. Saracatinib has not been studied in combination with other therapeutic agents in colorectal cancer but has not improved outcomes in combination studies with gemcitabine in pancreatic cancer [29] or with paclitaxel in platinum-resistant ovarian, fallopian and primary peritoneal cancer [30].…”

Section: Discussionmentioning

confidence: 99%

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Numerous human ovarian adenocarcinoma cells (HOAC) are sensitive to Dasatinib, an inhibitor of c-Src, which synergizes with carboplatin and paclitaxel in a cell-specific manner [8, 9]. A phase II clinical trial in platinum-resistant ovarian cancer patients showed no advantage in the association of Saracatinib, a dual inhibitor of Src and Abl, with paclitaxel [22]. Dasatinib, which entered in phase I in ovarian cancer patients, could however show more promising results because of its action on Src, Bcl-Abl, c-kit, PDGFβ and other kinases [23].…”

Section: Introductionmentioning

confidence: 99%

Dasatinib + Gefitinib, a non platinum-based combination with enhanced growth inhibitory, anti-migratory and anti-invasive potency against human ovarian cancer cells

Thibault

Jean‐Claude

2017

J Ovarian Res

View full text Add to dashboard Cite

BackgroundOvarian cancer is the leading cause of death for gynecological cancers and the 6th cause of women cancer death in developed countries. The late stage detection, the peritoneal dissemination and the acquisition of resistance against carboplatin are the main reasons to explain this poor prognosis and strengthen the need of alternative treatments to improve the management of ovarian cancer and/or to sensitize tumors to platinum salts. Epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (Met) and cellular Src kinase (c-Src) are crucial kinases implied in ovarian tumor growth, survival, invasion and resistance to carboplatin. Their expression is increased in advanced ovarian cancers and is correlated with poor prognosis. Despite a clear potential in inhibiting these proteins in ovarian cancer, as a single agent or in combination with a carboplatin treatment, we need to target kinases in tandem because of their capacity to trigger compensatory pathways that synergize to promote drug resistance.MethodsHere we target EGFR, c-Src and Met individually or in combination with carboplatin, using Gefitinib, Dasatinib and Crizotinib respectively, in a panel of carboplatin-sensitive (OVCAR-3, IGROV-1 and A2780) and carboplatin-resistant cells (SKOV-3 and EFO-21). We studied the ability of the most potent combination to induce apoptosis, regulate migration, invasion and to modulate the activation of proliferation and survival proteins.ResultsCrizotinib, Dasatinib and Gefitinib, alone or in combination with carboplatin, showed a cell-specific cytotoxic synergy in ovarian cancer cells. The Dasatinib plus Gefitinib combination was synergistic in OVCAR-3, SKOV-3 and, in IGROV-1 cells (high concentrations). This combination was unable to induce apoptosis but suppressed cell migration, invasion and the activation of EGFR, Erk, c-Src and Akt compared to single treatments.ConclusionsCombining carboplatin with kinase inhibitors lead to synergistic interactions in a cell-specific manner. Unlike platinum-based combinations, mixing Dasatinib with Gefitinib led to cytotoxic activity, inhibition of cell migration and invasion. Thus, the Dasatinib + Gefitinib combination presents anti-tumour properties that are superior to those of platinum-based combinations, indicating that it may well represent a promising new treatment modality to be tested in the clinic.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-017-0319-2) contains supplementary material, which is available to authorized users.

show abstract

“…The discovery of AZD0424 has not been previously described and this compound is currently partnered with Cancer Research UK -the sponsor of the ongoing clinical trials. c-Src as a target in oncology was initially pursued by AstraZeneca as an anti-invasive target but failed to deliver robust efficacy in clinical trials, including in gastric [24], castration-resistant prostate [25], hormone-receptornegative metastatic breast [26] and platinum-resistant ovarian [27] cancers. It is interesting to note that other Src inhibitors developed contemporaneously with saracatinib, such as dasatinib (Bristol Myers Squibb) and bosutinib (Pfizer) were ultimately approved for the treatment of chronic myeloid leukaemia (CML) on the basis of their potent activity against Bcr-Abl kinase rather than their Src activity.…”

Section: Inhibitors Of Src and Abl Kinases: Discovery Of Saracatinib mentioning

confidence: 99%

Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

Kettle

Wilson

2016

Drug Discovery Today

View full text Add to dashboard Cite

A randomised, placebo-controlled trial of weekly paclitaxel and saracatinib (AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer

Abstract: Clinicaltrials.gov NCT01196741; ISRCTN 32163062.

Cited by 74 publications

References 22 publications

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

Dasatinib + Gefitinib, a non platinum-based combination with enhanced growth inhibitory, anti-migratory and anti-invasive potency against human ovarian cancer cells

Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

Contact Info

Product

Resources

About