Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study

Ocaña, Alberto; Gil-Martín, Marta; Antolín, Silvia; Atienza, M.; Montaño, Álvaro; Ribelles, Nuria; Urruticoechea, Ander; Falcón, Alejandro; Pernas, Sònia; Orlando, Javier; Montero, Juan Carlos; Escudero, M.J.; Benito, Sara; Caballero, Rosalía; Carrasco, Eva; Rojo, Federico; Pandiella, Atanasio; Ruíz‐Borrego, Manuel

doi:10.1007/s10549-018-05100-z

Cited by 37 publications

(23 citation statements)

References 14 publications

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“…Administration of TAB-DAS-(PEI)NPs showed a slight increase in G1 compared to the free drug, what confirmed that the NPs mediates their effect in the same manner as DAS in its free formulation (Figure 9a). On the other hand, Figure 9b showed enhanced apoptosis in resistant cells, treated with TAB-DAS-(PEI)NPs in comparison with free DAS and free TAB, which suggests that the resistant cells rely more on this kinase that the naïve ones, a finding in line with previous reports [12].…”

Section: Das-loaded Tab-conjugated Nps Increment Cycle Arrest and Celsupporting

confidence: 90%

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Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer

et al. 2019

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Dasatinib (DAS) is a multikinase inhibitor that acts on several signaling kinases. DAS is used as a second-line treatment for chronic accelerated myeloid and Philadelphia chromosome-positive acute lymphoblastic leukemia. The therapeutic potential of DAS in other solid tumours is under evaluation. As for many other compounds, an improvement in their pharmacokinetic and delivery properties would potential augment the efficacy. Antibody-targeted biodegradable nanoparticles can be useful in targeted cancer therapy. DAS has shown activity in human epidermal growth factor receptor 2 (HER2) positive tumors, so conjugation of this compound with the anti-HER2 antibody trastuzumab (TAB) with the use of nanocarriers could improve its efficacy. TAB-targeted DAS-loaded nanoparticles were generated by nanotechnology. The guided nanocarriers enhanced in vitro cytotoxicity of DAS against HER2 human breast cancer cell lines. Cellular mechanistic, release studies and nanoparticles stability were undertaken to provide evidences for positioning DAS-loaded TAB-targeted nanoparticles as a potential strategy for further development in HER2-overexpressing breast cancer therapy.

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Section: Das-loaded Tab-conjugated Nps Increment Cycle Arrest and Celsupporting

confidence: 90%

“…For instance, SRC has been implicated in the development of resistance to the anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab (TAB) in HER2 positive breast cancer. In this context, inhibition of SRC with DAS has shown preclinical and clinical activity [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer

et al. 2019

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“…In women with invasive metastatic breast cancer, refractory to taxane and/or anthracycline therapy, partial response was found in 35% of HR positive tumors and only 6% in HR negative tumors when treated in combination with capecitabine [111]. Recently it has been demonstrated that dasatinib can be safely combined with trastuzumab and paclitaxel in HER2+ metastatic breast cancer patients (83% HR positive) and it resulted in being active with an ORR of 79% [121]. Indeed, combining trastuzumab with dasatinib has a strong preclinical rationale, as suggested by the key role of Src in trastuzumab resistant cancer cell models [122].…”

Section: Dasatinibmentioning

confidence: 99%

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far

Martellucci

Clementi

Sabetta

et al. 2020

Cancers

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Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory and invasive phenotype. Indeed, oncogenic activation of SFKs has been demonstrated to play an important role in solid cancers; promoting tumor growth and formation of distant metastases. Several drugs targeting SFKs have been developed and tested in preclinical models and many of them have successfully reached clinical use in hematologic cancers. Although in solid tumors SFKs inhibitors have consistently confirmed their ability in blocking cancer cell progression in several experimental models; their utilization in clinical trials has unveiled unexpected complications against an effective utilization in patients. In this review, we summarize basic molecular mechanisms involving SFKs in cancer spreading and metastasization; and discuss preclinical and clinical data highlighting the main challenges for their future application as therapeutic targets in solid cancer progression

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“…Associated with promising clinical outcomes, pharmacodynamic analysis of tumor tissues, blood samples and skin biopsies of 29 patients enrolled, revealed a significant decrease of phospho-Src, phospho-ERK and phospho-AKT in epidermal keratinocytes. These results definitely encouraged dasatinib use in combination with trastuzumab and paclitaxel, due to good toxicity profile and a high efficacy, as revealed by an objective response rate of 79.3% [ 99 ], however, because of the absence of a control arm, further investigations in subsequent Phase II/III controlled trials are required.…”

Section: Combined Therapy Of C-src and Egfr Inhibitors In Recent Cmentioning

confidence: 99%

c-Src and EGFR Inhibition in Molecular Cancer Therapy: What Else Can We Improve?

Belli

Esposito

Servetto

et al. 2020

Cancers

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The proto-oncogene c-Src is a non-receptor tyrosine kinase playing a key role in many cellular pathways, including cell survival, migration and proliferation. c-Src de-regulation has been observed in several cancer types, making it an appealing target for drug discovery efforts. Recent evidence emphasizes its crucial role not only in promoting oncogenic traits, but also in the acquisition and maintenance of cancer resistance to various chemotherapeutic or molecular target drugs. c-Src modulates epidermal growth factor receptor (EGFR) activation and amplifies its downstream oncogenic signals. In this review, we report several studies supporting c-Src kinase role in the intricate mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs). We further highlighted pre- and clinical progresses of combined treatment strategies made in recent years. Several pre-clinical data have encouraged the use of c-Src inhibitors in combination with EGFR inhibitors. However, clinical trials provided controversial outcomes in some cancer types. Despite c-Src inhibitors showed good tolerability in cancer patients, no incontrovertible and consistent clinical responses were recorded, supporting the idea that a better selection of patients is needed to improve clinical outcome. Currently, the identification of biological markers predictive of therapy response and the accurate molecular screening of cancer patients aimed to gain most clinical benefits become decisive and mandatory.

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Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study

Cited by 37 publications

References 14 publications

Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer

Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far

c-Src and EGFR Inhibition in Molecular Cancer Therapy: What Else Can We Improve?

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