TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis

Mitri, Zahi; Nanda, Rita; Blackwell, Kimberly; Costelloe, Colleen M.; Hood, I. M.; Wei, Caimiao; Brewster, Abenaa M.; Ibrahim, Nuhad K.; Koenig, Kimberly; Hortobágyi, Gabriel N.; Poznak, Catherine Van; Rimawi, Mothaffar F.; Moulder-Thompson, Stacy

doi:10.1158/1078-0432.ccr-15-2845

Cited by 32 publications

(22 citation statements)

References 51 publications

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“…These data suggest that SRC may be clinically relevant in the ER ϩ subtype, and, indeed, several studies provide hints that this may be the case. Clinical trials using multitar- geting kinase inhibitors that inhibit SRC, dasatinib (74,75) and bosutinib (76), have been largely disappointing; however, there were some hints of stable disease in ER ϩ breast cancer patients. While these trials did not take into account the p53 status of the ER ϩ patients, many primary ER ϩ breast cancers retain wild-type p53 (45,46).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, suppression of wild-type p53 function by SRC has important clinical implications. Several preclinical and clinical trials in breast cancer have suggested that inhibition of SRC using the multitargeting kinase inhibitors dasatinib (74,75) and bosutinib (76,84) resulted in stable disease in a fraction of the ER ϩ cohort. We postulate that these patients may have expressed wild-type p53 although p53 status was not reported in these studies.…”

Section: Discussionmentioning

confidence: 99%

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SRC Increases MYC mRNA Expression in Estrogen Receptor-Positive Breast Cancer via mRNA Stabilization and Inhibition of p53 Function

Abdullah

Korkaya

Iizuka

et al. 2018

Molecular and Cellular Biology

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The transcription factor is important in breast cancer and its mRNA is maintained at a high level even in the absence of gene amplification. The mechanism(s) underlying increased mRNA expression are unknown. Here we demonstrate that mRNA was stabilized upon estrogen stimulation of estrogen receptor-positive breast cancer cells, via SRC-dependent effects on a recently described RNA-binding protein ΔN-IMP1. We also show that loss of the tumor suppressor p53 increased mRNA levels, even in the absence of estrogen stimulation. However, in cells with wildtype p53, SRC acted to overcome p53-mediated inhibition of estrogen-stimulated cell cycle entry and progression. SRC thus promotes cell proliferation in two ways: stabilizing mRNA and inhibiting p53 function. Since estrogen receptor-positive breast cancers typically express wild-type p53, these studies establish a rationale for p53 status to be predictive for effective SRC inhibitor treatment in this subtype of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SRC Increases MYC mRNA Expression in Estrogen Receptor-Positive Breast Cancer via mRNA Stabilization and Inhibition of p53 Function

Abdullah

Korkaya

Iizuka

et al. 2018

Molecular and Cellular Biology

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“…ZA was recently used in association with Dasatinib for the treatment of Breast Cancer Bone Metastasis with good responses [57]. NZ, like ZA [13], inhibited the migration of MSCs and reduced the secretion of growth factors involved in breast cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

et al. 2017

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Zoledronic Acid (ZA) rapidly concentrates into the bone and reduces skeletal-related events and pain in bone metastatic prostate cancer (PCa), but exerts only a limited or absent impact as anti-cancer activity. Recently, we developed self-assembling nanoparticles (NPS) encapsulating zoledronic acid (NZ) that allowed a higher intratumor delivery of the drug compared with free zoledronic acid (ZA) in in vivo cancer models of PCa. Increasing evidence suggests that Bone Marrow (BM) Mesenchymal stromal cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis.We demonstrated that treatment with NZ decreased migration and differentiation into adipocytes and osteoblasts of MSCs and inhibited osteoclastogenesis. Treatment with NZ reduced the capability of MSCs to promote the migration and the clonogenic growth of the prostate cancer cell lines PC3 and DU145. The levels of Interleukin-6 and of the pro-angiogenic factors VEGF and FGF-2 were significantly reduced in MSC-CM derived from MSCs treated with NZ, and CCL5 secretion was almost totally abolished. Moreover, treatment of MSCs with supernatants from PC3 cells, leading to tumor-educated MSCs (TE-MSCs), increased the secretion of IL-6, CCL5, VEGF and FGF-2 by MSCs and increased their capability to increase PC3 cells clonogenic growth. Treatment with NZ decreased cytokine secretion and the pro-tumorigenic effects also of TE-MSCS. In conclusion, demonstrating that NZ is capable to inhibit the cross talk between MSCs and PCa, this study provides a novel insight to explain the powerful anticancer activity of NZ on PCa.

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“…Src inhibitor dasatinib, FDA-approved compound for the treatment of chronic myeloid leukemia, was found to suppress resistance of breast cancer cells to endocrine therapy [107,108] and to doxorubicin [109]. Dasatinib in phase II clinical trials exhibited limited single-agent activity in ER+ patients [37] and also showed potential in combinatory therapies with zoledronic acid in ER+ patients [38] as well as with paclitaxel in metastatic breast cancer patients [36]. Moreover, dasatinib in combination with trastuzumab prolonged progression-free survival in Her2+ breast cancer patients [39].…”

Section: Nf-κb Intercellular Adhesion and Nuclear Proteins Are Potenmentioning

confidence: 99%

How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

Lapčík

Pospíšilová

Janáčová

et al. 2020

Cancers

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Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastasis, analyze targetable molecular mechanisms in Gene Set Enrichment Analysis and identify relevant inhibitors. Lymph node positivity is generally associated with NF-κB and Src pathways and is related to high risk (OR: 5.062 and 2.401 in MMCI_706 and SUPERTAM_HGU133A, respectively, p < 0.05) of distant metastasis in luminal A patients. However, a part (≤15%) of lymph node negative tumors at the diagnosis develop the distant metastasis which is related to cell proliferation control and thrombolysis. Distant metastasis of lymph node positive patients is mostly associated with immune response. These pro-metastatic mechanisms further vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies.

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TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis

Abstract: Combination therapy was well tolerated and produced responses in bone in patients with HR-positive tumors. Clin Cancer Res; 22(23); 5706-12. ©2016 AACR.

Cited by 32 publications

References 51 publications

SRC Increases MYC mRNA Expression in Estrogen Receptor-Positive Breast Cancer via mRNA Stabilization and Inhibition of p53 Function

SRC Increases MYC mRNA Expression in Estrogen Receptor-Positive Breast Cancer via mRNA Stabilization and Inhibition of p53 Function

Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

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