Limits...
Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer.

Fox EM, Arteaga CL, Miller TW - Front Oncol (2012)

Bottom Line: In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy.PI3K activates several proteins which promote cell cycle progression and survival.In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Nashville, TN, USA.

ABSTRACT
Antiestrogen therapies targeting estrogen receptor α (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.

No MeSH data available.


Related in: MedlinePlus

Diagram of a clinical trial with a PI3K pathway inhibitor in AI-resistant breast cancer. Patients with breast cancer that progressed on AI therapy will be subjected to a biopsy to confirm ER+, HER2-negative, PIK3CA-mutant status. Eligible patients would then be randomized to another AI plus a PI3K inhibitor, or fulvestrant plus the PI3K inhibitor. FDG-PET scans would be performed before and after 4 weeks of therapy to identify early metabolic changes. Patients will be treated until progression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3472546&req=5

Figure 3: Diagram of a clinical trial with a PI3K pathway inhibitor in AI-resistant breast cancer. Patients with breast cancer that progressed on AI therapy will be subjected to a biopsy to confirm ER+, HER2-negative, PIK3CA-mutant status. Eligible patients would then be randomized to another AI plus a PI3K inhibitor, or fulvestrant plus the PI3K inhibitor. FDG-PET scans would be performed before and after 4 weeks of therapy to identify early metabolic changes. Patients will be treated until progression.

Mentions: Cancer cells harboring activating mutations in PIK3CA exhibit increased sensitivity to PI3K inhibition (Miller et al., 2010; Sanchez et al., 2011; Maira et al., 2012), suggesting that this class of drugs may be most effective against tumors with mutations in the PI3K pathway. In mice bearing ER+, HER2-negative, PIK3CA-mutant MCF-7 breast cancer xenografts, treatment with the combination of fulvestrant and BKM120 induced tumor regression (Miller et al., 2011b). Using [18F]FDG-PET imaging as an early biomarker of metabolic inhibition, treatment with BKM120 but not fulvestrant decreased tumor FDG uptake. BKM120 increased tumor cell apoptosis, while fulvestrant decreased tumor cell proliferation. These findings may be validated clinically in a phase II clinical trial where post-menopausal patients with AI-resistant, ER+, HER2-negative, PIK3CA-mutant breast cancer are randomized to treatment with another AI plus a PI3K inhibitor vs. fulvestrant plus a PI3K inhibitor (Figure 3). The novel agent in such a trial would be the PI3K inhibitor, but the comparison would be an AI vs. fulvestrant. The primary endpoint would be PFS. Incorporation of non-invasive imaging with [18F]FDG-PET at baseline and after several weeks of treatment could identify metabolic changes indicative of a pharmacodynamic effect. This comparison would inform us whether (1) the addition of a PI3K inhibitor to an AI is beneficial, (2) downregulation of ER is superior to estrogen deprivation (AI) therapy in the context of PI3K inhibition, and (3) metabolic inhibition at an early time point as reflected by FDG-PET is predictive of PFS.


Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer.

Fox EM, Arteaga CL, Miller TW - Front Oncol (2012)

Diagram of a clinical trial with a PI3K pathway inhibitor in AI-resistant breast cancer. Patients with breast cancer that progressed on AI therapy will be subjected to a biopsy to confirm ER+, HER2-negative, PIK3CA-mutant status. Eligible patients would then be randomized to another AI plus a PI3K inhibitor, or fulvestrant plus the PI3K inhibitor. FDG-PET scans would be performed before and after 4 weeks of therapy to identify early metabolic changes. Patients will be treated until progression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472546&req=5

Figure 3: Diagram of a clinical trial with a PI3K pathway inhibitor in AI-resistant breast cancer. Patients with breast cancer that progressed on AI therapy will be subjected to a biopsy to confirm ER+, HER2-negative, PIK3CA-mutant status. Eligible patients would then be randomized to another AI plus a PI3K inhibitor, or fulvestrant plus the PI3K inhibitor. FDG-PET scans would be performed before and after 4 weeks of therapy to identify early metabolic changes. Patients will be treated until progression.
Mentions: Cancer cells harboring activating mutations in PIK3CA exhibit increased sensitivity to PI3K inhibition (Miller et al., 2010; Sanchez et al., 2011; Maira et al., 2012), suggesting that this class of drugs may be most effective against tumors with mutations in the PI3K pathway. In mice bearing ER+, HER2-negative, PIK3CA-mutant MCF-7 breast cancer xenografts, treatment with the combination of fulvestrant and BKM120 induced tumor regression (Miller et al., 2011b). Using [18F]FDG-PET imaging as an early biomarker of metabolic inhibition, treatment with BKM120 but not fulvestrant decreased tumor FDG uptake. BKM120 increased tumor cell apoptosis, while fulvestrant decreased tumor cell proliferation. These findings may be validated clinically in a phase II clinical trial where post-menopausal patients with AI-resistant, ER+, HER2-negative, PIK3CA-mutant breast cancer are randomized to treatment with another AI plus a PI3K inhibitor vs. fulvestrant plus a PI3K inhibitor (Figure 3). The novel agent in such a trial would be the PI3K inhibitor, but the comparison would be an AI vs. fulvestrant. The primary endpoint would be PFS. Incorporation of non-invasive imaging with [18F]FDG-PET at baseline and after several weeks of treatment could identify metabolic changes indicative of a pharmacodynamic effect. This comparison would inform us whether (1) the addition of a PI3K inhibitor to an AI is beneficial, (2) downregulation of ER is superior to estrogen deprivation (AI) therapy in the context of PI3K inhibition, and (3) metabolic inhibition at an early time point as reflected by FDG-PET is predictive of PFS.

Bottom Line: In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy.PI3K activates several proteins which promote cell cycle progression and survival.In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Nashville, TN, USA.

ABSTRACT
Antiestrogen therapies targeting estrogen receptor α (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.

No MeSH data available.


Related in: MedlinePlus