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Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer.

Moestue SA, Dam CG, Gorad SS, Kristian A, Bofin A, Mælandsmo GM, Engebråten O, Gribbestad IS, Bjørkøy G - Breast Cancer Res. (2013)

Bottom Line: Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation.This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors.Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancer cells through numerous mutations and epigenetic changes. The recent development of inhibitors targeting different components of the PI3K pathway may represent a valuable treatment alternative. However, predicting efficacy of these drugs is challenging, and methods for therapy monitoring are needed. Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype, frequently associated with PI3K pathway activation. The objectives of this study were to quantify the PI3K pathway activity in tissue sections from xenografts representing basal-like and luminal-like breast cancer before and immediately after treatment with PI3K inhibitors, and to identify metabolic biomarkers for treatment response.

Methods: Tumor-bearing animals (n = 8 per treatment group) received MK-2206 (120 mg/kg/day) or BEZ235 (50 mg/kg/day) for 3 days. Activity in the PI3K/Akt/mammalian target of rapamycin pathway in xenografts and human biopsies was evaluated using a novel method for semiquantitative assessment of Aktser473 phosphorylation. Metabolic changes were assessed by ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy.

Results: Using a novel dual near-infrared immunofluorescent imaging method, basal-like xenografts had a 4.5-fold higher baseline level of pAktser473 than luminal-like xenografts. Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation. This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors. BEZ235 also caused increased glucose and glycerophosphocholine concentrations. No response to treatment or change in metabolic profile was seen in luminal-like xenografts. Analyzing tumor sections from five patients with BLBC demonstrated that two of these patients had an elevated pAktser473 level.

Conclusion: The activity of the PI3K pathway can be determined in tissue sections by quantitative imaging using an antibody towards pAktser473. Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts. This indicates that PI3K inhibitors may have selective efficacy in basal-like breast cancer with increased PI3K signaling, and identifies lactate, phosphocholine and glycerophosphocholine as potential metabolic biomarkers for early therapy monitoring. In human biopsies, variable pAktser473 levels were observed, suggesting heterogeneous PI3K signaling activity in BLBC.

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High-resolution magic angle spinning magnetic resonance spectroscopy demonstrates changes in glucose and choline metabolism. Example spectra from basal-like xenografts illustrate changes in (A) glucose and (B) choline metabolites. BEZ235 treatment (blue spectra) increased the glucose concentration compared with vehicle control (red spectra). A concomitant decrease in lactate concentration was observed. Both glycerophosphocholine (GPC) and phosphocholine (PCho) concentrations were also increased after BEZ235 treatment.
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Figure 7: High-resolution magic angle spinning magnetic resonance spectroscopy demonstrates changes in glucose and choline metabolism. Example spectra from basal-like xenografts illustrate changes in (A) glucose and (B) choline metabolites. BEZ235 treatment (blue spectra) increased the glucose concentration compared with vehicle control (red spectra). A concomitant decrease in lactate concentration was observed. Both glycerophosphocholine (GPC) and phosphocholine (PCho) concentrations were also increased after BEZ235 treatment.

Mentions: Treatment-related changes in metabolite concentrations were seen in basal-like xenografts, but not luminal-like xenografts (Figure 6). After treatment with MK-2206, PCho increased by 45% compared with vehicle controls whereas lactate decreased by 33%. In xenografts treated with BEZ235, the metabolic response was more pronounced. PCho and GPC concentrations increased twofold, and lactate concentrations were reduced by 44%. In addition, the glucose concentration was increased nearly threefold. The magnitude of change in the metabolic biomarkers was therefore closely associated with the reduction in pAktser473 level. Example spectra illustrating the metabolic changes are presented in Figure 7.


Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer.

Moestue SA, Dam CG, Gorad SS, Kristian A, Bofin A, Mælandsmo GM, Engebråten O, Gribbestad IS, Bjørkøy G - Breast Cancer Res. (2013)

High-resolution magic angle spinning magnetic resonance spectroscopy demonstrates changes in glucose and choline metabolism. Example spectra from basal-like xenografts illustrate changes in (A) glucose and (B) choline metabolites. BEZ235 treatment (blue spectra) increased the glucose concentration compared with vehicle control (red spectra). A concomitant decrease in lactate concentration was observed. Both glycerophosphocholine (GPC) and phosphocholine (PCho) concentrations were also increased after BEZ235 treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672699&req=5

Figure 7: High-resolution magic angle spinning magnetic resonance spectroscopy demonstrates changes in glucose and choline metabolism. Example spectra from basal-like xenografts illustrate changes in (A) glucose and (B) choline metabolites. BEZ235 treatment (blue spectra) increased the glucose concentration compared with vehicle control (red spectra). A concomitant decrease in lactate concentration was observed. Both glycerophosphocholine (GPC) and phosphocholine (PCho) concentrations were also increased after BEZ235 treatment.
Mentions: Treatment-related changes in metabolite concentrations were seen in basal-like xenografts, but not luminal-like xenografts (Figure 6). After treatment with MK-2206, PCho increased by 45% compared with vehicle controls whereas lactate decreased by 33%. In xenografts treated with BEZ235, the metabolic response was more pronounced. PCho and GPC concentrations increased twofold, and lactate concentrations were reduced by 44%. In addition, the glucose concentration was increased nearly threefold. The magnitude of change in the metabolic biomarkers was therefore closely associated with the reduction in pAktser473 level. Example spectra illustrating the metabolic changes are presented in Figure 7.

Bottom Line: Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation.This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors.Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancer cells through numerous mutations and epigenetic changes. The recent development of inhibitors targeting different components of the PI3K pathway may represent a valuable treatment alternative. However, predicting efficacy of these drugs is challenging, and methods for therapy monitoring are needed. Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype, frequently associated with PI3K pathway activation. The objectives of this study were to quantify the PI3K pathway activity in tissue sections from xenografts representing basal-like and luminal-like breast cancer before and immediately after treatment with PI3K inhibitors, and to identify metabolic biomarkers for treatment response.

Methods: Tumor-bearing animals (n = 8 per treatment group) received MK-2206 (120 mg/kg/day) or BEZ235 (50 mg/kg/day) for 3 days. Activity in the PI3K/Akt/mammalian target of rapamycin pathway in xenografts and human biopsies was evaluated using a novel method for semiquantitative assessment of Aktser473 phosphorylation. Metabolic changes were assessed by ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy.

Results: Using a novel dual near-infrared immunofluorescent imaging method, basal-like xenografts had a 4.5-fold higher baseline level of pAktser473 than luminal-like xenografts. Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation. This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors. BEZ235 also caused increased glucose and glycerophosphocholine concentrations. No response to treatment or change in metabolic profile was seen in luminal-like xenografts. Analyzing tumor sections from five patients with BLBC demonstrated that two of these patients had an elevated pAktser473 level.

Conclusion: The activity of the PI3K pathway can be determined in tissue sections by quantitative imaging using an antibody towards pAktser473. Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts. This indicates that PI3K inhibitors may have selective efficacy in basal-like breast cancer with increased PI3K signaling, and identifies lactate, phosphocholine and glycerophosphocholine as potential metabolic biomarkers for early therapy monitoring. In human biopsies, variable pAktser473 levels were observed, suggesting heterogeneous PI3K signaling activity in BLBC.

Show MeSH
Related in: MedlinePlus