Projectdetails

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Molecular imaging of estrogen receptor expression levels as a tool for improved decision-making in breast cancer treatment

Keywords:
breast cancer hormone receptors endocrine therapy PET imaging

Researchers:
dr. E.F.J. de Vries
Prof. dr. G.A.P. Hospers
drs. M. van Kruchten

Type of project:
Stage Wetenschap / Researchproject

Nature of the research:
This project involves translational research. Findings from in-vitro experiments will be further evaluated in animal models. This should lead to improved stratification of breast cancer patients by PET imaging

Fields of study:
oncology nuclear medicine

Background / introduction
Anti-hormonal therapy is the treatment of choice for the majority of breast cancer patients, because of its efficacy and relatively few adverse effects. After an initial response, however, patients will eventually become resistant. The estrogen receptor (ER) plays a vital role in anti-hormonal therapy. Therapy resistance is usually related to changes in the ER signaling pathway. Three types of resistant tumors can be discriminated: resistance in which ER expression is 1) lost, 2) preserved, or 3) increased. Changes in ER expression are not only caused by resistance to anti-hormonal therapy, but could also be induced by drugs that block other signaling pathways and epigenetic drugs regulating gene transcription.
We have shown that epigenetic drugs can induce ER-expression in ER-negative cells and that ER-expression can be down-regulated in ER-positive cells. Further evaluation on gene transcription levels and the influence of interacting hormones is needed to understand the exact biological mechanisms as well as the influence of ER-modulation on therapy resistance. In vitro data suggests that modulation of the ER-expression can be used as a target to overcome resistance to anti-hormonal therapy.
Different treatment strategies could be required for tumors with different ER expression levels. Unfortunately, knowledge of ER expression in resistant tumors is not taken into account in treatment decision-making at this moment. In general, patients are not rebiopsied, because of the invasive nature of this procedure. Therefore, up-to-date information on the resistance phenotype of the tumor is usually not available. In contrast to biopsy, molecular imaging techniques like positron emission tomography (PET) allow non-invasive monitoring of tumor characteristics, such as the ER expression. The radiolabeled estrogen derivate 16beta-[18F]fluoroestradiol (FES), which is a validated tracer for monitoring ER expression with PET, is available at the UMCG and a clinical trial with this PET tracer has started in 2010. The availability of the PET tracer for ER expression, a dedicated PET camera for studies in small animals and a PET/CT for patient studies offers the unique opportunity for in-vivo studies on the role of ER in treatment strategies, drug efficacy and therapy resistance.
Research question / problem definition
The aim of the study will be to investigate the effects of drug intervention on ER expression in-vitro and in-vivo.
Workplan
Two endocrine-sensitive ER-positive, and three endocrine resistant (2 ER-negative, 1 ER-positive) breast cancer cell lines will be chronically exposed to drugs acting on epigenetic regulation of ER-expression. The effects of these drugs on ER-expression will be determined by Western Blotting. Position of the ER (cytoplasmic or nucleus) will be evaluated using Immuno Fluoresence microscopy. Sensitivity for anti-hormonal treatment will be determined in an in vitro drug sensitivity assay (MTT) with single therapy and co-treatment with drugs targeting ER-expression. When the cell types have been characterized for ER-expression and anti-hormonal sensitivity, the effect of epigenetic drugs on ER-expression will be evaluated in an in vivo mouse model.
Mice with different types of subcutaneous breast cancer tumors will be treated with epigenetic drugs targeting ER-expression. Modulation of ER-expression and therapy response will be monitored repetitively by FES-PET (ER density) and micro-CT (tumor volume).
A clinical study to investigate whether ER expression levels as determined by FES PET can be used to identify patients eligible for estrogen therapy after resistance to endocrine therapy has developed, has now started and included its first patients. Visual analysis and quantitative image analysis of the FES positive PET tumor lesions will be performed.
Another clinical study evaluating the diagnostic value and therapeutic consequences of FES-PET used in patients presenting with a diagnostic dilemma is also in progress (31 patients included so far).

The aforementioned plan of investigation shows the scope of the possibilities (in vitro, in vivo mouse studies and clinical trials), but is far too comprehensive for a single student. A detail plan of investigation can be made that takes the specific interests of the student into account.
References
1. Linden HM, Stekhova SA, Link JM, Gralow JR, Livingston RB, Ellis GK, et al. Quantitative fluoroestradiol positron emission tomography imaging predicts response to endocrine treatment in breast cancer. J Clin Oncol 2006 Jun 20;24(18):2793-9.
2. Peterson LM, Mankoff DA, Lawton T, Yagle K, Schubert EK, Stekhova S, et al. Quantitative Imaging of Estrogen Receptor Expression in Breast Cancer with PET and 18F-Fluoroestradiol. J Nucl Med 2008 Mar;49(3):367-74.
3. Aliaga A, Rousseau JA, Ouellette R, Cadorette J, van Lier JE, Lecomte R, et al. Breast cancer models to study the expression of estrogen receptors with small animal PET imaging. Nucl Med Biol 2004 Aug;31(6):761-70.
4. Jordan VC. The 38th David A. Karnofsky lecture: the paradoxical actions of estrogen in breast cancer--survival or death? J Clin Oncol 2008 Jun 20;26(18):3073-82.
5. Walton TJ, Li G, Seth R, McArdle SE, Bishop MC, Rees RC. DNA demethylation and histone deacetylation inhibition co-operate to re-express estrogen receptor beta and induce apoptosis in prostate cancer cell-lines. Prostate 2008 Feb 1;68(2):210-22.
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