The biological functions of ERs, both in health and disease, have been studied scientifically for decades, with implications for oncology and endocrinology. These receptors, most often known as ER and ER, are proteins that mediate the biological actions of the hormones estrogens, dominant ones in the human body. They're also essential in many physiological processes ranging from reproduction to bone health and cardiovascular disease, making them important in healthy and pathological states. Specifically, the estrogen receptor contributes to the development and progression of oestrogen-related cancers, especially breast cancer, whose expression status directly impacts on therapy.

Figure 1. Structure and function of ERα and ERβ. (Rong C, et al.; 2018)

This is estrogen receptor imaging, a new method for developing medicines that targets and plots the levels, distribution and activity of ERs in living tissue. The technology offers invaluable data on the biology of tumours, the effectiveness of treatments, and the synthesis of targeted drugs. This article explains why the importance of ER imaging for drug development lies in diagnostics, treatment monitoring and designing new therapies for hormonal diseases.

Knowledge of Estrogen Receptors as a Mechanism for Disease

Estrogen receptors are a nuclear receptor family of transcription factors that modulate gene expression upon bind to oestrogen. ERα and ERβ are swathed differently in tissues; ERα was mostly located in the uterus and breast, whereas ERβ was found more in the brain, bones and cardiovascular system. Their dysregulation can cause disease, particularly in cancers where ER signals drive growth. Breast cancer, for instance, is ER-positive, that is, the cancer cells have estrogen receptors. Such tumours are often also better tolerant of hormone therapies that suppress oestrogen signalling (such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors). But ER expression is so variable in various cancer types and at different stages that accurate imaging to detect receptor activity and function needs to be developed.

The Benefits of Getting Your Estrogen Receptor Imaging Done Right

Estrogen receptor imaging is a non-invasive way to track ER levels and function in various tissues, particularly in tumors. ER presence in vivo can be tracked for the more precise staging of cancer, treatment response assessment and optimal treatment design.

The promise of estrogen receptor imaging for drug design is that it can:

• Support early diagnosis and staging: ER-positive tumors are visualized using ER-imaging early on for diagnosis and staging. It can even discriminate between breast cancer subtypes and detection of metastasis to other organs.
• Measure therapeutic response: In hormone-responsive cancers, imaging can monitor a treatment response in real time by measuring ER expression levels.
• Allow for personalized medicine: Because the estrogen receptor status of a tumor is what makes it susceptible to certain treatments, estrogen receptor imaging allows for more individualized treatments, giving patients exactly the right amount of therapy for their tumor biology.

Techniques for Estrogen Receptor Imaging

There are many imaging strategies that we use to see oestrogen receptor function, and each has advantages and disadvantages. Both clinical and research imaging techniques are positron emission tomography (PET) and single-photon emission computed tomography (SPECT), both based on radiolabeled ligands that attach themselves to ERs.

Positron Emission Tomography (PET)

For molecular imaging, PET imaging is the new black -magic. PET scans of the ER with radiotracers that react specifically to oestrogen receptors. The most widely used PET tracer for ER imaging is 18F-fluoroestradiol (18F-FES), an artificial estrosteroid analog, which binds ERs highly. This tracer allows the cell to view ER-positive tissues in the real world and see the location of tumors and oestrogen receptor status.

PET-MRI using 18F-FES can:

• Identify and track ER-positive tumours in breast cancer and other types of cancer.
• Measure ER levels in tissues potentially involved in metastasis: bone, lung, liver.
• Monitor changes in receptor expression during treatment (hormone therapy, endocrine-targeted therapies, etc.).

Single-Photon Emission Computed Tomography (SPECT)

SPECT imaging, like PET, uses radiolabeled ligands, but it's done using a different technique. SPECT generally has a lower resolution than PET, but it is still widely used to image the oestrogen receptors in places where PET isn't an option.

SPECT imaging of estrogen receptors is carried out with radiotracers like 99mTc-labeled estrogens and 123I-labeled estradiol. They stick directly to ERs and we can see the receptor activity in tissue. SPECT may be helpful in some clinical situations because it is cheaper and more available than PET.

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Estrogen Receptors Imaging Analysis

Estrogen Receptor Imaging for Drug Discovery

Estrogen receptor imaging is used in every phase of drug development from preclinical through clinical. It is used in drug discovery for:

Preclinical Drug Testing

Estrogen receptor imaging in preclinical settings is used to test novel targets for new drugs on oestrogen signaling pathways. Using estrogen receptor imaging, for instance, researchers could investigate binding affinity and specificity of new ER-targeting agents (eg, selective estrogen receptor degraders (SERDs) or new SERMs). Imagery allows drug pharmacokinetics and receptor bind analysis to be measured, which helps to explain how the drug works and is effective before they make it to human trials.

Clinical Trials

Estrogen receptor imaging in clinical trials is an excellent method to evaluate experimental treatments targeting estrogen receptors. For example, images could be used to follow how a patient responds to endocrine medications like tamoxifen, aromatase inhibitors or the new class of CDK4/6 inhibitors. Tracking changes in ER expression over treatment duration allows doctors to determine whether the drug is actually working on the receptor and whether a switch to a different treatment is warranted.

Images can even be used to detect resistance mechanisms early on. There are some tumors, particularly those that show high ER at the start, that can grow resistant to hormone treatments over time. Such resistance can be identified using oestrogen receptor imaging so treatment can be made to catch it in time.

Personalized Medicine

One of the best future use cases for estrogen receptor imaging is personalized medicine. In breast cancer patients, for instance, ER expression dictates therapy choice. A patient might respond to tamoxifen or other hormonal treatment, and another to chemotherapy or newer, more specific treatments. Using receptor imaging, oncologists can now decide which regimen to choose depending on the receptor profile of each patient's tumour.

This can also include new medicines – next-generation ER antagonists or selective estrogen receptor modulators (SERMs) aimed at more potently inhibiting estrogen signalling in resistant cancers. By using imaging to track the changes in receptor expression, scientists can learn better what these new drugs do in vivo, and produce the drugs quicker and more precisely.

Challenges and Future Directions

Although there is a lot of potential for estrogen receptor imaging for drug discovery, there are a few issues. One is receptor biology: complex as it is. Oestrogen receptor expression can be heterogeneous: between tumours, between tissues, and even among the regions of a tumor. Such a variance can affect the resolution of imaging and make interpretation difficult.

And even PET and SPECT scanning, which are extremely sensitive to ER-positive tissues, are not perfect. This may be partially alleviated by more targeted and sensitive imaging agents, as well as imaging technology improvements.

In future directions for estrogen receptor imaging might be:

• Developing dual-target imaging agents that will be able to see estrogen receptor expression as well as other molecular markers of cancer progression.
• Longitudinal studies that use ovarian receptor imaging and other biomarkers to track therapy efficacy and disease course in real-time.
• The pairing of ER imaging with therapeutic methods (eg, radioactive isotopes or conjugates that image and deliver therapeutic payloads directly to ER-positive tumours).

Conclusion

strogen receptor imaging is a breakthrough in drug discovery, and has fundamentally changed the way we understand how hormonal diseases like cancer work. With its capabilities for accurate diagnosis, treatment efficacy monitoring and personalised therapy, oestrogen receptor imaging will be useful in continuing the work of finding specific, effective therapies for breast cancer, endometrial cancer and other oestrogen-related diseases. In the long run, as the research continues, this technology could be used to transform the way we diagnose and treat hormone-related illness – to a more personalised and specific form of care.

1. Rong C, et al.; Estrogen Receptor Signaling in Radiotherapy: From Molecular Mechanisms to Clinical Studies. Int J Mol Sci. 2018, 19(3):713.

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