(From close in outwards) HER3 (human epidermal growth factor receptor 3) affibody uptake in mouse bearing human breast cancer tumour; HER3 staining of tumour tissue section showing heterogeneity of receptor expression; Confocal microscopy of HER3 positive breast cancer cells exposed to HER3 affibody labelled with florescent dye.
Imagine being able to focus in on a patient’s cancer right down to the molecular level — seeing a drug target, administering a treatment and watching as the drug takes effect; all within a matter of minutes.
A molecular imaging technique called Positron Emission Tomography (PET) allows us to do just that; taking a snapshot of biological processes inside the body, rather than in a petri dish in the laboratory or on a slide under the microscope.
It’s hardly surprising then that there is a buzz around molecular imaging and a recognition that it has the potential to transform many different facets of cancer care.
Dr Gabriela Kramer-Marek leads the Preclinical Molecular Imaging Team within the Centre for Cancer Imaging at The Institute of Cancer Research, London, and is investigating new ways of using molecular imaging to predict an individual patient’s response to treatment.
One particular interest of her team is in proteins called human epidermal growth factor receptors (EGFR), which promote the survival and growth of cancer cells.
New insights
HER3 (human epidermal growth factor receptor 3), one member of the family, is a critical player in the progression of breast, lung, ovarian, colon, and head and neck cancers. Upregulation of HER3 has been implicated in resistance to HER-targeted therapies including trastuzumab (Herceptin) and cetuximab.
Experts recommend that, before initiation of any targeted therapy, patients are tested for the presence of particular target — such as HER2 or HER1 — because the results can have a significantly impact on treatment recommendations and decisions.
Testing for these receptors is generally done in a hospital laboratory on a tissue samples removed during a biopsy or surgery.
The results are usually available one to three weeks later. But obtaining the sequential invasive tumour biopsies routinely used for the evaluation of receptor status and monitoring changes in receptor expression under treatment is practically and ethically challenging. Biopsies are also prone to sampling errors and may not capture the genetic diversity of tumours or the presence of resistant clones that may be residing in multiple sites where the cancer has spread.
Real-time adjustments
Dr Kramer-Marek may have the answer to this dilemma, and is developing and validating non-invasive, specific imaging biomarkers capable of accurately assessing HER receptor status.
“We are developing strategies to characterise molecular probes for the non-invasive imaging of HER receptors within a patient,” she says. “Such an approach will have the advantage of showing receptor expression across the entire tumour. In addition, the imaging tests can be repeated to monitor receptor changes during treatment.”
Several targeted therapies directed at the HER3 receptor are now in clinical trials – most famously patritumab. But the outcome of these therapies in individual patients depends on the receptor status of the treated tumours.
Using Dr Kramer-Marek’s approach, researchers could adjust the dose and treatment schedule for individual patients, based on the real-time status of these receptors. If imaging became a complementary method to the routine biopsy testing procedures, which are prone to human error and bias, the number of false-negative or false-positive results will also be reduced.
Sparing patients ineffective therapies
Molecular imaging relies on good indicators of cancer metabolism or drug response, known as biomarkers. The most commonly used specific imaging biomarkers in the lab are labelled antibodies, but applying these in the lab can be challenging because of their large molecular size, which means their uptake by tissues is slow and that they take a long time to show up in imaging.
To overcome these barriers, Dr Kramer-Marek is working on affibody-based imaging agents — small proteins engineered to bind to a target with high affinity and specificity. “We developed an affibody-based biomarker which can be detected within an hour, rather than days, after injection,” explains Dr Kramer-Marek. “Our affibody doesn’t interfere with HER-targeted drug binding either, so the agent can be used to monitor treatment in real time. We even found the scans more reliable than laboratory tests on biopsied tissue for detecting levels of these receptors.
“My work will enable non-invasive assessment of target levels and modulation, giving us the opportunity to optimise the drug dosing,” she adds. “Using this information, we will be able to develop better strategies for delivering personalised medicine, allowing greater treatment efficacy. Hopefully we can spare patients from being given ineffective therapies, which in many cases are associated with high toxicity.”
By viewing biological processes in real time in a real patient, researchers are beginning to gain a vivid snapshot of drug response and resistance. That should speed up drug discovery and ultimately result in better medicines — medicines whose actions researchers will be able to track in real time.