Looking for the Achilles heel of breast cancer

October 29, 2021

Breast cancer is the second cause of mortality among women around the world and the most common type of cancer in the UK. Despite recent advances in treatments, survival varies among patients, and efforts must continue to find new detection strategies and treatments for this disease. 

Breast cancer is a heterogeneous disease, often caused by the overexpression of hormonal receptors, in particular estrogen and progesterone receptors. When these hormones fuel abnormal cell growth, cancer can be treated with selective estrogen receptor modulators. However, in about 20% of the patients, cancer cells produce an excessive amount of the Human Epidermal Growth Factor Receptor 2 (HER2). Dimerisation of HER2 results in the autophosphorylation of tyrosine residues and triggers various signaling pathways that promote cell proliferation. These cancers are often aggressive and fast-growing. 

Current therapeutics for HER2-positive patients rely on anti-HER2 antibodies or tyrosine kinase inhibitors (TKIs). Antibodies, such as trastuzumab (brand name Herceptin), bind to the extracellular part of HER2 and prevent it from dimerising. TIKs, such as lapatinib, are small molecules that bind to the intracellular part of HER2, suppressing the downstream signalling pathways. These drugs have significantly improved the survival of breast cancer patients, but their side effects and cancer’s ability to develop resistance to the treatment, leading to cancer recurrence, have driven researchers to seek alternative therapeutic approaches. 

Inhibition of HER-2 signalling pathways. Antibodies, such as trastuzumab, block HER2 dimerisation, while small molecules, such as lapatinib, bind to the intracellular tyrosine-kinase domain of HER2 (Reference: Oh, Do-Youn, and Yung-Jue Bang. "HER2-targeted therapies—a role beyond breast cancer." Nature reviews Clinical oncology 17.1 (2020): 33-48.)

Among alternative binders, researchers are exploring designed ankyrin repeat proteins (DARPins) – artificial peptides with high stability and solubility. DARPins with high-affinity binding to one or more cancer-associated targets can be used for the delivery of cancer-killing agents and the disruption of specific cell signalling pathways.  

Developed by the Swiss biopharmaceutical company Molecular Partners AG, DARPins against HER2-positive tumours have shown promising results in the first phase of the clinical trials. Labelled MP0274, these DARPins lock the HER2 receptor in an inactive conformation and induce apoptosis.

Some research teams are also trying to replace breast biopsies with new medical imaging solutions that assess HER2 status in primary tumours and metastases. For example, researchers in Sweden tested anti-HER2 affibodies for positron emission tomography (PET) in metastatic breast cancer patients. This is an alternative to radioisotope-labelled trastuzumab which has slow kinetics and requires a long waiting time of several days between administration and imaging. DARPins have also been applied to cancer imaging in mice experiments.

HexagonFab’s Bolt can help you get your results faster. Are you developing anti-cancer peptides, DARPins, nanobodies, antibodies, small molecules or novel therapeutic designs? We are keen to hear from you!