Future Directions for Breast Cancer

Chris Vi, PhD Candidate (Medicine), B.H&MedSci(Hons), B.BioMedSci

Deeya Mahadooa, MSc Mental Health Psychology, BA(Hons) Psychology 

 

Aptamers

• Single stranded DNA or RNA nucleotides that binds to its target with high selectivity, specificity and affinity (Khalid et al., 2018).
• These oligonucleotides form secondary 3-D structures to recognise and bind to its selected target (Khalid et al., 2018).
• Also known as ‘chemical antibodies’ due to its ability to bind to its target via ‘shape recognition’ similar to how antibodies do(Khalid et al., 2018).
• A randomised DNA library is incubated with the target, such as a cancer biomarker, and bound sequences are isolated, washed, eluted and amplified (Hori et al., 2018). This selection-amplification cycle can be repeated up to 15 times to improve its target specificity (Hori et al., 2018).

 

Aptamers are generated in-vitro by a process known as SELEX: systematic evolution of ligands by exponential enrichment (Ruiz et al., 2018).

Ruiz et al., 2018

Aptamers can be functionalised to detect, diagnose and therapeutically treat cancer cells by attaching therapeutic payloads (cytotoxic drugs, siRNAs and radionuclides) which is released after binding to its target (Khalid et al., 2018; Odeh et al., 2019).

 

Aptamers are basically delivery vehicles which deliver goods (medications/radiotherapies) to the target (cancer/tumour).

This can allow for more targeted treatments which can be less invasive, with less off-target effects compared to current options, such as chemotherapy, which kills both healthy and cancerous cells resulting in commonly observed negative side effects (hair loss, nausea, weakness etc.)

 

Aptamers and HER2 Breast Cancer

A HER2 aptamer developed by Liu et al., (2012) specifically binds to HER2-positive BC cell-line, SK-BR-3, but not to a HER2-negative TNBC (triple negative breast cancer) cell-line to selectively deliver a chemotherapeutic (doxorubicin) and increase its efficacy (Liu et al., 2012).

Similarly, a HER2 aptamer developed by Kim et al., (2019) was found to specifically target HER2 in-vivo. PET imaging with the radiolabelled aptamer demonstrated significantly higher uptake in HER2-positive tumour bearing, compared to the decreased uptake in HER2-negative tumour bearing mice – suggesting the preferential and specificity of the aptamers (Kim et al., 2019).

Attachment of different radionuclides to the aptamers, via a chelator or linker, provides it with different functionalities (Khalid et al., 2018). For example, radiolabelling with gallium-68 is purely for diagnostics due to emissions of gamma rays, actinium-225 for therapeutics due to emission alpha-particles and lutetium-177 for theranostic (combined therapeutic and diagnostics) due to simultaneous emissions of gamma-rays and beta-particles (Khalid et al., 2018).

 

Kim et al., 2019

• The aptamer is linked with a radioisotope
• Once the aptamer binds to the target (HER2 receptor), it sends signals (gamma rays) through the body.
• These can then be detected using a PET/CT scanner, to show where the cancer or tumour is.

Aptamers can be generated to target breast cancer biomarkers such as HER2, EpCAM or nucleolin to better detect, diagnose and treat these heterogeneous breast cancers (Camorani et al., 2018; Khalid et al., 2018).

Using aptamers conjugated to specific radionuclides would enable early detection and treatments of BC, as they would increase the sensitivity and specificity for targeted and personalised medicine (Wu et al., 2017).

 

Subject to copyright Rehab Plus, 2020

 

References

Camorani, S., Fedele, M., Zannetti, A., & Cerchia, L. (2018). TNBC Challenge: Oligonucleotide aptamers for new imaging and therapy modalities. Pharmaceuticals (Basel, Switzerland), 11(4), 123. https://doi.org/10.3390/ph11040123

Hori, S. I., Herrera, A., Rossi, J. J., & Zhou, J. (2018). Current advances in aptamers for cancer diagnosis and therapy. Cancers, 10(1), 9. https://doi.org/10.3390/cancers10010009

Khalid, U., Vi, C., Henri, J., Macdonald, J., Eu, P., Mandarano, G., & Shigdar, S. (2018). Radiolabelled aptamers for theranostic treatment of cancer. Pharmaceuticals (Basel, Switzerland), 12(1), 2. https://doi.org/10.3390/ph12010002

Kim, H. J., Park, J. Y., Lee, T. S., Song, I. H., Cho, Y. L., Chae, J. R., Kang, H., Lim, J. H., Lee, J. H., & Kang, W. J. (2019). PET imaging of HER2 expression with an 18F-fluoride labeled aptamer. PloS One, 14(1), e0211047. https://doi.org/10.1371/journal.pone.0211047

Liu, Z., Duan, J. H., Song, Y. M., Ma, J., Wang, F. D., Lu, X., & Yang, X. D. (2012). Novel HER2 aptamer selectively delivers cytotoxic drug to HER2-positive breast cancer cells in vitro. Journal of Translational Medicine, 10, 148. https://doi.org/10.1186/1479-5876-10-148

Odeh, F., Nsairat, H., Alshaer, W., Ismail, M. A., Esawi, E., Qaqish, B., Bawab, A. A., & Ismail, S. I. (2019). Aptamers chemistry: Chemical modifications and conjugation strategies. Molecules (Basel, Switzerland), 25(1), 3. https://doi.org/10.3390/molecules25010003

Ruiz Ciancio, D., Vargas, M. R., Thiel, W. H., Bruno, M. A., Giangrande, P. H., & Mestre, M. B. (2018). Aptamers as diagnostic tools in cancer. Pharmaceuticals (Basel, Switzerland), 11(3), 86. https://doi.org/10.3390/ph11030086

Wu, X., Shaikh, A. B., Yu, Y., Li, Y., Ni, S., Lu, A., & Zhang, G. (2017). Potential diagnostic and therapeutic applications of oligonucleotide aptamers in breast cancer. International Journal of Molecular Sciences, 18(9), 1851. https://doi.org/10.3390/ijms18091851