How the body’s natural defences could be harnessed to design more effective treatments and ultimately a vaccine against breast cancer.
Design and test bi-specific antibodies
Based at the University of Southampton, Professor Crispin and his team are exploring innovative ways to develop anti-cancer antibodies that can detect and destroy breast cancer cells, including secondary breast cancer, without damaging surrounding healthy tissue. This approach involves developing new therapeutic approaches for the treatment of cancer which are based on refocusing of the immune system to destroy cancerous cells that have spread from the breast.
Secondary cancer cells are decorated with abnormal sugars which are implicated in their ability to move around the body and establish secondary tumours. These sugars are potential targets for the antibody component of the body’s immune system. People who develop secondary cancer may benefit from antibodies that have been made that stick to these targets on cancer cells and render these secondary cancerous cells detectable by the immune system wherever they are in the body.
By manufacturing antibodies that have been artificially engineered to recognise cancerous cells in preference to surrounding healthy cells. The team are exploiting changes in the surface of cancerous cells that can mark them out for immune recognition.
Professor Crispin runs the Glycoprotein Therapeutics Laboratory which is predominantly focussed on developing anti-viral vaccines and new antibody-based therapies against cancer. Based at the new Centre for Cancer Immunology, he and his team are carrying out their research in a new purpose-built facility. The Centre is the first of its kind in the UK to be designed to bring together scientists, cancer doctors and clinical trials specialists, allowing for better collaboration and to deliver newly discovered therapies into patients for the first time.
Increasing our knowledge of DNA repair mechanisms
We know that cancer is mainly a genetic disease caused by changes – also called mutations – that build up over time in our cells’ DNA. Damage to our DNA happens all the time, but our cells have repair mechanisms to fix this.
One repair mechanism is called ‘DNA double-stranded break repair’. There are two proteins, BRCA1 and BRCA2, that play a critical role in this process however, scientists do not understand exactly how BRCA1 and BRCA2 proteins repair DNA at the molecular level.
Certain regions in the BRCA1 and BRCA2 proteins are thought to be important for stopping tumours forming. It is to better understand the function of these ‘short, linear peptide motifs’ that is the key focus of the research being carried out by Dr Andrew Blackford, one of the Against Breast Cancer Junior Research Fellows at the University of Oxford.
Some of the most effective cancer treatments work by causing DNA damage; therefore, this research aims to increase our understanding of the DNA damage repair at the molecular level. This in turn may help to improve existing treatments as well as develop new ones for breast cancer.
Increasing our knowledge of the role of mitochondria in breast cancer
Cancer cells need nutrients including sugars, proteins and fats to grow and make new cancer cells. Mitochondria are like the batteries of the cell, producing the energy cells need to grow. They work by breaking down nutrients to make new building blocks for cell growth. Cancer cells often permanently switch on active mitochondria to grow faster.
Dr Simon Lord and colleagues at the University of Oxford have shown that metformin, a drug commonly used to treat diabetes, can target mitochondria in breast cancer cells. It seems that metformin makes some breast cancers take up more sugars but has no effect at all on other breast cancers. From what we already know, it seems that metformin might stop the growth only of those breast cancers that take up more sugar.
Dr Lord, the second of our Junior Research Fellows at the University of Oxford wishes to determine if mutations in mitochondrial genes can predict if a breast cancer will respond to metformin and take up more sugars. This research may help to find which patients could benefit from metformin.
In addition, it is known that breast cancer is more common in obese than non-obese women; therefore, so another aim of this research is to understand how mitochondria in cancer cells might work differently in breast cancers arising in obese women.
To answer this question, they are growing breast cancer cells taken from obese and non-obese women in the laboratory to understand how these cells may use nutrients differently. Genetic techniques are being used to find any differences in genes that control how sugars, fats and amino acids are used in cancer cells in these two groups of women.
Ultimately, the researchers are keen to understand how different drugs might be used to treat breast cancers that arise in these different groups of women.
Q&A, discussing therapies and the possible effect obesity plays in resisting current treatments
As part of our regular Research Q&A series, Dr Lord took the time to answer questions about his research which were posed by supporters of Against Breast Cancer;
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Glycolysis, via NADH-dependent dimerisation of CtBPs, regulates hypoxia-induced expression of CAIX and stem-like breast cancer cell survival Mira Kreuzer, A. Banerjee, Charles N. Birts, M. Darley, A. Tavassoli, M. Ivan, and Jeremy P. Blaydes. FEBS Letters 03 July 2020
p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators Charles N. Birts1,2, Arindam Banerjee1, Matthew Darley1, Charles R. Dunlop1, Sarah Nelson1, Sharandip K. Nijjar3, Rachel Parker1, Jonathan West1,2, Ali Tavassoli2,3, Matthew J. J. Rose-Zerilli1,2, and Jeremy P. Blaydes1,2 et al. Science Signaling 05 May 2020: Vol. 13, Issue 630, eaau9529 DOI: 10.1126/scisignal.aau9529
Window of opportunity clinical trial designs to study cancer metabolism Francesca Aroldi1 and Simon R. Lord 1. British Journal of Cancer https://doi.org/10.1038/s41416-019-0621-4
Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin Simon R. Lord 1,2,3, Jennifer M. Collins4, Wei-Chen Cheng1, Syed Haider5, Simon Wigfield2, Edoardo Gaude6, Barbara A. Fielding4,7,Katherine E. Pinnick4, Ulrike Harjes2, Ashvina Segaran1, Pooja Jha8, Gerald Hoefler8, Michael N. Pollak9, Alastair M. Thompson10, Pankaj G. Roy11, Ruth. English12, Rosie F. Adams12, Christian Frezza6, Francesca M. Buffa1, Fredrik Karpe3,4 and Adrian L. Harris 1,2,3. British Journal of Cancer https://doi.org/10.1038/s41416-019-0665-5
Collision Cross Sections and Ion Mobility Separation of Fragment Ions from Complex N-Glycans David J. Harvey, Yasunori Watanabe, Joel D. Allen, Pauline Rudd, Kevin Pagel, Max Crispin, Weston B. Struwe J. Am. Soc. Mass Spectrom. (2018) 29:6 1250-1261
Signature of Antibody Domain Exchange by Native Mass Spectrometry and Collision-Induced Unfolding Yasunori Watanabe,†,§,⊥ Snezana Vasiljevic,† Joel D. Allen,§ Gemma E. Seabright,†,§ Helen M. E. Duyvesteyn,⊥,# Katie J. Doores,∥ Max Crispin,*,§ and Weston B. Struwe Anal. Chem. 2018, 90:12, 7325−7331
Immune recruitment or suppression by glycan engineering of endogenous and therapeutic antibodies Le, N. P., T. A. Bowden, W. B. Struwe and M. Crispin (2016) Biochim Biophys Acta 1860 (8): 1655-1668
Optimal Synthetic Glycosylation of a Therapeutic Antibody Parsons, T. B., W. B. Struwe, J. Gault, K. Yamamoto, T. A. Taylor, R. Raj, K. Wals, S. Mohammed, C. V. Robinson, J. L. Benesch and B. G. Davis (2016) Angew Chem Int Ed Engl 55 (7): 2361-2367
Redirecting adenoviruses to tumour cells using therapeuticantibodies: Generation of a versatile human bispecific adaptor Snezana Vasiljevic, Emma V. Beale, Camille Bonomelli, Iona S. Easthope,Laura K. Pritchard, Gemma E. Seabright, Alessandro T. Caputo, Christopher N. Scanlan1,Martin Dalziel∗, Max Crispin, Mol Immunol (2015) 68 (2 Pt A): 234-243