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Seren is a drama therapist with a great deal of experience in helping people tackle their worries about chronic illness through creativity.  She was diagnosed with secondary breast cancer and decided that something needed to be done to help younger people with secondary cancer cope by means of writing, singing, art and poetry.   Together with Lorraine, Rachel and Jill, all of whom also have secondary cancer, she has created a collection of poems about their experiences called “Staying Alive: A Book of Hope”, which was published with help from Literature Wales.  The authors have made a generous donation from the launch of their book to Secondary1st to help fund vital research into secondary breast cancer.

We recently marked our 8th anniversary.  Since our launch in 2016 we have raised more than £890,000 and, thanks to our wonderful volunteers, 95% of the money raised goes to fund research.  We have already funded 3 projects researching secondary breast cancer and have just started funding a fourth project.  The first of these projects looked at how some breast cancer cells move and invade other parts of the body.  The second researched the relationship between cancer and the immune system.  The third project investigated ways of limiting the damage to healthy tissue caused by some very powerful cancer killing drugs.  This year we are funding a new project investigating the way that changes in the ER gene help breast cancer cells grow despite hormone therapy.  We are so grateful to everyone who has supported us, fundraisers, donors and volunteers. None of this would be possible without them.

Professor Klaus Pors and his PhD student Enrica have been working for three years on a project to improve an extremely toxic chemotherapy, so that it can be used to treat breast cancer. The researchers are working on duocarmycins which have been known to science for a long time. However, despite over 40 years of research on them, no duocarmycin has been approved for clinical use because in their original form they are too toxic to be used as cancer treatments. To overcome this, Professor Pors and his team have been changing the drug so that it only becomes active when it reaches the tumour, greatly limiting damage to other areas of the body. Their aim was to make this drug effective at killing breast cancer cells whilst minimising harmful side effects.

A group of proteins called CYP proteins are frequently overproduced in breast cancer cells. Professor Pors and others have designed a duocarmycin-based drug that relies on these proteins to turn it on. The team have been testing this modified duocarmycin in the laboratory to see if it is effective. If successful, this new treatment could be further tested in clinical trials for people living with secondary breast cancer.

The objectives for the third year of this project were to explore the effectiveness of their modified duocarmycin under different oxygen and nutrient levels in order to mimic the variations of these conditions found inside tumours and to analyse the tumour tissue penetration of the modified duocarmycin to better understand how it would move through tissue and its potential to treat breast cancer. Finally they wanted to test potential combination therapies with the modified duocarmycin.

Interestingly, the cancer cell killing ability of the modified duocarmycin was not significantly impacted by low nutrient and oxygen levels. This is an exciting and desirable property for a potential new treatment, as these harsh conditions can be found inside aggressive, fast-growing tumours. The effectiveness or the potency of the modified duocarmycin is dependent on the levels of the CYP protein needed to switch it on. Fortunately, the levels of the required CYP protein remained the same even under these stressed conditions.

Professor Pors and Enrica also tested potential new combination treatments with their drug. They tested it with the PARP inhibitor olabarib, and radiotherapy. The results were promising, suggesting that the treatments synergise together, boosting the cancer cell killing ability. However, further work is required to fully understand how this happens. The modified duocarmycin in its pre-activated form was also found to have good tissue penetration of 3D mini-breast tumours grown in the lab. The pre-active drug was better at getting to the centre of the 3D mini-tumour than the active duocarmycin.

Enrica is currently writing up her thesis whilst also working part time at the University of Bradford as a research assistant. She expects to submit her thesis in June, and be examined on it in July. During the course of her PhD, Enrica has presented her work to colleagues at conferences and meetings in the UK and internationally.

Secondary1st is proud to have been able to fund this research project led by Seth Coffelt, Professor of Cancer Immunology at Glasgow University. This report on the project is very detailed but we believe that our supporters will welcome the chance to learn more about the research they have helped to fund.

Immunotherapies are treatments that stimulate the immune system to recognise and fight cancer. The immune system is potentially a very powerful tool for cancer therapies. However, it is very finely tuned, and immune responses that are too strong can also be dangerous. Researchers are learning that in some contexts, and in different tissues, the same molecules and cells can have pro- or anti-tumour effects. Fully understanding these contradictory roles in the immune system is essential for designing successful immunotherapies for breast cancer.

For some cancer types, such as skin and lung cancers, immunotherapies can be very effective. However, current immunotherapy treatments are only effective for a small group of people with breast cancer. Professor Coffelt and his team are working to understand why existing immunotherapies are less effective for breast cancer than other cancer types, and exactly how the immune system might be involved in breast cancer spreading, so that new therapies can be designed to counteract it. They are studying a type of immune cell called gamma delta T cells which reside in tissues such as the lung. These appear to be responsible for creating a hospitable place for breast cancer cells to spread to. An aim of this project is to understand how exactly a molecule called NKG2D affects the behaviour of gamma delta T cells, and how they contribute to secondary breast cancer development. This research could lead to better immunotherapies for breast cancer.

Professor Coffelt and his team have produced a research paper detailing their latest discovery which has been published in the Journal of Experimental Medicine. In this paper the team show how gamma delta T cells can impede some immunotherapies via the IL-17A molecule. They found that two types of immune cells in the lungs, called V gamma and V gamma 4+ gamma delta T cells (Vγ6+ and Vγ4+ γδ T cells), have different responses to cancer. Vγ6+ cells have high levels of a protein called PD-1, while Vγ4+ cells increase production of a protein called TIM-3 when exposed to signals sent from the tumour. They found that blocking PD-1 or TIM-3 increased the numbers of these immune cells, but deleting these immune cells by using genetic techniques improved the effectiveness of certain immunotherapies, suggesting they play a role in resistance to immunotherapy. Overall, the research shows how these different gamma delta T cells are regulated differently during normal conditions and in response to cancer, and how they impact responses to treatment. This finding has revealed a way that might make immunotherapy treatments like pembrolizumab more effective. This could also make these types of treatments suitable for more people in the future.

More recently, Professor Coffelt and his team have been further investigating how delta gamma T cells which produce IL-17 control cancer. They have observed that when they injected breast cancer cells into mice that have had delta gamma T cells genetically deleted, tumours formed in the lung faster compared to normal mice. The team believe that another type of immune cell, Vγ4 cells which can make the molecule IFN-gamma, instead of IL-17, might help control cancer growth. This preliminary research suggests a more complex role for these cells in cancer.

Understanding the way immune cells may help or hinder the spread of breast cancer will help scientists to design effective and safe immunotherapies. Dr Coffelt’s research could eventually lead to new immunotherapy treatments to retrain the immune system to stop breast cancer spreading, instead of helping it.

Secondary1st is delighted to announce that it has just awarded a grant to a project led by Professor Simak Ali, who is Professor of Molecular Endocrine Oncology at Imperial College London.

Up to 80% of breast cancer diagnoses are ER-positive and many can be treated successfully with hormone therapy. However some ER-positive tumours stop responding after a time and can return, grow and spread. Professor Ali and his team are working to understand how changes in the ER gene help breast cancer cells grow despite hormone therapy. These changes can also help the disease become more aggressive and spread. This is secondary breast cancer and there is currently no cure.

The Charity will be funding a full-time post-doctoral researcher working with laboratory techniques such as epigenomic and transcriptomic profiling, involving the detailed study of changes in cancer cells to produce information on the consequences of these changes. Professor Ali’s team have already found that not all changes in the ER gene affect breast tumour cells in the same way. ER gene changes fall into two groups based on their impact on other genes and the team want to reach a better understanding of the differences between these two groups, leading to new and more effective ways to treat ER-positive secondary breast cancer.