Charity Soul funded research in the Cancer Research unit at York University for 5 years. At the time I said that the funding would help me to try out new ideas, ahead of grant applications to the Government and the major charities. This flexibility is simply not available in large so-called project grants, where you are normally restricted by specific aims and milestones.
So what did we do?
For many years we have studied the various different cell types which are present in almost every cancer type. The variability is called tumor heterogeneity. In particular we found that cells with the properties of stem cells were present at a frequency of less than 1:1000 in the tumor mass. The cancer stem cells do not divide and grow like the rest of the cancer, and like stem cells in normal tissues, are available to regrow the cancer after treatment kills most of the other dividing cells. This results in the frequently observed recurrence of a cancer after a period of remission. It would also help if the cancer stem cells were more resistant to common treatments…that too we showed with multiple experiments and more than 30 academic papers over 10 years study. For example, my colleague Dr Fiona Frame showed that the cancer stem cells were highly resistant to radiotherapy, unless hit by an extremely high dose of radiation. The cancers in almost 30% of prostate cancer patients treated with radiotherapy eventually recur. We wanted to find out whether the stem cells simply shielded themselves by ‘hiding’ in the cancer mass, or whether the process was more active.
With the help of Charity Soul funding we showed that the stem cells have a very specific mechanism of resistance. We even indicated a potential drug to overcome this resistance. So you can see that to achieve a cancer cure we need to kill the stem cells as well as shrinking the tumor mass, as we can do at the moment.
Most recently, and up until my retirement we were adopting a totally novel approach, where we were trying to cause cancer. Why? Mature cancers contain many changes to their DNA (mutations), some are important (drivers) and others are only needed for adaptation or occur as a result of treatment (passengers). To achieve a cancer cure you must attack the drivers, which are unique to cancers (relative to normal cells….which treatment should NOT kill!).
Because of human genome sequencing, and the Worldwide Cancer Genome Project, we now know the identity of many cancer mutations. What we do not know is the relative importance (although we know the frequency), the order in which these mutations MUST occur, and also what happens when you treat these specific mutations in the absence of others.
So we decided to use the technique of GENOME EDITING to CAUSE cancer in non-cancer cells from the prostate. We chose 10 of the most common mutations in prostate cancers, and used the editing (or gene clipping) to change one or both copies of these genes.
Due to the hard work of a series of talented undergraduate students, whose lab work was totally supported by Charity Soul., we generated both single and double mutations in these presumed driver genes. Just before my retirement we got the first indications that specific targeting to 2 of these genes could result in a cancer. This work was carried out together with Cardiff University… but has ground to a halt due to laboratory shutdowns during the Covid 19 pandemic.
But we can get so much more out of these edited cancer cells. We now know which of the 20,000 other human genes is affected by the changes, as a target for further treatments, perhaps using existing drugs. In fact we have already checked the susceptibility of the edited cells to one drug, recently developed in the USA, and the expected susceptibility was seen.
My aim is to distribute these cells to all interested researchers for further drug development, now that my Research Unit has closed down. Our work has been at the cutting edge of cancer genetics and biology over many years, but the availability and translation of our discoveries into treatments for real patients will take many years more, mainly because of safety and regulatory reasons. We are seeing labs all over the world repeating these experiments, and it is important to note that we were the first….and with Charity Soul’s support.
The future of Charity Soul funding will not be at York University, where my Research Unit closed on my retirement, and the talented group of researchers who worked there dispersed thoughout the world. Instead, we have identified researchers with closely related interests at the University of Newcastle. Still in “the North’ and with their research interests in prostate cancer.
Firstly, there is Prof Rahesh Heer, whose research has adopted a stem cell approach (like that in York) to the diagnosis and treatment of prostate diseases. Rakesh also uses cells taken directly from patients in this work, and has plans to use the edited cells from York and elsewhere in his experiments with mini-prostates, based on stem cell technology. Some of Rakesh’s training involved staff from the Cancer Research unit in York.
Secondly, Dr Jenny Munkley has exploited crucial biochemical differences between normal and cancerous prostates, also seen in stem cells, to devise a new diagnostic test, which could also perhaps be exploited in cancer treatment. At the moment we believe that this will offer a better means of determining those prostate cancer patients who require aggressive initial treatment, preparing for better outcomes, and treatment directed towards those in whom it will do the most good. In fact, not only was Jenny’s PhD obtained in the lab next to my Unit in York, the samples used to establish the distinct and diagnostically important differences were first identified in a collaboration between my Unit, and Dr Munkley, using the tissue samples we had obtained from prostate cancer patients. I am excited that all of the research my lab carried out, and Charity Soul’s support will not be wasted going forward.
Professor Norman Maitland