Drug repurposing and rare cancer by Emeritus Professor Andy Hall.


As a young trainee haematologist I saw many patients with chronic myeloid leukaemia (CML). Frequently in their early 30s they were about my age with everything to look forward to. After a brief period of remission using drugs with unpleasant side effects the very high level of cancerous white cells in the blood returned and almost all of them died. Then, in the 1990s, a drug was introduced which completely changed the outlook for patients with this disease. STI571, now known as Imananib was the first truly targeted drug to be used in the treatment of cancer and its arrival was stunning. It was so effective that patients quickly found out that it was of little use to be in the control arm of clinical trials and began to demand that they received active treatment rather than the vastly inferior alternatives.


Although some patients develop resistance to imatanib long term survival is now the norm for patients with CML but it is largely through the persistence of one man-  Brian Druker working in Portland Oregon- that it was ever introduced. CML is a rare disease so pharmaceutical companies were reluctant to spend any money on developing something with such a limited market. CML is caused by the formation of an abnormal chromosome which makes an enzyme in bone marrow cells which is in a permanent active state and drives cell division. Druker persuaded Novartis to give him access to a drug that had been developed against another similar enzyme-  the platelet derived growth factor receptor- which was also known to inhibit the enzyme active in CML. The performance of STI571 in this unanticipated role has revolutionised the treatment of CML and is a clear illustration of how effective drug repurposing can be.


So, what exactly is drug repurposing? Very few drugs have no side effects. In many cases drugs will fail to reach the clinic because these effects are too severe to be tolerated. This represents a major financial burden for drug companies, particularly if significant side effects only come to light late in the development process. However, occasionally, an unexpected effect of a drug can be used to treat patients with an unrelated condition. The most widely known example of this is sildenafil, better known by its trade name Viagra which was originally developed as treatment for heart related chest pain. During clinical trials male patients unexpectedly reported the improvement in erectile dysfunction which has now become the main indication for the repurposed drug.   


STI571 rapidly became the poster child for targeted drug development, cited in almost every talk and grant application on the subject. On May 28th2001, Time Magazine declared “There is new ammunition in the war against cancer- these are the bullets”. The success of ST571 led to a surge of interest in the production of drugs targeted against enzymes in an activated state in cancer but sadly the optimism was misplaced. We now know that CML is the exception rather than the rule because most common tumours have multiple abnormalities and if one is knocked out another can take its place in driving cell division or preventing cell death.  Focus has now moved to immunotherapy as offering the best hope of lasting cures in the majority of tumour types.


However, this has left many drug companies with a selection of drugs which have not made it into the clinic- representing a significant loss of investment for them and, I believe, possibly a missed opportunity in the treatment of rare cancers. As the cost of the development of a drug is estimated to be in the order of $700m to $2.5 billion any measure which can use these otherwise wasted resources would be very attractive to the pharmaceutical industry. 


Cancers are defined as being rare if they occur at a frequency of less than 6 per 100,000. They can arise in virtually any tissue and at any age from birth upwards. All of the childhood cancers fall within this group. Although each individual rare cancer is, by definition, uncommon they represent up to 30% of all types of cancer but for many types little is known about their biology and the best mode of treatment. Overall, rare tumours have an inferior response to treatment and have a significantly lower survival rate.


One of the main reasons why so little is known about many types of rare tumour is the challenge in gathering together enough cases to undertake meaningful research. The childhood cancers are an exception because for many years these patients have been treated in specialist centres. This has allowed scientists to have access to tissue samples and for multicentre clinical trials to be undertaken. As a consequence, the outcome for some children with cancer has now improved and cure rates of over 80% are reported for some tumour types, for example acute lymphocytic leukaemia. However, this by no means the case for all childhood cancers. The outcome for many types such as sarcoma, brain tumours and neuroblastoma, is considerably worse and treatment is associated with severe drug and radiotherapy associated side effects.  In order to address this problem the charity aPODD (accelerating Paediatric Oncology Drug Development) is actively promoting drug repurposing as a way of tackling the lack of progress in introducing better treatments for children with cancer, both to improve cure rates and reduce the side effects of current therapy which can have severe, life-changing, consequences.


The situation for adults with rare cancers is particularly challenging because they are usually not treated in specialist centres and any one oncologist will never see a patient with certain types throughout their working life. This makes research extremely difficult. However, a solution may be found by using a model already in place for research into dementia. Join Dementia Research was set up to enable patients to volunteer to take part in research projects and clinical trials. To date over 30,000 patients have enrolled and over 11,000 have been recruited to research projects. A similar system could be set up for patients with rare cancers- which brings us back to the potential role of drug re-purposing in this area. 


Until recently drug companies worked on a “block buster” model. If a particular drug only worked in a minority of patients it was shelved. We now know that cancer is extremely heterogeneous and that subgroups may exist which are very sensitive whilst the majority are not. The situation in rare cancers is largely uncharted but we do know of examples where the single target approach that works so well in CML does occur in at least one type- the gastro-intestinal stomal tissues where most patients have a mutation in a gene to produce an activated enzyme sensitive to imatanib-  a drug which has been repurposed twice. 


Patients with rare tumours often seek help from others with the same disease, using the internet to find national support groups or simply sharing information using social media. By providing them with a way of indicating their willingness to take part in research we could harness this enthusiasm for their potential benefit and possibly improve their chances of successful treatment using repurposed drugs.


With a long and distinguished career at Newcastle University, Professor Hall’s work focused on cancer research with particular interest in developing biobanks and promoting the use of human tissues samples to forward medical research and develop new treatments. This work has driven his interest in the ethics of using human tissues samples and has prompted the creation of givemysample.org . A website created to help patients decide if they want to give samples for medical research.

Thanks to Professor Andy Hall for editing our first blog post for 2019.

Thanks to Professor Andy Hall for editing our first blog post for 2019.

Narissa Gipp