The impact of ecological competition and cooperation on cancer adaptive therapy

This project aims to use mathematical and computational modelling, combined with preclinical and clinical data, to develop a deeper understanding of the importance of spatial interactions ("ecology") in regulating therapeutic resistance in cancer. Specific goals are to: 1) understand how various ecological niches regulate cancer resistance, 2) build multiscale models that integrate cancer evolution and ecology, 3) develop multi-drug adaptive therapies that exploit space. Therapy failure is virtually assured in most cancers that have disseminated into metastatic disease. Trying to eliminate all cancer cells that may now inhabit multiple locations in the patient results in cancer cells acquiring therapeutic resistance via evolution. In fact, therapy resistance is probably the largest impediment to curing the disease, or maintaining it at a level that does not compromise the patient's quality of life. Recently, mathematical oncology and cancer biology have been tightly integrated to deliver novel clinical treatments for cancer that exploit evolution, rather than ignoring it. The key to success in such strategies is to anticipate adaptation and thus adjust therapeutic strategies before they become ineffective. Initial work will focus on the development of an agent-based model that considers resistance as a plastic state, modulated by the microenvironment, and treated with a combination of 2-3 drugs. Understanding the time scale of the emergence of resistance and the return to sensitivity for each drug, as well as potential synergies, will be critical in deciding how to sequence the drugs effectively to manage resistance. Preclinical data will be available to support this project in metastatic melanoma, as well as recurrent ovarian cancer. Ultimately, the goal is to develop a robust platform for informing clinical application on the best forms of adaptive therapy when there are multiple drugs, and multiple resistance strategies. Previous work has focused on the tumour response to a single drug, and mathematical approaches are currently insufficiently detailed to offer practical guidance to clinicians. In addition to this, work will also be conducted on a novel application of deep reinforcement learning to adaptive therapy, with a particular focus on developing and characterising models that independently learn adaptive strategies. Preliminary studies by the student and collaborators at the Moffitt Cancer Centre have suggested that deep learning algorithms trained on simple (non-spatial) tumour models are able to outperform human-developed strategies, and may be applied to more complex (spatial) models through transfer learning. This work is conducted in collaboration with industrial supervisors Alexander Anderson and Robert Gatenby based at the Moffitt Cancer Centre in Florida, who will advise on mathematical, modelling and clinical aspects of the research. This project falls within the EPSRC mathematical biology research area. It also contributes towards EPSRC's strategic priority to transform healthcare, with the potential to improve quality of life for patients with treatment resistant cancers.

The main impact of the SABS CDT will be the difference made by the scientists trained within it, both during their DPhils and throughout their future careers.

The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.

Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners

"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."

New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.

For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,

"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."

However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.

The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students

"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."

To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.

The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.