Modelling Clonal Evolution in Tumours and Optimal Drug Scheduling Protocols
Lead Research Organisation:
University of Oxford
Department Name: SABS CDT
Abstract
Acquired drug resistance to chemotherapeutics prevents full remission in cancer patients. During treatment, drug-induced genetic and epigenetic reprogramming of cells gives rise to fully drug-resistant mutant clones via distinct pathways, each with corresponding timescales.
In this research, I will be investigating the clonal evolution in tumours by modelling the dynamics of their heterogeneity which is influenced by a number of drug-induced cellular changes. In doing so, I will investigate the impact treatments have on these drug-induced changes so as to test the optimal drug scheduling protocols in order to maximise the time to a fully drug-resistant tumour.
The aim of the project is to accurately model the dynamics of resistant clones in a tumour when taking into account the impact the tumour micro-environment as well as the evolutionary dynamics between the different resistant cell types. This allows for the testing of optimal drug scheduling hypotheses, for example, the Goldie and Coldman Hypothesis, which states that given two non cross-resistant chemotherapeutic drugs, one should alternate the drugs as quickly as possible to maximise the time to a tumour being fully resistant to therapy. Furthermore, an objective of this project is to determine whether we can differentiate between mutations which are drug-induced or random, spontaneous events to better inform suitable treatment protocols. In addition to this, the influence cancer persister cells have on the heterogeneity of the tumour over long periods of time will also be investigated.
This research is novel as it is incorporating the impact of the tumour micro-environment and the evolutionary dynamics between resistant clones when modelling the drug-induced heterogeneity of the tumour prior to testing optimal drug scheduling protocols. The Goldie and Coldman Hypothesis has been tested in the case where mutations occur as random, spontaneous events in the tumour, however a novel aspect of this research is that it is investigating whether the hypothesis holds in the case of acquired drug-resistance, induced by treatments themselves. Furthermore, this project will be looking at the impact of treatment scheduling of the tumour persister cell population, whose population when exposed to a drug increases, giving rise to further resistant mutations over long periods of time.
The project falls within the EPSRC Mathematical Biology research area, in particular, under ESPRC and MRC Systems approaches to Biomedical Sciences. I will be collaborating with my industrial supervisor, James Yates at AstraZeneca.
In this research, I will be investigating the clonal evolution in tumours by modelling the dynamics of their heterogeneity which is influenced by a number of drug-induced cellular changes. In doing so, I will investigate the impact treatments have on these drug-induced changes so as to test the optimal drug scheduling protocols in order to maximise the time to a fully drug-resistant tumour.
The aim of the project is to accurately model the dynamics of resistant clones in a tumour when taking into account the impact the tumour micro-environment as well as the evolutionary dynamics between the different resistant cell types. This allows for the testing of optimal drug scheduling hypotheses, for example, the Goldie and Coldman Hypothesis, which states that given two non cross-resistant chemotherapeutic drugs, one should alternate the drugs as quickly as possible to maximise the time to a tumour being fully resistant to therapy. Furthermore, an objective of this project is to determine whether we can differentiate between mutations which are drug-induced or random, spontaneous events to better inform suitable treatment protocols. In addition to this, the influence cancer persister cells have on the heterogeneity of the tumour over long periods of time will also be investigated.
This research is novel as it is incorporating the impact of the tumour micro-environment and the evolutionary dynamics between resistant clones when modelling the drug-induced heterogeneity of the tumour prior to testing optimal drug scheduling protocols. The Goldie and Coldman Hypothesis has been tested in the case where mutations occur as random, spontaneous events in the tumour, however a novel aspect of this research is that it is investigating whether the hypothesis holds in the case of acquired drug-resistance, induced by treatments themselves. Furthermore, this project will be looking at the impact of treatment scheduling of the tumour persister cell population, whose population when exposed to a drug increases, giving rise to further resistant mutations over long periods of time.
The project falls within the EPSRC Mathematical Biology research area, in particular, under ESPRC and MRC Systems approaches to Biomedical Sciences. I will be collaborating with my industrial supervisor, James Yates at AstraZeneca.
Planned Impact
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.
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.
Organisations
| Description | Using mathematical modelling techniques, we have analysed the effects of certain tumour ecological features such as mutation probability, fitness of resistant cells, cell turnover rate and the ability for a drug to induce resistance on the level of drug-resistance in a tumour both prior to and during treatment. We have demonstrated the sequential application of two tyrosine kinase inhibitors (TKIs) is beneficial in terms of maintaining a tumours sensitivity when TKIs have the ability to induce resistance and resistant cells have a higher fitness relative to the sensitive cells. Furthermore, we have predicted the prevalence of resistance at diagnosis on a tumour and demonstrated its dependence on the mutation probability, cell turnover rate and fitness of resistant cells. |
| Exploitation Route | AstraZeneca, my industrial collaborator may now test the hypotheses made using the mathematical modelling study and establish whether these ecological factors and application of TKIs influencing the level of resistance in this way. |
| Sectors | Healthcare |