Chromosomal instability in cancer pathogenesis and treatment
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
The genetic material within cancer cells is highly unstable. The overall purpose of our work is to understand how this instability contributes to cancer growth, and to use this new knowledge to better pinpoint genetic risks for human cancer, and to develop new approaches for cancer detection and therapy. In particular, we will study pancreatic cancer, a leading cause of death, for which there is an urgent unmet medical need to improve detection and therapy.
Technical Summary
Instability in the structure and number of chromosomes is a hallmark of human epithelial cancers. It is triggered during the poorly understood transition from pre-invasive to cancerous lesions early in carcinogenesis. What provokes genome instability, and how it fosters cancer pathogenesis, remain major unresolved questions central to understanding early steps in the evolution of cancer. How human genetic variations affecting the maintenance of genome stability may foster cancer risk, and how the near-universal occurrence of genome instability in common epithelial malignancies may be exploited in new approaches to cancer therapy, remain to be explored. We aim to understand how the mechanisms that engender genome instability contribute to early steps in epithelial carcinogenesis. We will exploit this knowledge to better stratify the genetic risks underlying human cancer predisposition, and to develop new approaches for cancer detection and therapy that can be applied in the clinic.
Organisations
Publications
Ahmad SS
(2018)
Science in Focus: Genomic Instability and its Implications for Clinical Cancer Care.
in Clinical oncology (Royal College of Radiologists (Great Britain))
Briese M
(2019)
A systems view of spliceosomal assembly and branchpoints with iCLIP.
in Nature structural & molecular biology
Cassidy LD
(2014)
Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation.
in Molecular oncology
Cole DJ
(2017)
Computationally-guided optimization of small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction.
in Chemical communications (Cambridge, England)
D'Alessandro G
(2018)
BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment.
in Nature communications
D'Alessandro G
(2018)
BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment.
Related Projects
| Project Reference | Relationship | Related To | Start | End | Award Value |
|---|---|---|---|---|---|
| MC_UU_12022/1 | 01/10/2013 | 31/03/2022 | £4,906,000 | ||
| MC_UU_12022/2 | Transfer | MC_UU_12022/1 | 01/10/2013 | 31/03/2022 | £3,901,000 |
| Description | Chaired the review panel for the National Centres of Competence in Research of the Swiss National Science Foundation |
| Geographic Reach | Europe |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Description | Governing Council member of INSTITUTE FOR STEM CELL BIOLOGY AND REGENERATIVE MEDICINE, Bangalore, India |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | As a member of the Governing council of this world renowned research Institute, have contributed to steering the direction and progress of fundamental research and training at the institute. |
| Description | Invited panel member of the Cambridge University Leadership Network (CULN) |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Description | Invited to the Basser Foundation Think Tank (New York/Philadelphia) |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Professor Venkitaraman was invited to be part of this Think Tank 'to develop a plan framed as a series of provocative questions'. His role was to assist a distinguished panel of expert scientists from the US to plans for future funding in various areas of cancer research. |
| Description | Invitied member of the Scientific Advisory Committee of Experimental Therapeutics Unit, IFOM, the FIRC Institute of Molecular Oncology |
| Geographic Reach | Europe |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Membership of the SAB of a leading biomedical translational sciences institute in Italy, which focuses on cancer research, has enabled contributions to: (a) national and international policy on translational research particularly concerning the discovery of new drugs against cancer (b) promotion of MRC and UK collaborations with Milan in particular and Europe more generally and (c) network nucleation at a high level with policy makers and thought leaders. |
| URL | https://www.ifom.eu/en/oncology-institute/ |
| Description | Invitied member of the Scientific Advisory Committee of Translational Health Science and Technology Institute (THSTI), India |
| Geographic Reach | Asia |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Membership of the SAB of a leading biomedical translational sciences institute in India has enabled contributions to: (a) national and international policy on translational research (b) promotion of MRC and UK collaborations with India and (c) network formation at a high level with policy makers and thought leaders. |
| URL | http://thsti.res.in/index.php |
| Description | Invitied member of the Steering Committee of the Institute for Stem Cell Biology & Regenerative Medicine (inStem), India |
| Geographic Reach | Asia |
| Policy Influence Type | Membership of a guideline committee |
| Impact | Membership of the SAB of a leading biomedical translational sciences institute in India has enabled contributions to: (a) national and international policy on translational research (b) promotion of MRC and UK collaborations with India and (c) network nucleation at a high level with policy makers and thought leaders. This has been instrumental in the Newton Fund award "A Joint Centre for Cancer Biology". |
| URL | https://instem.res.in/collaborative-science-chairs |
| Description | Member, interview panel for the Senior and Intermediate Fellowships of the Wellcome Trust / DBT India Alliance |
| Geographic Reach | Asia |
| Policy Influence Type | Influenced training of practitioners or researchers |
| Description | Steering committee member of The Early Detection Programme of the Cambridge Cance Centre |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | As part of the steering committee influenced the direction of research and training offered by this organisation |
| Description | Steering committee member of The National Centres of Competence in Research NCCR of the Swiss National Science Foundation (SNSF) |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | As part of the steering committee influenced the scientific drection and policy impact of this organisation |
| Description | COUNTERACTING IMMUNE EVASION IN DNA REPAIR-DEFICIENT PANCREATIC CANCERS FOR IMMUNOTHERAPY |
| Amount | £109,918 (GBP) |
| Organisation | Pancreatic Cancer UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2019 |
| End | 09/2022 |
| Description | Cambridge-NUHS Seed Funding |
| Amount | $30,000 (SGD) |
| Organisation | National University Health System (NUHS) |
| Sector | Public |
| Country | Singapore |
| Start | 09/2018 |
| End | 08/2019 |
| Description | DEVELOPMENT OF STRATEGIES TO TRACK AND PREVENT BREAST CANCER DEVELOPMENT IN BRCA MUTATION CARRIERS |
| Amount | $5,063,620 (USD) |
| Funding ID | 281760.5112728.0104 |
| Organisation | The Gray Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 09/2019 |
| End | 08/2022 |
| Description | Krishnan-Ang Fellowship - Shehata |
| Amount | £375,000 (GBP) |
| Organisation | Cambridge Cancer Centre |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 06/2017 |
| End | 05/2022 |
| Description | MRC - A Joint Centre for Cancer Biology & Therapeutics (fellowships) |
| Amount | £1,151,979 (GBP) |
| Funding ID | MR/N501876/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2015 |
| End | 04/2018 |
| Description | Modulation of physiological and oncogenic Ras protein signaling via plasma membrane clustering |
| Amount | £29,500 (GBP) |
| Funding ID | IA/E/15/1/502339 |
| Organisation | National Centre for Biological Science (NCBS) |
| Sector | Academic/University |
| Country | India |
| Start | 04/2017 |
| End | 03/2019 |
| Description | ParSortix - staff funding |
| Amount | £39,916 (GBP) |
| Organisation | ANGLE |
| Department | Parsotix Team |
| Sector | Private |
| Country | United Kingdom |
| Start | 09/2014 |
| End | 06/2016 |
| Description | PhoreMost |
| Amount | £76,462 (GBP) |
| Organisation | PhoreMost |
| Sector | Private |
| Country | United Kingdom |
| Start | 03/2015 |
| End | 02/2016 |
| Description | Attendee: The Futures of Sciences Two Day Meeting, Cambridge |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Attendee: The Futures of Sciences Two Day Meeting, Cambridge |
| Year(s) Of Engagement Activity | 2019 |
| Description | CRUK CC/CI SAB Meeting/Retreat |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Policymakers/politicians |
| Results and Impact | CRUK CC/CI SAB Meeting/Retreat |
| Year(s) Of Engagement Activity | 2019 |
| Description | CRUK Cambridge Institute International Symposium 2019 'Radical approaches to cancer prevention' |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Attendee at CRUK Cambridge Institute International Symposium 2019 'Radical approaches to cancer prevention' |
| Year(s) Of Engagement Activity | 2019 |
| Description | Cambridge Science Festival 2014 |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | Yes |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Group members spoke about their research and coordinated activities for the public such as DNA extraction. Increased awareness of cancer research and its importance. |
| Year(s) Of Engagement Activity | 2014 |
| Description | Cambridge Science Festival Talk to a wide public audience (200 people) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | A wide public audience (c 200 people) attended the public lecture entitled "The origins of cancer: What's in our genes and what isn't?" Several people stopped by aftert the talk to speak to Prof Venkitaraman and there were several email queries to discuss/follow up on his talk. The feedback about the content and presentation was also very positive. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Co-chair: 2019 Early Detection of Cancer Conference, Stanford, USA |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Supporters |
| Results and Impact | Co-chair: 2019 Early Detection of Cancer Conference, Stanford, USA |
| Year(s) Of Engagement Activity | 2019 |
| Description | Featured article in MRC Research Horizons |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Third sector organisations |
| Results and Impact | Article for MRC Research Horizons magazine on the incidence and treatment of TB in India. Promoted the Center for Chemical Biology and Therapeutics (CCBT) in India and created awareness of similar types of novel drug targets that have been implicated in infectious diseases, cancer and even developmental defects. |
| Year(s) Of Engagement Activity | 2015 |
| URL | https://www.cam.ac.uk/system/files/issue_28_research_horizons.pdf |
| Description | Festival Speaker Spotlight |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | Yes |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Interviewed for Cambridge Science Festival Speaker Spotlight Increased awareness of cancer research and festival activities. |
| Year(s) Of Engagement Activity | 2014 |
| URL | http://www.cam.ac.uk/science-festival/news-media/speaker-spotlights/speaker-spotlight-professor-asho... |
| Description | Hosted Students from Hills Road 6th Form College, Cambridge |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Hosted students from Hills Road 6th Form College |
| Year(s) Of Engagement Activity | 2019 |
| Description | Hosted a visit by the Cambridge MP Daniel Zeichner to the Unit |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Policymakers/politicians |
| Results and Impact | As part of the MRC Festival of research, 2017 a visit was organised for the local MP Daniel Zeichner, where he participated in a panel discussion (led by Professor Venkitaraman) involving all ther MRC Cancer Unit's group leaders. The MP was given an overview of the kind of research that the Unit undertakes, centred around its core mission of early detection/patient stratification/intervention in Cancer. Discussions also veered around the current and future issues related to Research funding and opportunities, particularly in a post Brexit environment. THE MP was also taken on a tour across the laboratories where he had a chance to interact with other research staff and students. |
| Year(s) Of Engagement Activity | 2017 |
| URL | https://www.mrc-cu.cam.ac.uk/news/CUvisitbyCambridgeMP |
| Description | Hosted week long lab-experience visit from Sixth Form students in 2016, 2017 and 2018 |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | A lab-experience tour for a week was organised at the Venkitaraman labs for students from the Hills Road Sixth Form College, Cambridge. During this visit, 6 students interacted with researchers from the Venkitaraman group, were given supervised exposure to laboratory techniques and Professor Venkitraman gave them an overview lecuture at the beginning of their visit. The students very appreciative of the whole experience and communicated their views through a post that is now hosted on the MRC CU blogsite. Very positive feedback was also received from the Head of Biology at the School about this experience, with a request for continuation of such visits to the Unit in the coming years. The visits were also organised in 2017 with similar outcomes to 2016. The 2016 blogpost can be found at : https://mrccancerunit.wordpress.com/2016/11/29/of-inspiring-fresh-minds-of-fresh-new-ways-of-looking-at-cancer/ |
| Year(s) Of Engagement Activity | 2016,2017,2018 |
| URL | https://mrccancerunit.wordpress.com/ |
| Description | Interview on BBC Radio Cambridgeshire |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Interview on local radion Drivetime programme to discuss cancer research and promote cambridge science festival activities Increased awareness of research and attendance at festival event |
| Year(s) Of Engagement Activity | 2014 |
| Description | Invited Speaker: University of Leeds |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Supporters |
| Results and Impact | Invited Speaker: University of Leeds |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited Speaker: University of Manchester |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Supporters |
| Results and Impact | Invited Speaker: University of Manchester |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited Speaker: University of Toronto |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Supporters |
| Results and Impact | Invited Speaker: University of Toronto |
| Year(s) Of Engagement Activity | 2019 |
| Description | Panel Chair: Swiss National Science Foundation: NCCR full proposal panels, Berne |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Supporters |
| Results and Impact | Panel Chair: Swiss National Science Foundation: NCCR full proposal panels, Berne |
| Year(s) Of Engagement Activity | 2019 |
| Description | Participant 6th RNA Biology Symposium |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Professional Practitioners |
| Results and Impact | Participant 6th RNA Biology Symposium |
| Year(s) Of Engagement Activity | 2020 |
| Description | Participant: MRC Open Day, Cambridge |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | MRC Open Day, Cambridge |
| Year(s) Of Engagement Activity | 2019 |
| Description | Participant: Early Detection conference |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Professional Practitioners |
| Results and Impact | Participant Early Detection conference |
| Year(s) Of Engagement Activity | 2020 |
| Description | Participant: LMB Lab Symposium October 2020 |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Professional Practitioners |
| Results and Impact | Participant: LMB Lab Symposium October 2020 |
| Year(s) Of Engagement Activity | 2020 |
| Description | Participant: NUS e-Open day |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Participant: NUS e-Open day |
| Year(s) Of Engagement Activity | 2020 |
| Description | Participation in AZ-CRUK Cambridge Centre Symposium |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Professional Practitioners |
| Results and Impact | Participation in AZ-CRUK Cambridge Centre Symposium |
| Year(s) Of Engagement Activity | 2020 |
| Description | Participation in Open Day at MRC Cancer Unit as part of MRC Festival of Research (2016, 2017 and 2018) |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | 60 sixth-form students from across 8 schools in Cambridge visited the MRC Cancer Unit on the afternoon of the 22nd of June, 2016 for an Open Day. All students, accompanied by their teachers, were given a tour of the enitre building with an opportunity for engaging with researchers about the state of the art in cancer research and gaining hands-on experience with setting up experiments. Talks about career opportunities and challenges associated with pursuing cancer research were also available to all attendees. The event sparked a great deal of interest and enthusiasm in students and teachers alike and we have had a request for this event to be continued. We will be pursuing a similar format of activities for the MRC Science Festival in 2017, but reach out to more number of schools, including those outside of Cambridge city perimeters. For the 2017 Open day we havd 4 local schools but with more number of students frome ach school. A totla of 60 students along with their teachers visited the Unit and were given a tour across the various laboratories at the Unit and a chance to engage with researchers at the Unit. |
| Year(s) Of Engagement Activity | 2016 |
| URL | https://www.mrc-cu.cam.ac.uk/news/MRCFESTIVAL2017 |
| Description | Public Lecture as part of Cambridge Alumni Festival 2019 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Supporters |
| Results and Impact | TAlk delivered on 28th September, 2019 as part of the University of Cambridge Alummi Festival to a broad public audience. Talk title: "The origins of cancer: What's in our genes and what isn't?" |
| Year(s) Of Engagement Activity | 2019 |
| Description | Speaker at the Cambridge Science festival |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Delivered a lecture about the recent scientific advances that promise to transform our ability to translate biological knowledge into new medicines. The talk, although heavily charged with information about the state of the art advances in the field of cancer research and medicine development, was tailored to provide clarity about these complex issues to the general audience and was very well received by all attending. |
| Year(s) Of Engagement Activity | 2016 |
| URL | http://www.sciencefestival.cam.ac.uk/events?search_api_views_fulltext=cancer |
| Description | Speakers for Schools (Castle Manor Academy, Haverhill) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Castle Manor Academy, is a school in Haverhill, adjoining Cambridge. It does not have a huge culture of engaging with the numerous scientific talks and public engagement activities in Cambridge; however it had a teaching crew and a head teacher with huge enthusiasm for changing this. Hence, Professor Venkitaraman was invited to visit the school to inspire and enthuse the students that research and science is for everyone. During his visit, Prof Venkitaraman introduced 6th form students to concepts in cancer biology and cancer prevention. |
| Year(s) Of Engagement Activity | 2018 |
| Description | co-Organizer and Conference Chair, Early Detection Conference, Stanford, USA |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Cancer Research UK, OHSU Knight Cancer Institute and the Canary Center at Stanford, were teh main organisers of the Early Detection of Cancer Conference The annual Conference brings together experts in early detection from multiple disciplines to share ground breaking research and progress in the field. The Conference is part of a long-term commitment to invest in early detection research, to understand the biology behind early stage cancers, find new detection and screening methods, and enhance uptake and accuracy of screening. |
| Year(s) Of Engagement Activity | 2019 |
| URL | http://earlydetectionresearch.com/wp-content/uploads/2019-Conference-Agenda_Legal-Horizontal.pdf |