Tumor priming sequences combined with novel nanoparticle drug carriers for enhanced therapeutic efficacy in pancreatic cancer: a tripartite USA/Northern Ireland/Republic of Ireland consortium
Lead Research Organisation:
Queen's University Belfast
Department Name: UNLISTED
Abstract
Pancreatic cancer is lethal to the vast majority of patients, largely because the disease is advanced when discovered, and tumor blood flow is so low that drugs do not readily access the tumor. This project will address the ‘drug delivery’ barrier by establishing a conceptual understanding of how ‘tumor priming’ agents work; they attack the barrier between the blood stream and the tumor interior, creating a ‘window of opportunity’ for delivery of a second agent. We hypothesize that nanoparticle-based drug carriers may have unique advantages that enable them to exploit tumor priming strategies more effectively and improve therapeutic outcomes; inclusion of several clinically-approved agents in our research plan will provide strong rationale for near-term clinical trials in pancreatic cancer, and we propose novel novel nanoparticle agents of longer-term developmental potential.
Technical Summary
Pancreatic cancer (PaCA) has significant incidence, and is usually advanced at diagnosis. Regardless of treatment, 94% die within 2 yrs. Treatment challenges include tumor genetic heterogeneity, so that "one size fit all" treatment approaches are a dismal failure. Personalizing treatment based on patients' cancer biology is needed. Another challenge is that poor tumor blood perfusion limits delivery of effective chemotherapeutic drugs. Tumor stromal cells collaborate with malignant cells to establish a microenvironment that promotes metastasis, invasion, and treatment resistance, and therefore constitutes an additional target in PaCA treatment. We hypothesize that a specific, sequential, pharmacology-based combination approach will exploit this potential vulnerability: first, a `tumor priming' step will be employed to compromise vascular barrier properties. When vascular compromise is achieved, a persistent, intra-tumor drug depot will be established to extend pharmacological exposure of the tumor cells, even if the barrier is re-established. Nanoparticulate drug carriers containing high drug cargo loads will be employed to achieve this objective. Employing low-passage, patient-derived (PDX) tumor models, Aim 1 will investigate the tumor priming characteristics of two distinct types of agents: a stroma-modifying drug and a clinically-approved chemotherapeutic that primes by inducing tumor decompression. The key objectives are to understand the temporal interrelationships of (i) the primary pharmacological effects that lead to (ii) the tumor priming effect and (iii) enhanced nanoparticle deposition. Of particular interest is (iv) the role of discharging tumor interstitial pressure in the temporal onst (and waning) of the priming effect. A novel, quantitative pharmacological model will be developed to interrelate all these constituent effects into a predictive framework so that mathematical simulation can be used to develop testable hypotheses as to the appropriate priming and therapeutic sequence. In Aim 2 we will investigate distinct drug-containing nanoparticles for their efficacy; high drug-content sterically-stabilized liposomes (SSL) and PEGylated polymeric nanoparticles will be investigated for their therapeutic and mechanistic effects in a tumor- priming regimen. These formulations enable us to test the hypothesis that the aggregate properties of drug and carrier, rather than those of drug alone, determine the tumor pharmacological effects observed. In Aim 3 we will test the hypothesis that under tumor priming conditions, tumor clearance (efflux) of therapeutic nanoparticles can be reduced by employing a tumor- or stroma-targeting ligand, resulting in significant increases in efficacy. Cetuximab- (anti EGFR) bearing nanoparticles will provide proof-of-concept, owing to the predominance of EGFR expression in PaCA. Novel targeting ligands (such as anti-Death Receptor 5) will be explored also. These studies will provide a comprehensive understanding of the `tumor priming' phenomenon to enable their rational design, as well as a strong rationale for therapeutic combinations and agents that could rapidly transition to clinical evaluation in PaCA, a cancer of nearly uniform lethality.
People |
ORCID iD |
Christopher Scott (Principal Investigator) |
Publications
Cogo F
(2019)
Application of nanotechnology to target and exploit tumour associated proteases.
in Biochimie
Greene MK
(2018)
Forming next-generation antibody-nanoparticle conjugates through the oriented installation of non-engineered antibody fragments.
in Chemical science
Greene MK
(2020)
Controlled coupling of an ultrapotent auristatin warhead to cetuximab yields a next-generation antibody-drug conjugate for EGFR-targeted therapy of KRAS mutant pancreatic cancer.
in British journal of cancer
Johnston M
(2020)
DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models
in Journal of Controlled Release
Leach A
(2020)
Anti-DLL4 VNAR targeted nanoparticles for targeting of both tumour and tumour associated vasculature.
in Nanoscale
McCann AP
(2018)
USP17 is required for trafficking and oncogenic signaling of mutant EGFR in NSCLC cells.
in Cell communication and signaling : CCS
Description | KTP Scheme |
Amount | £230,000 (GBP) |
Organisation | Knowledge Transfer Partnerships |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2017 |
End | 10/2020 |
Description | MRC CASE |
Amount | £110,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2017 |
End | 08/2021 |
Description | UCL |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Staff travelled to London to learn new chemistry and develop relationship |
Collaborator Contribution | supply of modified antibodies |
Impact | N/A |
Start Year | 2016 |
Description | Visit to Buffalo laboratory |
Organisation | University at Buffalo |
Country | United States |
Sector | Academic/University |
PI Contribution | Supply of nanoparticles for evaluation purposes and visit to laboratory for training |
Collaborator Contribution | conducted experimentations for us using their pancreatic cancer models |
Impact | Studies completed and more being planned |
Start Year | 2016 |
Description | Keynote Lecture - European Nanomedicine Conference, London April 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Part of the international annual meeting for European Nanomedicine, this year held by the British Society of Nanomedicine |
Year(s) Of Engagement Activity | 2017 |
Description | Keynote lecture British Society of Nanomedicine |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Keynote lecture at the young researchers meeting in Swansea |
Year(s) Of Engagement Activity | 2017 |
Description | Oral Presentation at the Human Antibodies and Hybridomas meeting by Michelle Greene |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Michelle Greene gave an oral presentation entitled "Re-bridging of antibody disulphide bonds: applications in nanoparticle functionalisation" |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.meetingsmanagement.co.uk/index.php?option=com_content&view=article&id=502&Itemid=904 |
Description | Pancreatic Cancer Research Day organised |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | This session and open day was held to showcase pancreatic research being done at QUB and with our international collaborators. This led to engagement with patient families , who have since raised over £33000 for our research efforts, helping fund a new PhD studentship |
Year(s) Of Engagement Activity | 2016 |
Description | Poster Presentation at the Irish Association for Cancer Research (IACR) by Julie Nicholl |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Julie Nicholl presented a poster at the IACR meeting entitled "Novel mechanisms of overcoming apoptotic resistance in pancreatic cancer". |
Year(s) Of Engagement Activity | 2019 |
URL | http://www.iacr.ie/2019-iacr-annual-meeting/ |
Description | Poster Presentation at the Irish Association for Cancer Research Annual Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Poster Presentation entitled "Overcoming apoptotic resistance mechanisms in Pancreatic Cancer. |
Year(s) Of Engagement Activity | 2019 |
Description | Poster presentation at the British Society of Nanomedicine Early Career Researchers Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Peter Smyth was accepted for a poster presentation entitled "Single-domain antibody-functionalized pH-responsive amphiphilic block copolymer nanoparticles for Epidermal Growth Factor Receptor (EGFR) targeted cancer therapy" |
Year(s) Of Engagement Activity | 2018 |
Description | Presentation at Belfast Philosophical Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Talked to general public about our work in pancreatic cancer, leading to new debate and interest in the research at QUB |
Year(s) Of Engagement Activity | 2017 |
Description | Presentation at Irish Association for Cancer Research Conference by William McDaid |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | William McDaid presented his work entitled "Re-purposing Cetuximab as a targeting agent for drug-loaded nanoparticles directed against Cetuximab-resistant cancer cells". |
Year(s) Of Engagement Activity | 2019 |
URL | http://www.iacr.ie/2019-iacr-annual-meeting/ |
Description | Presentation at Keystone Antibodies as Drugs by Michael Johnston |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Michael was selected for a talk at this highly prestigious conference in Feb 2018 |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.keystonesymposia.org/18C1 |
Description | Presentation at the Antibodies as drugs: translating molecules into treatments Conference by Michelle Greene |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Michelle Greene gave a presentation entitled "Generating superior antibody-nanoparticle conjugates through the oriented installation of non-engineered antibody fragments" |
Year(s) Of Engagement Activity | 2018 |
Description | Presentation at the Antibody as drug targets conference in whistler by William McDaid |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | William McDaid presented his work entitled "Re-purposing Cetuximab as a targeting agent for drug-loaded nanoparticles directed against Cetuximab-resistant cancer cells". |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.keystonesymposia.org/18C1 |
Description | Presentation at the Antibody/Targeted-Drug Conjugates Meeting in QUB by Michelle Greene |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Presentation entitled "Re-bridging of antibody disulfide bonds: applications in nanoparticle functionalisatioin and ADC design" |
Year(s) Of Engagement Activity | 2019 |
Description | Presentation at the British Society of Nanomedicine Early Career Researchers meeting by Michelle Greene |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Michelle Greene gave a presentation entitled "Generating superior antibody-nanoparticle conjugates through the oriented installation of non-engineered antibody fragments" |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.crick.ac.uk/whats-on/british-society-of-nanomedicine-early-career-researchers-meeting |
Description | Presentation at the Faculty of Medicine, Health and Life Sciences Postdoctoral Symposium by Michelle Greene |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Michelle Greene gave a presentation entitled 'Generating superior antibody-nanoparticle conjugates through the oriented installation of non-engineered antibody fragments' |
Year(s) Of Engagement Activity | 2018 |
Description | Presentation at the NCRI Meeting by Julie Nicholl |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation at the NCRI meeting 3-5 November 2019 entitled "Overcoming apoptotic resistance mechanisms in Pancreatic Cancer". |
Year(s) Of Engagement Activity | 2019 |
Description | Presentation at the School's Postgraduate Research Symposium by Julie Nicholl |
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 | Postgraduate students |
Results and Impact | Presentation at the School's Postgraduate Symposium on 7 November 2019 entitled "Novel Drug Therapeutics for the treatment of Pancreatic Cancer". |
Year(s) Of Engagement Activity | 2019 |
Description | Science Festival Open Day 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Lead presentation for the Centre explaining the work we do to the general public as part of the National Science week |
Year(s) Of Engagement Activity | 2018 |
Description | Science Open Week presentations |
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 | Demonstrating to the audience the critical need for drug formulation in the development of more effective cancer medicines |
Year(s) Of Engagement Activity | 2016,2017 |
Description | Volunteer at World Cancer Day by Julie Nicholl |
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 | World Cancer Day Event in the Centre. |
Year(s) Of Engagement Activity | 2019 |
Description | Volunteer at the Patrick G Johnston Centre for Cancer Research Open Day by Julie Nicholl, Michelle Greene and Christopher Scott |
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 | Public/other audiences |
Results and Impact | Volunteered at the Open Day on 15 February 2020 |
Year(s) Of Engagement Activity | 2020 |
Description | talk at Rotary Club |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Talked to local Rotarians about our work in pancreatic cancer, leading to them organising a gala dinner and presenting us with a cheque for money raised at this event for our research |
Year(s) Of Engagement Activity | 2017 |