Ultrasound-Guided Activation and Imaging of Engineered Bacteria for Stroma Reprogramming

In this project, we propose a cross-disciplinary research programme aimed at addressing the critical unmet needs of pancreatic ductal adenocarcinoma (PDAC). These cancers have a five-year survival rate of just 3%, despite many attempts to combine existing therapies to improve outcomes. We believe an entirely new approach is needed, and have brought together a diverse team of researchers at multiple career stages and across the disciplines of synthetic biology, materials chemistry, cancer biology, advanced engineering and clinical medicine to address this problem. Context of the research: Pancreatic cancer has a complex and heterogeneous tumour microenvironment (TME) rendering it unresponsive to most conventional therapies. The TME is composed of multiple interacting biomolecules which form a dense matrix, and in addition to cancer cells there are immune cells including tumour associated macrophages (TAMs), natural killer (NK) and CD8+ T-cells which play a significant role in regulating tumour growth and resistance to treatment. Current treatments largely fail to consider the dynamic nature of the TME, leading to poor patient outcomes. Challenge the Project Addresses The primary challenge addressed by this cross-disciplinary project is the need for more effective and targeted therapies for PDAC. Traditional treatments focus on eliminating cancer cells, but this approach often fails due to the protective role of the TME. The project aims to reprogram the stroma (the supportive tissue surrounding the tumour) rather than directly targeting the cancer cells, thereby overcoming the limitations of current therapies. Aims and Objectives: The main aim of the project is to develop a new concept in cancer therapy that uses engineered bacteria to reprogram the tumour stroma. The specific objectives are: 1. Engineering bacteria to produce compounds that release immunomodulators, such as TRAIL and IL-15SA , which can reprogram macrophages and recruit NK cells and reduce resistance to therapies. 2. Deploy responsive polymers that can be co-injected with bacteria and which gel in situ, retaining the bacteria at the peri-tumoural injection site, and which can release bacterial activators on-demand when activated by ultrasound, allowing precise control over the timing and location of treatment. 3. Validating the efficacy of this approach using 3D culture models of PDAC to demonstrate the potential for clinical application. Potential Applications and Benefits: This project has the potential to revolutionize the treatment of PDAC and other solid tumours by offering a more targeted and effective therapy. By reprogramming the tumour stroma, this approach could improve patient outcomes and reduce the side effects associated with conventional treatments. Additionally, the use of ultrasound for on-demand activation of the therapy provides a non-invasive and precise method for controlling treatment, making it more adaptable to individual patient needs. The interdisciplinary nature of the project also paves the way for future collaborations and innovations in cancer therapy, with the potential to extend this approach to other types of cancer and diseases with complex microenvironments. The work has been inspired by MRC and Cambridge Pancreatic Cancer Centre workshops with clinicians and patient representatives, and has been co-created by researchers across different disciplines and career stages to address a critical unmet need.