Colorectal cancer (CRC) is increasingly being recognized as a heterogeneous disease with distinct molecular subtypes. These subtypes have different biological processes at the basis of their disease and consequently their prognosis and responses to therapy are also different. We have previously developed molecular diagnostic assays using a single platform on routine FFPE tumour biopsies. These assays identify gene expression profiles with distinct prognosis and drug response phenotypes (CMS4/c-type, BRAF mutant-like, and MSI-like). Our overall objective is to develop targeted therapies more effective than the current therapies that do not take advantage of molecular classification of the disease to select patients for therapy. We therefore propose to perform 3 two-stage single arm multi-centre open-label phase II studies based on solid preclinical evidence and a sound scientific rationale for these subgroups of CRC patients: 1) combination of chemotherapy and a TGF-βR inhibitor (LY2157299) in patients presenting a C-type signature; 2) vinorelbine in patients with a BRAFm-like signature; and 3) an immunotherapeutic anti-PD-L1 drug (MPDL3280A) in combination with bevacizumab in patients with a MSI-like signature. The primary objectives of these studies are to determine the clinical efficacy (progression-free survival as primary endpoint), safety and tolerability of the experimental treatments in these molecularly selected populations. Mutation analysis at the beginning of treatment and monitoring by liquid biopsies might reveal further biomarkers that predict response in retrospective analysis. The project outcomes may have a significant impact in CRC patients with poor-risk prognosis worldwide as 40-50% of them present gene expression profiles matching one of the 3 approaches. Around 40,000 European CRC patients may potentially benefit from the results. Also, these may be translated to other cancer types with equivalent gene expression patterns/deregulated signalling pathways.

Diabetes mellitus is a chronic disease characterised by high blood glucose due to inadequate insulin production and/or insulin resistance which affects 382 million people worldwide. Pancreatic islet transplantation is an extremely promising cure for insulin-sensitive diabetes mellitus (ISDM), but side effects of lifelong systemic immunosuppressive therapy, short supply of donor islets and their poor survival and efficacy in the portal vein limit the application of the current clinical procedure to the most at-risk brittle Type I diabetes (T1D) sufferers. The DRIVE consortium will develop a novel suite of bio-interactive hydrogels (β-Gel) and on-demand drug release systems to deliver islets in a protective macrocapsule (β-Shell) to the peritoneum with targeted deposition using a specialised injection catheter (β-Cath). Pancreatic islets will be microencapsulated in β-Gels; biofunctionalised injectable hydrogels containing immunosuppressive agents and polymeric microparticles with tuneable degradation profiles for localised delivery of efficacy cues. These β-Gels will be housed in a porous retrievable macrocapsule, β-Shell, for added retention, engraftment, oxygenation, vascularisation and immunoprotection of the islets. A minimally invasive laparoscopic procedure (O-Fold) will be used to create an omental fold and at the same time deliver β-Shell. An extended residence time in β-Gel will enhance long-term clinical efficacy of the islets and result in improved glycemic control. The novel β-Gels will also be developed as human three-dimensional in-vitro models of in-vivo behaviour. Islet harvesting and preservation technologies will be developed to facilitate their optimised yield, safe handling and transport, and ease of storage. DRIVE will also enable the future treatment of a broader range of T1 and insulin-sensitive T2 diabetics by working with induced pluripotent stem cell experts to ensure the compatibility of our system with future stem cell sources of β-cells.