What we do
Cannabis-based medicines were rescheduled under UK law in 2018 allowing doctors to prescribe these treatments to patients for a wide range of conditions. We are interested in the evaluation and development of novel cannabinoid therapies targeting: 1) inflammation & cancer, with a current focus on pancreatic ductal adenocarcinoma (PDAC) and 2) acute/post-surgical, neuropathic and cancer-related pain. We are also interested in clinical outcomes-based research and the use of Real World Evidence (RWE) in cannabinoid drug development.
Inflammation & Cancer
We investigate the mechanism of action of cannabinoids and relevant compounds at a molecular level through the study of relevant oncological signalling pathways. We also evaluate the efficacy and interaction of cannabinoids in combination with cytotoxic and immune-modulating therapies for the treatment of cancer.
Pain
We aim to test the efficacy and potency of a range of novel cannabinoid related compounds, including those that target receptors such as the cannabinoid receptors CB1 and CB2, and to develop new analgesic treatments for use in the clinic. These novel agents are evaluated using in vitro models of hypersensitivity in cultured neurons from rodent and human sensory ganglia. We have recently shown that Cannabidiol (CBD) at low doses, corresponding to plasma concentrations observed physiologically, inhibits or desensitizes neuronal TRPV1 signalling by inhibiting the adenylyl cyclase – cAMP pathway, which is essential for maintaining TRPV1 phosphorylation and sensitization. CBD also facilitated calcineurin-mediated TRPV1 inhibition. These mechanisms may underlie nociceptor desensitization, and the therapeutic effect of CBD in animal models and patients with acute and chronic pain.
Real World Evidence
We use health data sourced from non-interventional studies, registries, electronic health records and administrative datasets to broaden and streamline the process of evidence generation for cannabis-derived medicinal product development. We evaluate the use of RWE as an additional tool in the drug development pipeline.
Why it is important
Inflammation & Cancer
Cannabinoids have shown merits in not only alleviating the unwanted side–effects of cancer treatments but have also displayed promising pre-clinical antitumour properties, through modulating processes which include apoptosis and autophagy. Co-administration of cannabinoids with cytotoxic therapies may enhance the potency of these outcomes. In cancers that are refractory to systemic therapy, these synergistic effects warrant further investigation to select combinations for clinical translation and evaluation.
Pain
There is an increasing unmet clinical need for several types of pain treatment. Many current pharmacological treatments have limited efficacy and significant side-effects. Chronic neuropathic pain represents a great need – between 4 and 12 patients are treated before a single patient reports 50% pain relief, and clinical trials in chemotherapy-induced painful neuropathy have been disappointing. Advances in the non-opioid treatment of acute and chronic pain, such as with novel cannabinoids, are therefore urgently needed.
Real World Evidence
Access to cannabis-based medicinal products has increased globally as more countries have revised scheduling laws however one of the main barriers for patient access remains a paucity of high-quality clinical evidence. RWE can provide immediate impact on clinical care, inform well-conducted RCTs and contribute to market authorisation dossiers.
How it can benefit patients
Inflammation and Cancer
Understanding the specific molecular and biological actions of cannabinoids in the context of inflammation and cancer will help to reveal novel targets for therapeutic interventions. The study of combination treatments will provide data to accelerate translation to clinical trials.
Pain
Up to 50% of all cancer patients experience pain, and as many as 90% with advanced cancer live with chronic debilitating pain that can be difficult to treat. The pain contributes significantly to increased morbidity and reduced quality of life, characterised by fatigue, depression, insomnia, and weight loss. The evaluation and development of cannabinoid compounds may lead to novel therapies which provide better pain relief and improve the quality of life in patients with chronic pain conditions.
Real World Evidence
Cannabis-based medicinal products are a complex range of pharmaceuticals which pose challenges to traditional pathways of drug development and translation. The Medicines and Healthcare Products Regulatory Agency (MHRA) has issued new guidance to confirm that RWE can be used to support regulatory approval, helping to bring medicines to patients who need them in a quicker and more cost-effective way.
Summary of current research
Inflammation and Cancer
In vitro:
- Pharmacological evaluation of cannabinoids in PDAC cell lines by analysis of cell viability, cytotoxicity, cell proliferation, cell death and cell cycle state
- Identification of oncological signalling pathways and targets which maybe upregulated or downregulated using qt-PCR, western blots and FACS analysis
- Defining and comparing molecular pathway changes of cannabinoid treatment in chemotherapy resistant versus chemotherapy sensitive cell lines
- Investigate synergistic effects of cannabinoids in combination with standard cytotoxic therapy using Combenefit analysis
In vivo:
- Investigate the effects of single agent cannabinoid therapy and in combination with cytotoxic treatment in syngeneic PDAC mouse models by analysing changes in tumour burden and survival
- Gene expression profiles of whole tumour biopsies is performed using a specific panel of immune genes and its reduced versions using nCounter platform (NanoString Technologies). This analysis provides an extensive view of immune microenvironment changes and the mechanisms associated with them.
- Quantifying and analysing the immune landscape of cannabinoid treatment by immunohistochemistry (IHC) and FACs analysis using a panel of T cells, B cells, neutrophils and macrophages
Pain
- We model specific disease-related conditions (e.g. cancer chemotherapy with oxaliplatin or Ara C, co-cultures of sensory neurons with cancer cells, and metabolic conditions such as uraemia). These provide in vitro models of pain, to enable a “clinical trial in a dish”. The neurons are stimulated with a “painful” stimulus, such as capsaicin, that activates the pain receptor TRPV1.
- We are using these in vitro models to evaluate cannabinoids as analgesic agents, which can be compared with the effects of endocannabinoid molecules Anandamide and 2-Arachchidonyl glycerol.
- We have established target validation studies of the CB2 receptor, described its histological localization in rats and humans, and observed increased CB2 expression in painful human neuromas. We also assayed the inhibitory effect of CB2 agonists in blocking capsaicin mediated calcium influx in nociceptors, via the TRPV1 receptor.
Real World Evidence
- Evaluate terminology to define cannabis-based medicines accurately and a global, common dataset for reporting of clinical outcomes as RWE
- We use large registry-based datasets from the UK to analyse clinical outcomes for several different conditions following the initiation of cannabinoid therapies
- Use RWE to investigate cannabinoid interventions in chronic disease states with identification of causative and therapeutic components
- Investigate novel methods of multi-modal RWE data integration and analysis