Translational research at ICT
Researchers at ICT specialise in the discovery and development of novel cancer therapeutics from identification of a lead compound through to full preclinical validation. In addition ICT researchers have a number of projects focused on identification and development of novel targets and biomarkers.
The Institute understands that for our research to have an impact it needs to be translated into new and more effective medicines for cancer patients. To achieve this key objective the ICT seeks external collaboration and investment for the progression of a number of exciting research programs in order to advance them through the preclinical phase, into clinical trials and beyond.
ICT has a successful track record in attracting investment for its research programs including:
ICT research projects currently seeking external investment include:
Focus on ICT2588
ICT2588 is the lead compound to emerge from a project focused on the development of a new type of cancer therapy, and is the ICT’s most recent success, heading towards the clinic. The drug is inactive in the body until it reaches the tumour, where a specific protease (MT1-MMP) recognises and ‘activates’ the drug, releasing the active cytotoxic agent selectively in tumour tissue.
This project is an example of the full capabilities of the ICT, living up to our goal of achieving ‘concept to clinic’. It is the result of close collaboration between medicinal chemists (led by Dr Robert Falconer) and pharmacologists (led by Prof Paul Loadman). The project was jointly funded by Cancer Research UK and Yorkshire Cancer Research.
Following evaluation of in vivo pharmacokinetics and efficacy, the patents associated with the technology formed the basis for the launch of Incanthera Ltd, an ICT/University of Bradford spin-out company, which is now charged with progressing ICT2588. A major (£4.9m) recent investment into the company means ICT2588 is now heading towards a clinical trial in patients in Yorkshire in 2019.
Membrane-type matrix metalloproteinases (MT-MMPs) are known to be elevated in the majority of solid human tumours and to be central to tumour invasion and angiogenesis. MT-MMPs are absent or inactive in normal tissues. The objective has been to design inactive prodrugs that are converted to the active drug by selected MMPs specifically within the tumour microenvironment.
This technology has a very strong, proven track record of success. Previous studies using this approach with both azademethylcolchicine (ICT2588, see above) and paclitaxel (ICT3205) were successful in targeting the drug release to the tumour in vivo, resulting in impressive 10-fold increases in tumour concentrations of warhead and impressive tumour responses with a single dose. The agents are now licenced to Incanthera Ltd.
CLIO-ICT, a combined therapy and diagnostic version of ICT2588 (a ‘theranostic’) developed in conjunction with Prof Heike Daldrup and colleagues at Stanford University Medical School. CLIO-ICT has shown impressive activity in orthotopic glioma models in mice, a deadly cancer which is notoriously difficult to treat. CLIO-ICT is currently being evaluated by the Nanotechnology Characterization Laboratory (NCL) branch of the National Cancer Institute, USA, and is a further potential candidate for clinical trials.
Current research, led by Dr Robert Falconer and Prof Paul Loadman, involves application of this exciting technology to other drugs and to other proteases. We currently have funding from Bone Cancer Research to investigate delivery of methotrexate, a drug with horrendous side-effects and used routinely in osteosarcoma treatment.
Opportunities are available for PhD research can be found here.
Medicines Discovery – Yorkshire Cancer Research
The ICT has a long association with Yorkshire Cancer Research, which currently funds our Medicines Discovery programme (£1.5m, 2014-20) which is focused on the development of two exciting new approaches to therapy, and funds four researchers with skills in medicinal chemistry, pharmacology, and proteomics.
The Cytochromes P450 project, led by Dr Klaus Pors, is focused on the selective delivery of ultrapotent chemotoxins to tumours by exploiting the differential expression of specific Cytochrome P450 isoforms in tumour tissue. This project is at an exciting stage, with compounds demonstrating efficacy and improved therapeutic index in vivo. Further details of the project can be found here.
The Polysialyltransferase project, led by Dr Robert Falconer, aims to discover a potent enzyme inhibitor to prevent biosynthesis of polysialic acid (polySia, an unusual carbohydrate polymer) found on the surface of neuroendocrine tumours. PolySia plays a key role in the metastatic spread of tumours. We have a focus on neuroblastoma, a devastating childhood cancer with a desperate need for new therapeutic approaches. Further details can be found here.
The programme supports the development of a lead agent for each project area, complete with analysis of pharmacokinetics and in vivo efficacy.
Cytochromes P450 as Targets for Tumour-selective Activation of Ultrapotent Chemotoxins
Cytochromes P450 (CYPs) are a superfamily of mixed function oxidases of which CYP1-4 subfamily members are unique in their ability to oxidise drugs. CYP1A1, 1B1 and 2W1 are expressed in many human tumour types to a high frequency and we have developed therapeutics based on the duocarmycin scaffold that are selectively activated by these CYPs.
A patent covering compound structures based on the duocarmycin pharmacophore to treat CYP-expressing cancers has been granted in most territories and is licenced to Incanthera Ltd., while new IP is being generated for second generation duocarmycin analogues.
Current efforts are focused around treatment of CYP-expressing tumours, including: bladder, breast, colon, glioma and head and neck cancers. We are aiming to demonstrate anticancer activity of lead compounds in a number of in vivo models. The project is led by Dr Klaus Pors and is currently funded by Yorkshire Cancer Research. Opportunities for PhD research can be found here.
Polysialyltransferase – a Novel Target for Neuroblastoma
Polysialyltransferase (PolyST) catalyses the biosynthesis of polysialic acid (polySia) on the surface of neuroendocrine tumours, notably neuroblastoma (a paediatric cancer with high mortality and a desperate need for novel therapies). PolySia plays a key role in tumour migration, invasion and tumour dissemination and its expression is limited to tumour tissues post-embryogenesis. PolyST is thus a novel, validated target for anti-metastatic therapy.
We are engaged in a drug discovery programme to identify potent, selective polyST inhibitors. We have established a novel biochemical assay, a panel of cell lines (including naturally expressing, isogenic and knock-out cells) and cell-based functional assays to assess compound inhibition. Selective polyST inhibitors with low micromolar potency have been identified to-date. Ongoing experiments are focused on assessment of effects of compounds on polysialylation, migration and invasion in vitro. Systemic and orthotopic in vivo models have been identified.
This project is led by Dr Robert Falconer and currently supported by Yorkshire Cancer Research, and has additionally benefited from support from EPSRC, AICR, Neuroblastoma UK and most recently The Wellcome Trust. For PhD project opportunities, more information can be found here.
Focus on Breast Cancer
The ICT has a strong interest in breast cancer, and has been successful in securing three grants from Breast Cancer Now in 2018.
- Catalyst grant, £131K - led by Prof Paul Loadman, looks at novel experimental combinations of existing breast cancer drugs with palbociclib (Ibrance®, Pfizer), an oral cyclin-dependent kinase (CDK) 4 and 6 inhibitor approved for use in breast cancer (BC). Palbociclib is essentially a cytostatic agent, arresting cells in the G1 phase of the cell cycle, so there is the potential to synchronise cells and enhance the efficacy of cytotoxic chemotherapies such as anti-metabolites (e.g. the fluoropyrimidines), taxanes and anthracyclines. These cytotoxics are active in metastatic BC but this activity is limited and resistance common.
2. PhD studentship, £91K - led by Dr Klaus Pors, is focused on gaining understanding if cytochrome P450 enzymes, frequently expressed in breast cancer patients, can be utilised as targets for selective bioactivation of duocarmycin bioprecursors. Specifically, the project seeks to determine the efficacy of duocarmycins as single-agents or in combination with radiotherapy. 2D and 3D breast cancer models will be analysed for CYP1A1 and CYP1B1 expression and new duocarmycin bioprecursors will be assessed for capacity to destroy breast cancer cells.
3. Project grant, £191k, led by Dr Robert Falconer, brings together the ICT’s interests in ultrapotent chemotoxins (specifically the duocarmycin family of natural products) and protease-targeted selective tumour delivery. The aim of the project is to develop an MMP-targeted duocarmycin prodrug for breast cancer therapy, and will involve medicinal chemistry, in vitro/ex vivo pharmacology and in vivo evaluation of the most promising agent.
Ran GTPase inhibitors
Ran GTP (Ran) is a Ras-related GTPase that is critical for mitosis, apoptosis and nucleo-cytoplasmic transport, and is overexpressed in breast and lung cell lines and tumours. High Ran expression in tumours has been shown to be associated with poor patient outcomes in breast, lung, ovarian and renal cell cancers. The project team led by Prof. Mohamed El-Tanani have demonstrated that Ran expression can predict breast and lung patient survival and plays an important role in breast and lung cancer metastasis, highlighting a novel role for Ran in cancer progression.
The IP position
The patent for the use of RanGTP as a marker has been granted in most territories and a patent for its use as a therapeutic target in cancer has also been filed.
To greatly increase the potential value of the IP through studies to support its use as a target and/or marker in cancer. The next milestones would be to (1) progess a selected Ran inhibitor to first-in-man clinical trials and (2) establish whether Ran in liquid biopsy is a diagnostic marker (IUK grant funded project).
Migration of cancer cells to the lymph nodes is a prelude to metastasis. We have shown that this process is initiated when tumour cells gain the expression of chemotactic receptor CCR7 enabling them to migrate towards the lymph nodes, guided by CCR7’s ligand CCL21.
We have discovered a series of novel small molecule CCR7 antagonists, which prevent migration and invasion of head & neck tumour cells in a number of in vitro models.
The IP position
ICT13069, and other member of this series, are the only known small molecule CCR7 antagonists. A patent application is currently being prepared.
To consolidate and expand the potential value of the IP, supporting CCR7 antagonism as a key anti-metastatic target in cancer.
The next milestones are: (1) show clinical application of ICT13069 in an orthotopic model of head & neck cancer (Sheffield University collaboration). (2) complete the evaluation of ICT13069 and related novel CCR7 small molecule antagonists in a number of in vitro and in vivo models for other solid tumours (prostate, breast, pancreatic).
New Strategies for Integrin Antagonism
The RGD binding integrins are involved in growth and metastasis of a number of cancers with significant unmet clinical need. Despite being the target of significant interest by the pharmaceutical industry, no effective integrin based anticancer agents have reached the clinic. We have developed a new integrin antagonist chemotype which can be applied to selective and polypharmacological antagonism or combination therapy involving integrin targeting.
Not yet patented. In vivo studies to support filing a composition of matter patent are in progress.
To progress selected compounds through lead optimisation.
TMEM92 A novel target for prostate cancer
TMEM92 has a single transmembrane domain and is strongly expressed in a number of prostate cancer derived cell lines and primary prostate tumours, but not in normal prostate tumour or benign prostatic hyperplasia. We have produced mouse mAbs against the extracellular domain of the mature protein, revealing a distinct pattern of protein expression in cells strongly related to mitosis.
The IP position
The patent for the use of TMEM92 as a marker and therapeutic target in cancer has been granted in most territories.
To greatly increase the potential value of the IP studies to support its use as a target and/or marker in cancer. The next milestones would be to (1) demonstrate anti-tumour activity of the TMEM92 mAb in animal models and (2) establish whether TMEM92 in liquid biopsy is a diagnostic marker.
FPR1 antogonist for Glioma
Progression of many solid cancers is associated with the development of necrotic areas. In glioma and other cancers (prostate, breast, neuroblastoma), necrotic cells release peptides that activate the formylpeptide receptor-1 (FPR-1), which is highly expressed on the surface of tumour cells, but not on healthy cells.
Activation of FPR-1 is upstream of many drivers of cancer expansion, therefore a FPR-1 antagonist can affect multiple aspects of the disease progression (angiogenesis, invasion, proliferation and metastasis), without causing toxicity.
ICT12035 is a non toxic small molecule FPR-1 antagonist which abrogates progression of glioma tumours in vitro and in vivo (sub-cutaneous model).
The IP position
A patent application for the use of ICT12035 in glioma has been prepared and is being filed by the Universities of Bradford/Leeds.
Data collection to complete a second patent application, including novel proprietary FPR-1 antagonists, is underway.
To consolidate and expand the potential value of the IP, supporting FPR-1 antagonism as a key therapeutic target in cancer.
The next milestones are: (1) show clinical application of “radiotherapy+ICT12035” treatment for glioma in an orthotopic model (Leeds University collaboration). (2) complete the evaluation of novel FPR-1 small molecule antagonists in other solid tumours (prostate, breast, neuroblastoma).