An innovative oncology healthcare company

The future of cancer therapy lies in the ability to match patients to treatments they will respond favourably to. Celleron has developed biomarkers using epigenetic techniques that match drugs to responsive disease. Our portfolio of technologies can be used to develop a new class of mechanism-based cancer drugs. Drugs that will improve the success rates of treatment, reduce the side effects in patients and deliver more cost effective healthcare.

About us

Tackling cancer with personalised medicine

Celleron is focussed on personalised medicine targeting epigenetic control

Advances in understanding the biology of cancer have aided the rational design and development of molecularly targeted mechanism based drugs. An equally crucial venture has been the individualization of these therapies in accordance with the unique genetic and molecular profile of the disease type. The complexity and heterogeneity of various cancer types along with their inherent inter-individual variability have necessitated the move towards personalized or precision cancer therapy. Accordingly, there has been a clinical need to stratify patients and target specific therapies to those subpopulations, which are most likely to benefit, whilst avoiding unnecessary harm and toxicity to those who are predicted non-responsive.

Developing biomarkers that predict patient responsiveness to cancer medicine

The realization of personalized cancer medicine requires both an in-depth molecular understanding of the cancer type, as well as validated and robust diagnostic tests to profile the disease and tease out the relevant molecular information. Biomarkers in general terms refer to those characteristics, whose objective measurement in the body, reproducibly correlates with a given physiological or pathological state. Biomarkers can serve prognostic, diagnostic or predictive purposes. Predictive biomarkers, which help predict and assess the probability of disease response to a given therapy, are particularly valuable to the application of personalized medicine. The identification and validation of a defined biomarker for a given cancer medicine, proves crucial to stratifying patients according to the presence or absence of the biomarker and hence likelihood of therapeutic response.

Identifying relevant biomarkers is becoming as important as developing new cancer therapies

With the exponential rise in the number of mechanism based therapies in the clinic and in development, and with on-going issues regarding patient toxicity and lack of efficacy to therapies, identifying and employing relevant biomarkers in the coming years becomes as important as developing new cancer therapies.

Histone acetylation on lysine residues is regulated by two groups of enzymes, histone acetyl transferases (HATs), which utilize acetyl-coA to transfer acetyl group to the ε-amino site of lysine residues, and histone deacetylases (HDACs), which remove the acetyl group. From the perspective of cancer therapy, HDACs have gained recognition as an important target, which, in part, reflects the identification of proteins other than histones that are subject to acetylation control. The activity of cell cycle regulators including E2F, p53, and the retinoblastoma protein (pRb) is influenced by acetylation, and pRb controls E2F activity through the recruitment of chromatin-modifying enzymes, such as HDACs. Several oncogenic proteins have altered recruitment of HDACs, which leads to aberrant gene transcription. This is exemplified by the fusion protein PML-RARα, which occurs through a chromosomal translocation in acute promyelocytic leukemia (APL). The PML-RARα fusion protein recruits HDAC and represses transcription, causing a block to differentiation and promoting the oncogenic phenotype in APL. Not surprisingly therefore, compounds that inhibit HDAC activity, cause potent cell cycle effects and frequently induce apoptosis.

In line with this, the recent development of specific inhibitors of histone modification reading modules has been an exciting achievement, particularly the small molecule inhibitors of the acetyl-lysine recognition domain, or bromodomains. Compounds have been reported to inhibit the bromo-domains with high potency and to induce strong anti-proliferative effects. These findings illustrate the possibility of exploiting specific epigenetic readers as reasonable drug targets, and lead way for many more for the coming years.

The epigenetic targeting of cancer cells is an exciting new area for therapeutic intervention

Recent advances have highlighted a new and exciting area for therapeutic intervention, namely that of epigenetic targeting of cancer cells. Chromatin is the DNA-proteinaceous material in which chromosomal DNA resides in the nucleus. The majority of chromatin is composed of histones that assemble into nucleosomes, and thereby assist in DNA packaging and transcriptional control. The basic structure of the nucleosome consists of 146bp of DNA wrapped around an octamer of four core histones. The histone tail is subject to a variety of enzymatic modifications, including phosphorylation, acetylation, and methylation. Many of these histone modifications, as part of a heritable, self-perpetuating system form the basis of the epi-(above)-genome. Epigenetic events can direct phenotypically distinct outcomes from an identical underlying genetic material (DNA), and thus can be thought of as non-genetic cellular memory.

Targeting the enzymes and readers of epigenetic events as a way to target cancer cells

It has emerged in recent years that cancer cells can exhibit altered epigenetic modifications, such as hypermethylation of various tumour suppressor genes, and hence exhibit aberrant gene silencing. Such ‘epimutations’ justify targeting the enzymes and readers of these epigenetic events as a means of selectively targeting the cancer cells.

Histone acetylation on lysine residues is regulated by two groups of enzymes, histone acetyl transferases (HATs), which utilize acetyl-coA to transfer acetyl group to the ε-amino site of lysine residues, and histone deacetylases (HDACs), which remove the acetyl group. From the perspective of cancer therapy, HDACs have gained recognition as an important target, which, in part, reflects the identification of proteins other than histones that are subject to acetylation control. The activity of cell cycle regulators including E2F, p53, and the retinoblastoma protein (pRb) is influenced by acetylation, and pRb controls E2F activity through the recruitment of chromatin-modifying enzymes, such as HDACs. Several oncogenic proteins have altered recruitment of HDACs, which leads to aberrant gene transcription. This is exemplified by the fusion protein PML-RARα, which occurs through a chromosomal translocation in acute promyelocytic leukemia (APL). The PML-RARα fusion protein recruits HDAC and represses transcription, causing a block to differentiation and promoting the oncogenic phenotype in APL. Not surprisingly therefore, compounds that inhibit HDAC activity, cause potent cell cycle effects and frequently induce apoptosis.

In line with this, the recent development of specific inhibitors of histone modification reading modules has been an exciting achievement, particularly the small molecule inhibitors of the acetyl-lysine recognition domain, or bromodomains. Compounds have been reported to inhibit the bromo-domains with high potency and to induce strong anti-proliferative effects. These findings illustrate the possibility of exploiting specific epigenetic readers as reasonable drug targets, and lead way for many more for the coming years.

A unique series of products focused on epigenetic control

CXD101

Structural biology image of an HDAC inhibitor like CXD101 in the active site of an HDAC enzyme sub-unit.

CXD101

CXD101 is a novel HDACinhibitor with multiple positive differentiation properties from competing products which is supported by a predictive biomarker.

Eighteen different human HDACs have been identified and classified into four classes according to their homology with yeast proteins and functional criteria. The four classes are divided into Zn2+-dependent classes (class I, class II and class IV) and NAD-dependent (class III) enzymes. Class I consists of the members HDAC1, 2, 3, and 8; class IV has a single member, HDAC11. Class II HDACs are subdivided into class IIa consisting of the members HDAC4, 5, 7 and 9 and into class IIb with the members HDAC6 and HDAC10. Class III HDACs are also called sirtuins after their homology with Sir2 and consists of the members SIRT1 – SIRT7. Most HDAC inhibitors target the classes I, II or IV HDACs.

Summary of the HDAC family

Summary of the HDAC family

HDACs play both direct and indirect roles in cancer. On the one hand, there is evidence that certain oncogenic fusion proteins like CBFb/SMMHC specifically associate with HDAC8. On the other hand there are several reports that increased HDAC levels are found in certain types of cancer. Examples are increased levels of HDAC1 in gastric cancer and hormone refractory prostate cancer and higher expression of HDAC2 and HDAC3 in colon cancer. Sequencing studies identified HDAC4 mutations in breast cancer samples, and HDAC4 is highly expressed in patients with Waldenstrom’s macroglobulinemia. Conversely, homozygous deletions of HDAC4 were observed in melanoma cells. Other members HDAC5, HDAC7 and HDAC9 have been reported to be upregulated in several types of cancer, including medulloblastomas, hepatocellular carcinomas (HCCs) and pancreatic cancers [29, 30].

Given the many roles HDAC6 fulfils in the cell, it is not surprising that it has also been associated with certain types of cancers. Overexpression of HDAC6 correlated with tumourigenesis and in oral squamous cell carcinomas HDAC6 expression was increased in advanced stage cancers compared to early stages. One prominent mechanism through which HDAC6 may act in cell survival is its ability to deacetylate HSP90, another tumour therapy target. For example, it has been demonstrated that treatment with HDIs could lead to the disassembly of the HDAC6/Hsp90 complex and activates a p53-dependent apoptotic pathway.

Celleron’s proprietary HDAC inhibitor, CXD101, has multiple superior positive differentiation properties from any of the other competing HDAC inhibitors in clinical development. Moreover, Celleron has used a predictive cancer biomarker, the H-Test, to target the drug towards responsive tumours. This approach significantly accelerates the drug’s clinical development and, if successful, the time to launch, as well as offering a potential competitive edge over other rival candidates in the class. The combined benefit of a predictive biomarker applied to Celleron’s drug with potentially class-leading properties means that CXD101 is more likely to demonstrate greater clinical value than other HDAC inhibitor based therapies.

Example tumour biopsy

An example of tumour biopsies from a patient immuno-stained with the H-Test biomarker. Note that tumours with the brown colour (detecting the biomarker)respond to the drug, whereas the blue tumour (without biomarker expression) fails to respond to the HDAC inhibitor (ref).

T-ARG-et

T-ARG-et

There is increasing interest in arginine methylation as a new level of post-translational modification (PTM). It has been shown to play an important role in the function of a diverse number of proteins and processes, such as epigenetic control, chromatin regulation, transcriptional control, DNA repair and RNA processing. Arginine methylation is carried out by a family of enzymes, and the protein arginine methyltransferase (PRMT) 5 functions in growth-promoting and pro-survival pathways.

PRMT5 is aberrantly expressed in a variety of human cancers. Our studies have suggested that PRMT5 expression in tumour biopsies found that in a sub-group of colorectal cancer patients, high levels of PRMT5 coincides with poor clinical outcome. This raises the possibility that the level of PRMT5 could be used to stratify patients into groups that respond favourably to drugs targeting PRMT5.

Most significantly, PRMT5 activity is integrated with cancer cell proliferation. A hallmark of cancer cells is apparent in the transition from G1 into S phase of the cell cycle, which is tightly regulated in normal cells, but universally under abnormal control in tumour cells. The key pathway involves the retinoblastoma tumour suppressor (pRb) protein, which acts to negatively regulate the G1 to S phase transition through its critical target, the E2F family of transcription factors. E2F transcription factors control the expression of a variety of genes that are intimately connected with cell proliferation, including many involved with DNA synthesis. In tumour cells, normal regulation of E2F is lost (due to mutation in the Rb gene or deregulation of Rb activity), liberating E2F which subsequently drives cells into S phase.

The first member of the family, E2F-1, is an important regulator of cell fate. E2F-1 is not only able to promote proliferation, but also cause the opposing outcome, namely cell death through apoptosis. Accordingly, E2F-1 has been described as both tumour suppressor and oncogene. However, the mechanisms that control the opposing outcomes of E2F-1 remain largely unknown. If the pathway which controls E2F-1 biological activity were known, we could devise approaches to develop a drug, targeted to the E2F pathway, which reinstates apoptosis in tumour cells.

Celleron has access to this important information. E2F-1 has been found to be arginine methylated, and arginine methylation controls its biological activity. A robust drug discovery tool ‘T-ARG-et’, focussed in identifying inhibitors of PRMTs, has been established and proven to effectively identify compounds which regulate PRMTs. Celleron is progressing the products through pre-clinical development.

Colorectal cancer biopsies

Examples of colorectal cancer biopsies expressing high PRMT5/low E2F-1, or low PRMT5/high E2F-1. The expression of PRMT5 and E2F-1 is being used to select patients likely to undergo a favourable response to inhibitors of arginine methylation.

Bromo-Fix

Structural biology image of a bromo-domain together with its inhibitor compound.

Bromo-Fix

Targeted lysine acetylation is regulated by two groups of enzymes, histone acetyl transferases (HATs), which utilize acetyl-coA to transfer acetyl group to the ε-amino site of lysine residues, and histone deacetylases (HDACs), which remove the acetyl group. In turn, the acetylated lysine residue is ‘read’ by an expanding class of reader domains, referred to as bromo-domains. From the perspective of cancer therapy, bromo-domains are gaining recognition as an important target, which, in part, reflects the identification of diverse proteins and pathwaysthat are subject to acetylation control and bromo-domain control.

In line with this, specific inhibitors of bromo-domains are under evaluation using Celleron’s platform ‘Bromo-Fix’. The compound, JQ1, which inhibits the bromodomain and extra-terminal (BET) family member BRD4 with high potency has proved to be a valuable tool compound. Recurrent oncogenic translocations of BRD4 have been found in several subtypes of human squamous carcinoma, and accordingly the binding of JQ1 to BRD4 was shown to induce strong anti-proliferative effects in xenograft models. Since then JQ1 has been shown to have promising activity against NUT midline carcinoma, several hematopoietic cancers and glioblastoma tumours. These findings illustrate the potential value of exploiting specific epigenetic readers as drug targets. Celleron has developed Bromo-Fix and has deployed the platform to characterise a new class of bromo-domain inhibitors which strongly inhibit cancer cell proliferation.

Top
News image

Celleron Therapeutics announces first patients to receive personalised cancer treatment in Oxford

The first human trial of a pioneering personalised cancer treatment will begin this week at Oxford University Hospitals NHS Trust, with the potential to tackle a wide range of late-stage cancers.

A major challenge in drug development is that all cancer patients respond differently to treatment, making it difficult to know how best to treat each patient. For the first time, a phase 1 trial using Celleron’s proprietary HDAC inhibitor CXD101, will investigate not only the new drug, but also a new test to predict which patients could be successfully treated by this class of drug.

“When patients’ cancers do not respond to a treatment, this can cost tens of thousands of pounds and cause patients to suffer side effects for nothing” said lead researcher Professor Nick La Thangue of Celleron Therapeutics and Oxford University’s Department of Oncology. “Personalised medicine promises to prevent this by predicting how well a patient will respond to a drug before administering it and this is exactly what this trial will do. This is really the shape of things to come and avoids the problem of testing drugs on patients who have little chance of benefiting from the treatment.

Dr John Whittaker, Celleron’s Chief Operating officer commented: “I am delighted to see Celleron, Oxford ECMC, Oxford Hospitals NHS trust and Oxford Cancer Biomarkers (OCB) cooperating on this exciting project to take Celleron’s proprietary targeted therapeutic, CXD101, into clinical testing on patients, identified by a companion diagnostic, as likely to be suitable for treatment.”

The drug CXD101 is being developed by Celleron Therapeutics. The biomarker measures levels of a protein called HR23B that could determine the effectiveness of CXD101 and similar drugs. The trial will involve 30-40 cancer patients, the first set of whom will be given increasing doses of CXD101 to determine the most effective dose. The second cohort of patients will then be tested for HR23B and those with high levels of the protein will be treated with the best dose of CXD101.

CXD101 is a next generation histone deacetylase (HDAC) inhibitor, a class of drug that kills cancer cells by blocking the vital functions of HDAC enzymes. The HDAC enzymes are important for cell multiplication, migration and survival, so blocking them can stop tumours from growing and spreading, and even kill cancer cells entirely.

“HDAC inhibitors have had limited success in the past but CXD101 works in a completely new way and has great potential to treat many different cancers,” said Professor La Thangue. “Our previous research suggests that high levels of the HR23B protein make tumours more vulnerable to HDAC inhibitors, so we will now be putting this into practice to identify the patients who are most likely to benefit from CXD101. Any cancer could be high in HR23B, from breast cancers to blood cancers, so we are screening a broad range of patients to identify anyone who might benefit.

The trial is a unique collaboration between Celleron Therapeutics, Oxford Cancer Biomarkers, Oxford University Hospitals NHS Trust and the ECMC (Experimental Cancer Medicine Centre) network. The Oxford ECMC is led by Mark Middleton, Professor of Experimental Cancer Medicine at Oxford University’s Department of Oncology, clinical lead for the CXD101 trial.

Contact Dr John Whittaker on: +44 (0) 7860 286799 for more information

*The trial’s entry on the UK Clinical Trial’s Gateway can be found at Http://www.ukctg.nihr.ac.uk/trialdetails/NCT01977638

*Celleron Therapeutics is a clinical stage cancer medicine company focussed on developing personalised therapies targeting epigenetic control. The company has built a proprietary platform around histone deacetylases and methyl-transferases. Celleron’s approach seeks to align the right drug with the right patient enabling a personalised approach to cancer therapy. The company is a spin-out from Oxford University and located on the Oxford Science Park. For more information see www.cellerontherapeutics.com.

*Oxford Cancer Biomarkers translates ground-breaking scientific discovery into predictive biomarker diagnostic products that allow medicines to be personalised for the benefit of the cancer patient. Its unique platform, CancerNav ®, isolates biomarkers which allow drugs to be tailored to the disease. It is a spin-out of the University of Oxford and is located on the Oxford Science Park. For more information, please visit www.oxfordcancerbiomarkers.com.

*Oxford University’s Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is ranked the best in the world for medicine, and it is home to the UK’s top-ranked medical school.

*Conducting the majority of early-phase cancer clinical trials in the UK, experimental cancer medicine centres (ECMC’s) provide infrastructure funding to enhance the quantity and quality of research in developing new medicines to help beat cancer. Each ECMC brings together lab-based experts in cancer biology with cancer doctors to speed up the flow of ideas from the lab bench to the patient’s bedside. Launched in 2007, the network of 18 ECMC’s is jointly supported by Cancer Research UK, the National Institute for Health Research I England, and the Departments of Health of Scotland, Wales and Northern Ireland who together, have provided £35m from 2007-2012 and a further 35m from 2012 to 2017. Find out more at www.ecmcnetwork.org.uk.

Management team

Professor Nick La Thangue

Professor Nick La Thangue,
CEO

He is a Fellow of the Royal Society of Edinburgh, a Member of the European Molecular Biology Organisation (EMBO), a Fellow of the Academy of Medical Sciences, a Fellow of the Lister Institute and Professorial Fellow at Linacre College Oxford. Nick is Professor of Cancer Biology at the University of Oxford.

He has founded several companies, including Prolifix and Celleron Therapeutics, and more recently Oxford Cancer Biomarkers, and has considerable commercial experience derived from the biotechnology and pharmaceutical sectors.

Professor David Kerr

Professor David Kerr CBE,
CMO

David has an international reputation for the treatment of, and research into, colorectal cancer and the quality of his work has been recognised by the award of several international prizes and the first NHS Nye-Bevan award for innovation.

David has made a significant contribution to reforming the NHS as a Founding Commissioner for Health Improvement; Chair of the National Cancer Services Collaborative, instigator of the Department of Health’s networked approach to clinical cancer research and developed a 20 year plan for the future of the NHS in Scotland, the "Kerr Report".

He was elected Fellow of the Academy of Medical Sciences in 2000, Honorary Fellow of Royal College of General Practitioners in 2007, appointed Commander of the British Empire in 2002 and was elected President of the European Society of Medical Oncology in 2010. David contributes to Oxford as Professor of Cancer Medicine, where he has worked with colleagues to build a new Institute for Cancer Medicine and Cancer Hospital.

Dr John Whittaker

Dr John Whittaker,
COO

John has over 30 years’ experience in cancer research, drug development and clinical research. . He was previously UK General Manager and Country Manager, Israel at Kendle International and Director Global Clinical Development. Prior to that he was Director, Clinical Operations (Europe) for SEQUUS Pharmaceuticals and ALZA International and Director of Oncology, at ICON Clinical Research. His PhD is in genetic toxicology and he was a post-doctoral research fellow at the Sir William Dunn School of Pathology, Oxford University. He has an MBA and has held senior positions with a number of Pharmaceutical and Clinical Research Organisations.

Contact us

Celleron Therapeutics Ltd

25 Milton Park
Oxfordshire
OX14 4SH
UK

Email: enquiries@cellerontherapeutics.com

Terms and conditions
Privacy Policy
© 2013 Celleron Therapeutics Limited. All rights reserved
Registered Address: Park Gate, 25 Milton Park
Abingdon, Oxon, OX14 4SH
Company Registration Number: 05162047