Pioneering Combination Therapy Approach to Treating Colorectal Cancer

Celleron Therapeutics, the UK-based company and Oxford University spin-out developing personalised medicine for cancer patients, has today announced the initiation and first patient enrolment of its clinical study that will evaluate the effect of a novel combination therapy approach for colorectal cancer.

Professor Mark Middleton, Consultant Medical Oncologist and Professor of Experimental Cancer Medicine at the University of Oxford commented: “We are delighted to be part of this important trial, which has the potential to bring immunotherapy to patients who hitherto have not benefitted from this approach. It is also very satisfying to see CXD101, a drug first given to patients at the Experimental Cancer Medicine Centre here in Oxford, developed further in the clinic based upon scientific insights made here in the city.

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Celleron Therapeutics Clinical Trial Authorisation to conduct a Phase Ib/II clinical trial with CXD101, a highly potent class 1 histone deacetylase inhibitor, in combination with an immune oncology (IO) agent, nivolumab. Celleron appointed Syneos Health as the CRO to support the trial which is investigating the clinical activity of CXD101 in combination with nivolumab, measuring the anti-tumour effect on a type of colorectal cancer (microsatellite stable) which typically does not respond to IO agents alone. The clinical trial strategy rests on compelling pre-clinical results which provide novel insights into how CXD101 and IO drugs work together to re-engage recognition of tumours by the immune system. The trial will also allow exploration of a range of new biomarkers to help select those patients likely to benefit most from combination therapy.

Professor Nick La Thangue, Founder and Chief Executive of Celleron Therapeutics, and Professor of Cancer Biology in the Department of Oncology at Oxford University, commented: “CXD101 is a very interesting drug with great clinical potential. The new trial is a major step forward in understanding its therapeutic application. We have observed striking effects on late stage cancer patients in previous studies. This trial exploits our deep scientific understanding of how CXD101 exerts anti-cancer activity, which underpins the hypothesis being tested in the novel combination approach.”

CXD101 is Celleron Therapeutics’ next generation epigenetic immune-regulator representing a class of drug that kills cancer cells by blocking certain vital functions involved in gene expression and reactivates the patient’s immune system so that cancer cells can no longer evade immune recognition.

Professor David Kerr CBE, Founder and Chief Medical Officer, Celleron Therapeutics and Professor of Cancer Medicine, University of Oxford commented: “There is a very significant unmet need for novel therapy for patients with advanced colorectal cancer. As colorectal tumours progress, they find a variety of ways to avoid recognition and destruction by the immune system, increasing their potential to grow and spread. We have discovered that CXD101 can reverse this process of “immune silencing” making it, potentially, an ideal partner for existing immune oncology agents.”

 

Content adapted from Celleron Therapeutics website.

 

 

 

 

 

 

 

www.cellerontherapeutics.com

Rare cancer could be caught early using simple blood tests

A pioneering study into myeloma, a rare cancer, could lead to GPs using simple blood tests to improve early diagnosis.

CRUK Centre members, in collaboration with the University of Exeter and Chiddenbrook Surgery, Crediton, found that a simple combination of blood tests, which are routinely conduced in GP surgeries, could improve early diagnosis of myeloma.

Dr Brian D Nicholson, clinical researcher at the Nuffield Department of Primary Care in Oxford, and co-author of the study stated: “We wanted to develop a simple rule based on existing commonly used blood tests to help GPs identify which patients  should be investigated further for Myeloma. By achieving this we offer guidance that can be implemented immediately in routine primary care to benefit all patients.

Researchers investigated how useful a number of different measures were for indicating the presence of the disease, and suggested what combinations of these tests were sufficient to rule out the disease, and to diagnose it, saving the patient from the worry of specialist referral.

Blood tests of 2703 cases taken up to five years prior to diagnosis were analysed and compared with those of 12,157 patients without the cancer, matching cases with control patients of similar age amongst other relevant parameters.

They demonstrated that a simple combination of two blood parameters could be enough to diagnose patients. Such blood tests are routinely conducted in GP surgeries.

Constantinos Koshiaris, lead author of the study, from Oxford University, said: “The combination of levels of haemoglobin, the oxygen carrier in the blood, and one of two inflammatory markers (erythrocyte sedimentation rate or plasma viscosity) are a sufficient test rule out myeloma. If abnormalities are detected in this test, it should lead to urgent urine protein tests which can help speed up diagnosis.”

Each year approximately 5,700 people are diagnosed with myeloma in the UK alone. It can lead to symptoms such as bone pain, fatigue and kidney failure. It has the longest diagnosis process of all common cancers, and a large number of patients are diagnosed after emergency care, over a third of which having had at least three primary care consultations.

Professor Willie Hamilton, of the University of Exeter Medical School, is principal investigator on the study. He said: “Ordinarily a GP will see a patient with myeloma every five years – and early diagnosis matters. More timely treatment could significantly improve survival rates for this disease. We report a simple way a GP can check patients presenting symptoms such as back, rib and chest pain, or recurrent chest infections, and determine whether they have myeloma or not.

The authors also suggest the possibility of integrating a system in the electronic health record to alert clinicians to relevant symptoms or changes in blood parameters related to myeloma.

 

The case-control study was led by Constantinos Koshiaris (Oxford University) and published in the British Journal of General Practice. https://bjgp.org/content/early/2018/08/13/bjgp18X698357

This project was funded through a DPhil scholarship awarded to Constantinos Koshiaris by the University of Oxford, the Primary Care Research Trust, and the National Institute for Health Research (NIHR) Oxford CLAHRC.

Content adapted from University of Oxford news site.

 

Oxford researchers discover DNA repair protein complex important in drug resistance in cancers driven by BRCA mutations.

A team of Cancer Centre researchers lead by Associate Professor Ross Chapman have discovered a novel DNA repair protein complex called ‘Shieldin’.

Published in Nature, the paper describes the identification of ‘Shieldin’, which was shown to be essential for generating genetic diversity in antibodies produced during immune responses.

When activated following an infection or immunisation, B cells activate the expression of enzymes that induce multiple breaks in the genes encoding the different antibody fragments. Highly specialised DNA repair proteins are essential for the generation of the deletions and mutations required to generate new antibody genes, which enables the production of antibodies with different or improved specificities towards an antigen. Researchers found Shieldin binds to specific DNA structures present at the ends of DNA breaks formed during these processes, and was essential for their repair.

Shieldin was found to link the adaptive immune system to a mutagenic DNA repair process associated with the progression of hereditary breast and ovarian cancers caused by BRCA1 mutations.

Commenting on the link between DNA, the immune system and cancer, Associate Professor Ross Chapman, lead author of the study and group leader at the Wellcome Centre for Human Genetics remarked “For some time, my lab has been puzzled over why a DNA repair pathway that normally only functions in the immune system, is also the primary pathway responsible for cancers driven by BRCA1 gene mutations. In finding Shieldin, we have taken a major step in answering this question. DNA breaks generated during antibody class-switch recombination are known to have single stranded DNA tails at their ends. The fact that Shieldin binds these structures and promotes their repair, also suggests that the recognition and repair of similar DNA structures by Shieldin when the BRCA1 protein is no longer functional, may be what leads to the mutations that cause cancer.”

The group’s findings also provide new insights into how cancer cells can become resistant to anti-cancer drugs: “PARP inhibitors are proving to be an extremely powerful drugs to treat cancers driven by BRCA mutations, however a lot of these cancers are known to then go on to develop resistance. Our work shows mutations that effect any of the four Shieldin proteins will render these cancers completely resistant to PARP inhibitors. By working out exactly how Shieldin works, we hope to identify secondary vulnerabilities in these resistant cancers, which can be exploited in anti-cancer therapies to counteract the threat of this resistance.”

Sarah Blagden Associate Professor of Experimental Cancer Medicine & Consultant Medical Oncologist, and Director of Early Phase Cancer Trials Unit & Oxford ECMC lead, emphasises the importance of the new findings: “In this paper, Ross Chapman and his team have unpicked the main method of DNA damage repair in patients with BRCA1 mutations called non-homologous end joining (NHEJ). By comparing NHEJ in different cellular processes they have shown that, in cells lacking BRCA1, NHEJ is reliant on the four-protein complex Shieldin. Not only do they indicate Shieldin is responsible for the cancers that develop in patients with BRCA1 mutations, but also that Shieldin drives resistance to PARP inhibitors. Chapman’s findings are important in our understanding of why it is that patients with BRCA1 mutations that are taking PARP inhibitors like olaparib, rucaparib or niraparib eventually become resistant to them. By providing these new insights into BRCA1 biology, they open future avenues for tackling PARP resistance and improving outcomes for BRCA1-cancer patients in the future.”

This project was funded by Medical Research Council (MRC) Grant (MR/ M009971/1) and Cancer Research UK Career Development Fellowship (C52690/A19270) awarded to J.R.C.

https://www.nature.com/articles/s41586-018-0362-1