Genetic mutations associated with medulloblastoma relapse 

A study led by ICR researchers discovered the unique genetic paths that the childhood brain tumour medulloblastoma follows when the disease comes back.

Professor Louis Chesler and colleagues at the ICR worked with researchers at Newcastle University to identify genetic mutations associated with relapse of the childhood brain tumour medulloblastoma.

Our researchers took samples from 29 patients’ tumours at diagnosis and when the cancer relapsed and analysed their DNA.

They were able to identify a number of changes in their DNA that only appeared when the disease returned and showed that these changes were responsible for the cancer becoming more aggressive.

One particular combination of genetic faults was common among a number of different subtypes of medulloblastomas and accounted for a very aggressive form of the disease.

The team then looked for ways to treat relapsed medulloblastomas in mice and were able to slow the growth of the tumour with an experimental drug that targets one of the genetic faults.

The study, which was published in the journal Cancer Cell, was a collaboration between researchers at the ICR and Newcastle University and showed that some children with relapsed medulloblastoma – which currently has no effective treatment options – could benefit from existing targeted drugs.

Currently, tumour samples are not routinely taken from children when the cancer returns, but this study provides a rationale for samples to be taken at the time of relapse. By taking samples at the time of relapse, doctors could start to identify patients that might benefit from existing targeted drugs, improving outcomes for children with relapsed medulloblastoma.

The study was funded by Cancer Research UK, Action Medical Research, Sparks, The Brain Tumour Charity, the JGW Patterson Foundation and Christopher's Smile.

Reference:                                               

Hill et al. Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease, Cancer Cell (2015), 27, 72–84, DOI: 10.1016/j.ccell.2014.11.002

A new family of melanoma drugs discovered 

A new family of cancer drugs called panRAF inhibitors that are designed to block several key cancer-causing proteins at once could potentially treat incurable skin cancers.

A study co-led by the ICR’s Professor Caroline Springer with Professor Richard Marais from the Cancer Research UK Manchester Institute found a brand new family of cancer drugs that could be effective at treating incurable melanomas.

We know that about half of melanomas are driven by a faulty version of a protein called BRAF. Existing drugs to target this protein are initially very effective, but within a year the disease invariably becomes resistant and the patient relapses.

The new family of drugs, called panRAF inhibitors, could be effective in treating patients with melanomas resistant to BRAF inhibitors.

Our researchers and those from the Cancer Research UK Manchester Institute found that two drugs – named CCT196969 and CCT241161 – were able to inhibit growth of BRAF-driven melanomas, including those that had stopped responding to BRAF inhibitors. The drugs were also found to inhibit tumour growth in cancers in which BRAF-targeted drugs never worked in the first place.

The study, published in Cancer Cell, found that for both drugs, a dose of 20mg per kg per day – which could be taken in capsule form by humans – caused tumour regression without significant side-effects.

The complex research involved designing and synthesising molecules shaped to overcome major drug resistance cell signalling pathways in melanoma, testing the molecules in cultures of melanoma cells, in melanoma in mice, and studying the compounds using drug-resistant tumours from patients grown in mice.

Clinical trials to test one of the new drugs in patients are already under way. 

The research was funded by the Wellcome Trust and Cancer Research UK.

Reference:

Girotti et al. Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma, Cancer Cell (2015) 27 DOI: 10.1016/j.ccell.2014.11.006

Normal prostate cells harbour potentially cancer-causing mutations 

A study led by ICR researchers found that in some men with prostate cancer, large numbers of apparently normal prostate cells actually harbour multiple genetic mutations that could drive the development of cancer.

A study co-led by the ICR’s Professor Ros Eeles gave us a powerful new insight into how prostate cancers develop. 

Our researchers found that large numbers of prostate cells that looked normal under the microscope actually had many mistakes in their genes which could cause cancer to develop. 

Prostate cancer is often made up of lots of small tumours each with a different genetic make-up and until now it wasn’t clear why. 

The findings – which were published in the journal Nature Genetics – help researchers understand more about the beginnings of prostate cancer and suggest that the disease develops earlier than previously thought. 

This could lead to a change in prostate cancer treatment so that we tackle the disease at its roots – destroying the precancerous cells at the same time as tumour cells to reduce the chance of the disease coming back. 

The research was conducted as part of the International Cancer Genome Consortium (ICGC) prostate cancer project which uses advanced genome sequencing technology to uncover the genetic changes that cause the disease. Collaborators include the ICR, Cancer Research UK, the Wellcome Trust Sanger Institute, University of East Anglia, and the University of Cambridge. 

The research was funded by Cancer Research UK, the Dallaglio Foundation and the Wellcome Trust. 

Reference:

Cooper C. et al., Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue, Nature Genetics (2015) 47, 367–372, DOI: 10.1038/ng.3221

A gene involved in sperm and egg development has a role in breast cancer 

A gene normally used in the development of sperm and egg cells has been shown to be active in some types of breast cancer, suggesting new treatments might be available.

A study led by Professor Andrew Tutt with colleagues at the ICR and  King’s College London found that a gene normally involved in sperm and egg development may have a role in the development of some breast cancers.

The gene HORMAD1 is normally active in the testis and ovaries where its job is to turn off accurate DNA repair during sperm and egg development as a way of creating genetic diversity between parents and offspring.

In this study, our researchers found evidence of HORMAD1 activity in the patterns of mutations and gene messages in breast cancers – the first time it had been shown to be active in cells outside of the testis and ovaries. Cells with active copies of the gene seemed to use a messier and less effective form of DNA repair, leading to some genes being duplicated or deleted. The study, which was published in Cancer Discovery, suggests that when the gene is activated out of context and switches off accurate DNA repair in normal cells, it can cause genetic instability that could potentially turn cells cancerous.

The researchers went on to look specifically at triple-negative breast cancer, a hard-to-treat cancer with low survival rates. They found HORMAD1 could drive genetic instability in cancer cells from this tumour type. Interestingly, if the cells from these cancers had HORMAD1 activity, the researchers found that they were vulnerable to treatment with platinum-based chemotherapies and PARP inhibitors.

This suggests that looking for HORMAD1 could be used in the future as a way to identify cancers that might be susceptible to these treatment types. If future clinical trials can confirm the finding, it could open up new options for women with triple-negative breast cancer, which is particularly difficult to treat.

The research was funded by Breast Cancer Now.

Reference:

Watkins et al. (2015) Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers. Cancer Discov. 5(5) DOI: 10.1158/2159-8290.CD-14-1092

Structure of a key cell protein involved in cancer is imaged 

Dr Edward Morris and colleagues at the ICR revealed the structure of a protein central to life and cancer.

Scientists at the ICR and the Medical Research Council Laboratory of Molecular Biology in Cambridge were able to visualise in exquisite detail the proteasome complex – a recycling unit which is involved in many diseases including cancer.

The proteasome is crucial to the functioning of healthy cells in our body – facilitating cell division, renewal and death – and plays a critical role in cancer by allowing cancer cells to divide rapidly.

Our researchers pioneered the use of an advanced imaging technique called electron
cryo-microscopy, which involves imaging samples at ultra-low temperatures, to visualise the complex to a resolution of tens of billionths of a metre. 

The images they obtained showed the proteasome complex in such extraordinary detail that it was possible to view a prototype drug bound to its surface and blocking the proteasome’s action.

The research, which was published in Nature Communications, could help improve scientists’ ability to develop molecules that interact very specifically with target sites on proteins – a fundamental part of designing new anti-cancer drugs.

The research was funded by Cancer Research UK and the Medical Research Council.

References:

da Fonseca P. & Morris E. Cryo-EM reveals the conformation of a substrate analogue in the human 20S proteasome core, Nature Communications (2015)
6 (7573) DOI: 10.1038/ncomms8573

Phase III clinical trial first to demonstrate benefits of viral immunotherapy 

A phase III trial led in the UK by Professor Kevin Harrington at the ICR and The Royal Marsden was the first to definitively show that viral immunotherapy can have benefits for patients with cancer.. 

The trial results, published in the Journal of Clinical Oncology, showed that the viral immunotherapy Talimogene laherparepvec, or T-VEC, can halt the progression of melanoma by killing cancer cells and sparking the immune system into action against tumours.

T-VEC is a genetically modified form of herpes simplex virus type-1 which multiplies inside cancer cells and bursts them from within. It has been genetically engineered to produce a molecule called GM-CSF, which stimulates the immune system to attack and destroy the tumour.

The virus was modified to remove two key genes, called ICP34.5 and ICP47, so that it couldn’t replicate within healthy cells. Normal cells detect and destroy T-VEC before it can cause damage – but it replicates easily in cancer cells because their infection defences are compromised by genetic errors.

Researchers from 64 research centres worldwide randomised 436 patients with aggressive, inoperable malignant melanoma to receive either an injection of T-VEC, or a control immunotherapy.

They found that 16.3 per cent of the group given T-VEC showed a durable treatment response of more than six months, compared with 2.1 per cent given the control treatment.

Some patients had a response extending past three years, a mark oncologists often use as a proxy for cure in immunotherapy.

Importantly, responses to treatment were most pronounced in patients with less advanced cancers (stage IIIB, IIIC, IVM1a) and those who had yet to receive any treatment – underlining the potential benefits of T-VEC as a first-line treatment for metastatic melanoma which cannot be surgically removed.

Patients with stage III and early stage IV melanoma treated with T-VEC – a total of 163 people – lived an average of 41 months. This compared with an average survival of 21.5 months in the 66 earlier-stage patients who received the control immunotherapy.

The trial was funded by the manufacturer of T-VEC, Amgen.

Since the publication of the trial results, T-VEC has been recommended for approval for patients with advanced, inoperable melanoma by the European Medicines Agency and fully approved by the FDA in the US. It is now the first in a new class of cancer-fighting agents called oncolytic immunotherapies.

References:

Andtbacka et al Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma, Journal of Clinical Oncology (2015) DOI: 10.1200/JCO.2014.58.3377

Trial finds breast cancer drug delays disease progression 

Research by ICR scientists found that a new breast cancer drug could delay the onset of advanced breast cancer in conjunction with standard treatments. 

A phase III clinical trial led by Dr Nicholas Turner at the ICR and The Royal Marsden found that novel cancer drug palbociclib significantly delays progression of advanced breast cancer when used with hormone therapy.

In the trial, palbociclib was given in combination with fulvestrant – a standard hormone therapy – in one group of women, while fulvestrant and placebo were given to the other group. It took an average 9.2 months for women treated with palbociclib to progress, compared with an average of 3.8 months in the placebo group – a gain of almost an extra five months.

Palbociclib is a ‘first in class’ drug because of its unique mechanism of action. It blocks two proteins that help cancer cells divide, CDK4 and CDK6. By selectively targeting cancer cells, the drug causes far fewer side-effects than traditional chemotherapy.

Palbocicib was found to be well tolerated, with only 2.6 per cent of patients on palbociclib experiencing side-effects that led them to stop taking the drug. The trial was stopped earlier than planned, on the advice on an independent monitoring committee, because of the positive results.

The study, published in the New England Journal of Medicine, was conducted in women with hormone-receptor positive, HER-2 negative breast cancer – a type that accounts for 75 per cent of cases. All women on the trial, which was run at 144 international research centres in 17 countries. had seen their disease relapse or progress after first receiving hormone therapy.

Hormone treatment is the first step for many women with this type of cancer, but the disease will often eventually progress or relapse – meaning that patients will need to be treated with chemotherapy

By combining a targeted therapy with a standard hormone drug, the trial aimed to identify an effective strategy to delay the need for women to start chemotherapy.

 The trial was funded by Pfizer.

References:

Turner et al. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer, New England Journal of Medicine (2015); 373 DOI: 10.1056/NEJMoa150527

Cancer drug resistance found to pre-exist in healthy tissue 

ICR research shows that genetic mutations which drive resistance to some cancer drugs are present in breast cancer cells right from the beginning of treatment. 

Dr Spiros Linardopoulos and colleagues at the ICR discovered that genetic mutations which cause resistance to cancer treatment can be present in breast cells before treatment and even before breast cancer has developed. 

One of the main challenges in treating cancer is when it develops resistance to treatment, which can occur very quickly in some patients. Our researchers were investigating how cancer cells develop resistance to a new type of cancer drug called MPS1 inhibitors, currently in development for several tumour types including breast cancer.

In the study, which was published in the journal Cancer Research, they discovered five separate mutations in cancer cells that cause resistance to MPS1 inhibitors within the gene for MPS1. These genetic mutations driving resistance were present in cells right from the beginning of treatment – and are even found at a low frequency in normal, healthy breast tissue. The findings suggest that these resistant mutations can pre-exist naturally in the breast.

Researchers found that mutations that confirm resistance to other drugs such as gefinitib, an EGFR inhibitor to treat breast and lung cancers, also pre-exists in cancer cells and normal tissue. The findings may allow early identification of patients whose cancers are likely to develop resistance, enabling treatment to be adjusted accordingly.  

The research also shows how clinical trials of new targeted drugs need to be planned carefully, as in many cases treatment will kill susceptible cells but leave resistant cells alive, selecting for mutations that will make the cancer resistant.

The research was funded by Breast Cancer Now and Cancer Research UK.

References:

Gurden et al. Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance, Cancer Research (2015) doi: 10.1158/0008-5472.CAN-14-3272

New drugs could stop skin cancer from spreading 

Two drugs discovered at the ICR could stop melanoma from spreading to other parts of the body. 

Professor Chris Marshall, Professor Ian Collins and colleagues at the ICR found that two new drugs could stop melanoma from spreading to other parts of the body.

The drugs – which were discovered at the ICR – were able to dramatically reduce the ability of melanoma cells to move through tissue.

The new drugs work by inhibiting the activity of a group of proteins called ROCK and stop cancer cells from employing two different types of movement that they use to spread to other parts of the body.

This is a new approach, as earlier generations of ROCK inhibitors do not block both forms of movement and are therefore not capable of blocking cell migration completely. The new inhibitors could be an effective way of stopping tumour spread and growth at new sites in melanoma – which is the most dangerous form of skin cancer, and normally becomes untreatable once it has spread to other sites in the body.

Our researchers tested one of the drugs in mice with melanoma and found that it not only stopped cellular movement, but also slowed tumour growth. That suggests that ROCK is required both for tumour spread and also growth at the site of spread.

The study, which was published in the journal Cancer Research, was a collaboration between researchers from a range of disciplines including cancer biologists and chemists. It suggests that ROCK inhibitors could be an effective new way of preventing melanoma cells from metastasising – the most common way that the disease kills patients.

The study was funded by Cancer Research UK, with additional support from a Marie Curie Intra-European Fellowship.

References:

Sadok A et al., Rho kinase inhibitors block melanoma cell migration and inhibit metastasis, Cancer Research (2015), 75(11) DOI: 10.1158/0008-5472.CAN-14-2156

Genetic map of prostate cancer mutations created 

Professor Johann de Bono and his team at the ICR mapped the genetic mutations of aggressive prostate cancer, in a paper hailed as the disease’s ‘Rosetta Stone’ (photo: Mateus Crespo/Professor Johann de Bono, the ICR)

Professor Johann de Bono worked with colleagues at the ICR and several US institutions to create a comprehensive map of the genetic mutations within lethal prostate cancers that have spread around the body.

The study, published in the prestigious scientific journal Cell, found that nearly 90 per cent of men with advanced prostate cancer carry genetic mutations in their tumours that could be targeted by either existing or new cancer drugs.

Researchers believe doctors could start testing for these ‘clinically actionable’ mutations. Men with advanced prostate cancer could then receive drugs or drug combinations targeted at the specific genomic aberrations in their cancers.

The study has been hailed as prostate cancer’s ‘Rosetta Stone’, because of the ability it gives researchers to decipher the complexity of the disease. It was the first in the world to carry out in-depth analysis of metastatic prostate cancer – incorporating tumour samples taken from the bone, soft tissues, lymph nodes and liver of 150 patients.

Nearly two thirds of the men in the study had mutations in a molecule that interacts with the male hormone androgen, which is targeted by current standard treatments – potentially opening up new avenues for hormone therapy.

Mutations in the BRCA1 and BRCA2 genes – most famous for their roles in breast cancer – were found in nearly 20 per cent of patients. Recent work at the ICR and The Royal Marsden has shown that these patients can be treated effectively by drugs called PARP inhibitors.

Our researchers also discovered new mutations, never detected before in prostate cancer, but which do occur in other cancers.  

The researchers also took blood tests to analyse patients’ own genomes, and found that 8% were born with DNA errors that predisposed them to prostate cancer. They said this could strengthen the case for genetic screening for people with a family history of the disease.

The research was funded by Stand up to Cancer and the Prostate Cancer Foundation.

References

Robinson et al. Integrative Clinical Genomics of Advanced Prostate Cancer, Cell (2015), 161 DOI: http://dx.doi.org/10.1016/j.cell.2015.05.001