New Breast Cancer Therapy: Drug Targets Defects in Cancer Cell's 'Velcro'

A drug used in treating non-small cell lung cancer could offer a new targeted therapy for thousands of breast cancer patients following the discovery that it can kill breast cancer cells with a particular genetic defect, new research by Breast Cancer Now-funded scientists has found.

In a new study, scientists at the charity’s Toby Robins Research Centre at The Institute of Cancer Research, London, have established that lung cancer drug crizotinib could be used to target ‘lobular’ breast cancers, using an approach known as ‘synthetic lethality’ that attacks weaknesses in the tumour cells.

Such is the promise of this approach that a major clinical trial (ROLO, phase II) of crizotinib in patients with advanced lobular breast cancer is being launched by the ICR and The Royal Marsden NHS Foundation Trust – funded by new grants worth over £750,000 from the Breast Cancer Now Catalyst Programme.

Dr Ilirjana Bajrami and Professor Nick Turner talk about the promise for using a lung cancer drug to treat a certain type of breast cancer.

Targeting defects in cancer cell's 'velcro'

The new approach targets cells with genetic defects which mean that they have faulty versions of a protein called E-cadherin. In normal cells this protein acts like ‘velcro’ to help bind them together, but defects in E-cadherin are common in cancer and cause cancer cells to grow and divide abnormally.

E-cadherin defects occur in over 13% of all breast cancer cases, and, in particular, are seen in up to 90% of all lobular breast cancers – where the tumour has formed in the milk-producing lobes – as well as some ‘triple negative’ breast cancers.

It is estimated that around 7,150 women in the UK are diagnosed with breast tumours that are E-cadherin defective each year. However, despite their prevalence, there are currently no treatments that specifically target E-cadherin-defective breast tumours.

Very little is known to date about what weaknesses exist in these types of cancer cell.

New breakthrough research

In new research, published in Cancer Discovery, leading scientists – led by Professor Chris Lord and Dr Ilirjana Bajrami at the Breast Cancer Now Toby Robins Research Centre at the ICR – tested 80 small-molecule inhibitors to see if any of these drugs caused cancer cells with a defective E-cadherin gene to die.

The breakthrough research explored an approach to targeting tumours called ‘synthetic lethality’ which exploits two key genes that cancer cells need to survive. Where one of these two genes doesn’t function properly due to a mutation, blocking the other with a drug has a synthetic lethal effect, causing the cancer cell to die.

Working with scientists at Breast Cancer Now’s Research Unit at King's College London and investigators in the Netherlands, Professor Lord and Dr Bajrami found that the most significant synthetic lethality was demonstrated by crizotinib – manufactured by Pfizer and one of a class of drugs known as ROS1 inhibitors – which killed the E-cadherin defective breast tumour cells and left normal cells relatively unaffected.

The discovery demonstrates that by inhibiting ROS1 – a form of cell surface receptor – cancer cells without fully-functioning E-cadherin proteins are unable to survive, paving the way for a brand new, targeted approach to treating the disease.

Overcoming drug resistance

Lobular breast cancers are typically driven by oestrogen, and hormone therapy is therefore the mainstay treatment for these patients, following surgery. However, resistance is unfortunately very common, and lobular breast cancers also respond less well to chemotherapy, meaning there are currently few treatments available for those whose disease progresses after hormone therapy.

Having tested the approach in cells in the lab and in mice, Professor Lord’s team found that the synthetic lethal effects of crizotinib and other ROS1 inhibitors also worked in models of endocrine resistance, suggesting they could provide an important option for patients who have become resistant to their hormone therapy.

Following the discovery, the ROLO (phase II) clinical trial will now test the effectiveness of crizotinib in patients with E-cadherin defective, ER-positive, advanced lobular breast cancer – led by Dr Alicia Okines, Consultant Medical Oncologist at The Royal Marsden, and Professor Nicholas Turner, Professor of Molecular Oncology at the ICR.

The trial, funded by the Breast Cancer Now Catalyst Programme in collaboration with Pfizer, is the only recruiting study worldwide investigating novel therapies specifically for advanced lobular breast cancer patients.

Second drug to target 'synthetic lethality'

If proven effective in trials, it is hoped the finding could now lead to only the second targeted breast cancer drug to use ‘synthetic lethality’, following the PARP inhibitor olaparib – which UK scientists from the very same lab showed in 2005 could be used to target breast tumour cells with defects in two other breast cancer genes, BRCA1 or BRCA2. Olaparib was approved by the FDA for use in BRCA-mutated advanced breast cancers in January 2018.

With E-cadherin defects being one of the most common genetic changes found in all human cancers, it is also hoped treatment with ROS1-inhibitors such as crizotinib could be applied effectively in treating a number of other cancers, including stomach cancers.

Lead author Professor Chris Lord, Professor of Cancer Genomics in the Breast Cancer Now Toby Robins Research Centre at the ICR, said: “These are hugely promising laboratory findings and we’re very keen to learn whether this class of drug really works as a treatment for women with breast cancer.

“What we have seen so far suggests this is certainly an approach worth pursuing and we are very enthusiastic about the prospect of applying our scientific results in clinical trials.”

Exciting move to clinical trials

Professor Nicholas Turner, Head of Clinical Translation in the Breast Cancer Now Toby Robins Research Centre at the ICR and Consultant Medical Oncologist at The Royal Marsden, said: “We are in the middle of a new age of progress against breast cancer in which precision medicine is increasingly becoming a reality for women with the disease.

“This latest treatment approach offers the exciting prospect of personalising treatment for individual women based on our knowledge of their tumours, and we hope can offer a more effective therapy with fewer side-effects.

“We’re excited to build on these laboratory findings in our clinical trial and are optimistic that the new approach can prove effective for thousands of women with breast cancer.”

Demonstrating the benefits of collaboration

Baroness Delyth Morgan, Chief Executive at Breast Cancer Now, which funded the study, said: “This is an extremely exciting discovery that, if proven as effective in trials, could enable the breakthrough re-purposing of a lung cancer drug to provide the first targeted therapy for thousands of women with lobular breast cancer.

“Over seven thousand patients each year are diagnosed with breast cancers with this particular genetic defect, but until now we have had little idea how to tailor their treatment to target these faults.

“Hormone therapies can be incredibly difficult for women to take long-term, and with resistance unfortunately common among these patients, we hope this exciting class of drugs could offer a much-needed new option for many.

“While there is still some way to go, this promising approach demonstrates the real potential of collaboration between academia and industry to speed up the discovery of new cancer treatments – and we very much look forward to following the progress of this trial.”

This article has been republished from materials provided by The Institute of Cancer Research. Note: material may have been edited for length and content. For further information, please contact the cited source.