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Targeting molecular ‘hooks’

We are currently funding Dr Patrick Caswell at The University of Manchester to study how targeting molecular ‘hooks’ could possibly work to stop the spread of ovarian cancer. We recently caught up with him to find out how the project is progressing.

Ovarian cancer is the sixth most common cancer in women worldwide. Most patients only start having symptoms at a late stage, after the cancer has spread away from the original tumour site to other organs when it becomes much more difficult to treat successfully. Sadly this means that survival rates after treatment are amongst the lowest when compared to other common cancers and it is often referred to as the silent killer. It is therefore vital to be able to identify ovarian cancer when it first begins and to find new treatments for women in the future.

Dr Caswell explains “Our research findings so far have allowed us to delve into the mechanisms that control the movement of ovarian cancer cells in a physiological environment which mimics what goes on inside a woman.

Cells detect components in the tissue and material that surrounds them using cell surface proteins called integrins as ‘sensors’. Integrins are taken up inside the cell before being recycled back to the cell surface. The recycling of a specific integrin called α5β1 increases the movement of ovarian cancer cells in response to certain components surrounding the cell. It is this increased movement that helps ovarian cancer to spread.

We have uncovered a series of proteins responsible for controlling this recycling of integrin α5β1 from the surface to inside the cell and back again. This knowledge is being used to study samples from patients, with high-grade serous ovarian cancer, the most deadly form. We have also developed 3D systems to study cell growth and movement that more closely mimic the physiological environment experienced in humans to support ovarian cancer spread.

Our investigations into integrins and related proteins in human samples are ongoing, and we hope they will reveal specific proteins that are involved in ovarian cancer spread. We will then ‘interfere’ with these proteins in our 3D systems by switching them on or off and seeing what effect that has on cell growth and movement. This will help us to identify new drug targets and understand how to treat ovarian cancer patients more effectively in the future.”

Longer-term treatment with olaparib can maintain quality of life and stop cancer progressing

AstraZeneca has today reported that the drug olaparib (Lynparza), which Worldwide Cancer Research played a key role in developing, can be used as part of a maintenance programme to ensure women maintain their quality of life, with few side effects, throughout their treatment. These findings were presented today at the 2017 ASCO Annual Meeting in Chicago, US taking place from 2-6 June 2017.

The SOLO-2 phase III clinical trial was open to women with BRCA-mutated, platinum-sensitive serous ovarian cancer which had relapsed. The women received 300mg, which equates to 4 tablets, of olaparib, twice a day as part of a maintenance programme. This new tablet form of the drug is significantly less than the 16 capsules a day which is currently prescribed.

The olaparib maintenance programme significantly prolonged the amount of time the women had before the disease progressed, eliminated symptoms of the disease and had low levels of toxicity for up to 27 months after they began taking the drugs. On three separate rating scales (functional, physical well-being and symptoms), women reported a similar quality of life to those taking the placebo which means that the drug had very few side effects. This means that women are more likely continue with their treatment, unlike with traditional chemotherapy drugs where prolonging life often comes at the price of a reduced quality of life, meaning women tend not to continue with the treatment.

Dr Lara Bennett from Worldwide Cancer Research said: "This is extremely exciting, and fantastic news for these women, as it means the drug not only prolongs their life but ensures that it is a good quality of life. It also consolidates our belief that funding discovery stage research, at the start of the drug development journey is vital. Without our research grants to Professor Steve Jackson almost 20 years ago to study DNA repair, this drug might never have been developed. It was Professor Jackson who believed that targeting a DNA repair weakness in cancer cells had the potential to lead to a new generation of cancer drugs and now we can see that he was right."

Read more about our role in helping kick start the development of olaparib here.

About SOLO-2

SOLO-2 was a Phase III, randomised, double-blind, multicentre trial designed to investigate the efficacy of olaparib tablets as a maintenance monotherapy compared with placebo, in patients with platinum-sensitive relapsed gBRCA-mutated ovarian cancer. The trial, conducted in collaboration with the European Network for Gynaecological Oncological Trial Groups (ENGOT) and Groupe d’Investigateurs National pour l’Etude des Cancers de l’Ovaire et du sein (GINECO), randomised 295 patients with documented germline BRCA1 or BRCA2 mutations who had received at least two prior lines of platinum-based chemotherapy and were in complete or partial response to their most recent regimen. Eligible patients were randomised to receive either olaparib tablets (300mg twice daily) or placebo.

Ovarian Cancer

Worldwide, ovarian cancer is the 7th most-commonly diagnosed cancer and the 8th most common cause of cancer death in women. The risk of developing ovarian cancer is increased in women with specific inherited genetic abnormalities, including BRCA mutations.

About olaparib (Lynparza)

Olaparib (Lynparza) is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that may exploit tumour DNA damage response (DDR) pathway deficiencies to preferentially kill cancer cells. It is approved by regulatory authorities in the EU and US for the treatment of women with BRCA mutated ovarian cancer.

 

References

  1. Friedlander M., et al. Relationship of health-related quality of life (HRQOL) and   patient-centered outcomes with the clinical outcomes with olaparib maintenance following chemotherapy in patients with germline (g) BRCA-mutated (m) platinum-sensitive relapsed serous ovarian cancer (PSR SOC): SOLO2 phase III trial. Presented at the American Society of Clinica Oncology (ASCO), June 2-6, 2017. Chicago, Illinois, US.

Olaparib approved for use in Scotland

This week the drug olaparib (also known as Lynparza) was approved for use in Scotland for women with ovarian cancer by the Scottish Medicine’s Consortium. Scottish charity Worldwide Cancer Research funded work which kick-started the development of this drug over 20 years ago.

Trials have shown the drug, can allow patients, who are often young women, with advanced ovarian cancer to live for an average of 7 months longer compared to standard treatments. Olaparib has already been approved for use in the USA and in Europe. It was also approved last year by NICE for use in England.

The journey started in in 1995 Worldwide Cancer Research (which was known as AICR at the time), based in St Andrews, Fife gave funding to Professor Steve Jackson at the University of Cambridge for a series of projects studying DNA repair. He used findings from these projects, along with others, to set up a company called KuDOS Pharmaceuticals Ltd.  KuDOS went on to develop olaparib, a drug targeting DNA repair. KuDOS was taken over by AstraZeneca in 2005, at which point AstraZeneca took over testing of the drug.

Later in the mid 2000’s the charity then funded Professor Alan Clarke, who’s work supported the case for using olaparib in cancers with BRCA mutations and helped olaparib on its way to clinical trials in patients.

Dr Lara Bennett, Science Communications Manager for Worldwide Cancer Research, commented: "As a charity based in Scotland, we’re proud to say that people giving locally has allowed us to make a local impact for cancer patients.

Ovarian cancer lags behind other cancers when it comes to the availability of modern, targeted treatments, and the prognosis for women diagnosed with ovarian cancer is often poor. All cancer patients should be able to benefit from the most advanced treatments medicine has to offer. That’s why it’s essential we keep supporting and funding early research for the future so we can develop the treatments we need. We are relieved that olaparib will finally be available for patients in Scotland."

Olaparib is in clinical trials for a wide range of other cancer types including breast and pancreatic cancer.  Worldwide Cancer Research continues to be involved in the drug and is funding work looking at how to stop patients becoming resistant to the treatment.

(Image source: AstraZeneca PLC)

Developing a new treatment for ovarian cancer

Dr Alice Soragni and her team in the US are testing a new drug which could help treat ovarian cancer.

Around 20 new cases of ovarian cancer are diagnosed in the UK every day. The majority of women are diagnosed with an aggressive, hard to treat form of the disease called high-grade serous ovarian carcinoma (HGSOC). With this type of cancer, as with many other tumours, an important cancer-protecting protein called p53 has been deactivated. p53 is often called ‘the guardian of the genome’ for its important role in protecting DNA and stopping normal cells from transforming into cancer cells.

Mutations are a very common cause of p53 deactivation in HGSOC. The mutations can cause p53 proteins to clump together, which prevents p53 from working correctly, and favours cancer progression.

Dr Soragni has developed a new prototype drug, ReACp53, which stops p53 proteins sticking together and helps them stay functional.

“Our experimental data so far suggest this new type of drug might help reactivate p53 function and eliminate cancer cells,” explains Dr Soragni. “We now want to test if ReACp53 might be effective against the very first cells which initiate cancer in the body, called cancer stem cells.”

Cancer stem cells are usually resistant to chemotherapy. They can divide and grow into more cancer cells indefinitely, and are involved in cancer initiation, recurrence after treatment, and spreading to distant parts of the body (metastasis).

“In this project we will test ReACp53 in combination with standard chemotherapy drugs or other novel drugs in the lab to find out how to make this new therapy as effective as possible,” says Dr Soragni.

“Unfortunately the majority of women diagnosed with this aggressive cancer still succumb to the disease. The support of the Worldwide Cancer Research grant will be instrumental in helping us develop ReACp53 into a new approach for the treatment of HGSOC.”

Understanding why chemotherapy drugs stop working in ovarian cancer patients

Worldwide, there are more than 204,000 new cases of ovarian cancer diagnosed each year. The most common treatment for ovarian cancer is surgery followed by chemotherapy using drugs that contain the metal platinum. There are several different types of ovarian cancer and one of the most common is called serous. About three quarters of patients with serous ovarian cancer normally respond well to their first chemotherapy treatments but many women with advanced forms of the disease find the cancer returns after months or even years. When the cancer recurs women are then given the chemotherapy again but in many cases the drugs no longer work as the cancer has become resistant and so develops further. Sadly many women with serous cancer will die several years from the date they were initially diagnosed. The reasons why the cancers become resistant to treatment are poorly understood and they are the focus of Professor Bowtell's Worldwide Cancer Research grant. Using samples from ovarian cancer patients collected before and after treatment he has found a gene which he believes could play a role in this resistance to the drugs and he is now working to understand how it may do this.

Targeting molecular hooks to stop the spread of ovarian cancer

Ovarian cancer (cancer of the ovaries) is the 7th most common cancer in women worldwide and the 5th most common cancer in women in the UK. Unfortunately, many women who develop ovarian cancer are not diagnosed until the cancer has already spread. This means that the survival rates for patients with this type of cancer are low compared to other common cancers.

Dr Caswell is interested in integrins, a family of molecules which act like tiny hooks. They stick out from the cell surface and anchor the cell to its physical surroundings (a bit like Velcro). Integrins are constantly being ‘recycled’; moved inside the cell and then back out to the surface again. This helps control the number of integrins at the cell surface, and the movement of the cell through its surroundings. The role of integrins in cancer is complex.

With his grant from Worldwide Cancer Research, Dr Caswell is studying the recycling patterns of one particular integrin which has been linked to ovarian cancer. He wants to find out exactly how it affects the movement of cancer cells through a 3D environment in the lab, similar to how they might spread in the body. By doing so, he hopes to reveal new ways of targeting drugs to stop the spread of ovarian cancer.

Building a cancer-killing virus

Professor Elliott is developing a virus which can target and kill ovarian cancer cells.

Over 4,000 women die from ovarian cancer in the UK each year*. Unfortunately, many patients are not identified until the disease is very advanced. Although improving, survival over 10 years remains low compared to many other cancers.

One exciting new approach to treating cancers is the development of special viruses to destroy cancer cells while leaving normal, healthy cells alone.

“Other groups have carried out clinical trials of these cancer-killing viruses, showing them to be promising treatments,” says Professor Elliott, “however, one major hurdle is their failure to spread through the whole of a solid tumour- sometimes there is just too much tumour.”

“This is where we come in. Using our knowledge of HSV biology, we want to discover ways of altering the virus so it will spread much faster between cancer cells.”

Professor Elliott and her team are focusing on the herpes simplex virus (HSV), which normally causes minor symptoms such as the cold sore, but which in its cancer-killing form has already been trialed for a range of cancers.

“Our ultimate goal is to build a virus with all the necessary properties needed for destroying cancer. That is, it will only infect cancer cells not healthy cells, it is easy to track and importantly it will spread rapidly through the cells,” says Professor Elliott.

* Latest statistics from Cancer Research UK