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Ovarian cancer study identifies key genes for potential treatments
Around 7,500 women are diagnosed with high-grade serious ovarian cancer every year
A new study has highlighted the unique nature of ovarian cancer and the extent of variability between patients.
The study, conducted by researchers at Imperial College London, has confirmed that the tumours of some women with high-grade serious ovarian cancer (HGSOC) contain a type of lymphoid tissue, known as tertiary lymphoid structures or TLS, of which presence gives women a better prognosis.
They have also identified genes in high-grade serious ovarian cancer that are important for TLS formation and function.
The lymphatic system in our bodies helps fight off infection by producing immune cells such as T cells and antibodies. But TLS, which are in some ways similar to “normal” lymphatic tissues, are being found by researchers in different types of tumours.
By analysing tumours from 242 high-grade serious ovarian cancer patients before treatment and comparing them to progression free survival rates, the researchers found that women that had TLS in their tumours had a significantly better outcome.
The study, published in Cell Reports Medicine and funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre, is one of the first times scientists have found TLS in women with high-grade serious ovarian cancer and linked them to a better outcome.
“People tend to think of all cancer cell activity as purely malignant, but the reality is less clear-cut,” explained lead researcher Dr Haonan Lu, from the Department of Surgery and Cancer.
“Tumours can hijack a number of normal body processes and here, they seem to be hijacking the formation of normal human lymph tissue within themselves. Some of these lymphoid structures are able to then mature and activate T cells, which could attack the cancer itself.”
Around 7,500 women are diagnosed with high-grade serious ovarian cancer each year. Due to late diagnosis, many experience disease relapse, leading to a five-year survival rate of below 40 per cent.
The researchers were able to pinpoint the relevant genetic mutations involved in the cancer’s TLS formation, some of which are known to have immune-suppressing functions.
The team found that copy number mutations in the genes IL15 and CXCL10 in HGSOC can inhibit the lymphoid tissue forming. They also found that another set of genes, including DCAF15, plays a role in interacting with the TLS tissues after they have been formed, probably making them more or less active.
Dr Lu said: “There is great potential for targeting these genes for benefits in ovarian cancer treatment. It’s now becoming clear how the genetic background of the tumour type interacts with a TLS to have more or less TLS function, and that will help us identify potential targets for therapy.”
The scientists have also, for the very first time, developed a potential method of identifying patients with high levels of TLS from standard CT scans, using AI. This could ensure that those women who would benefit from different treatments are found more quickly, they said.
Although CT scans form part of standard treatment of the condition, TLS tissues are not visible to the human eye from a normal CT scan.
However, the research team has developed an AI algorithm that was trained to detect the structures within the tumours and have successfully tested the algorithm on scans of patients at Hammersmith Hospital, known to have TLS tissues.
Professor Eric Aboagye, professor of cancer pharmacology and molecular imaging at Imperial College London, said: “This non-invasive identification test means that oncologists will be able to determine if a patient has high or low TLS in future and treat them accordingly.”
The researchers have now received a project grant from Target Ovarian Cancer to further investigate the relevant genetic mutations identified, and explore whether it is possible to activate anti-tumour immunity for all high-grade serious ovarian cancer patients.
A drug targeting a key regulator in triple-negative breast cancer reduced tumour growth and cancer stem cell viability in laboratory models.
Triple-negative breast cancer is an aggressive subtype that disproportionately affects women under 40 and accounts for about 15 to 20 per cent of breast cancers.
The disease lacks receptors for oestrogen, progesterone and the HER2 protein, which are targeted by several cancer drugs, making it particularly difficult to treat.
Researchers from the National University of Singapore’s Yong Loo Lin School of Medicine investigated mechanisms that allow triple-negative breast cancer cells to spread and resist treatment.
They examined regulators of Wnt signalling, a pathway involved in processes including cell growth and movement, and identified a master regulator called DP103.
DP103 is a gene that controls a major biological process. The researchers found it creates a cycle in which cancer cells continue to grow and spread while resisting treatment and maintaining cancer stem cells linked to disease recurrence.
The team then investigated whether a targeted drug known as Supinoxin, or RX-5902, could block DP103 and its effects in triple-negative breast cancer.
Analysis of 21 samples, including patient tumour tissue, laboratory-grown breast cancer cells and organoids derived from local cancer patients, found that the drug reduced cancer stem cell viability by 40 to 60 per cent.
Tumour growth in laboratory-grown tumour models fell by about 50 per cent.
In laboratory models, treatment also reduced tumour size by around 90 per cent while largely sparing healthy cells.
It also extended survival, with half of the treated laboratory models reaching 70 days and beyond, compared with none in the untreated group.
DP103 had previously been identified as a biomarker for triple-negative breast cancer by a team led by Alan Prem Kumar, an assistant professor with the NUS Centre for Cancer Research and principal investigator for the new study.
RX-5902 is already being studied as a treatment for breast cancer, and Kumar said the findings could help identify patients who may be more likely to benefit.
“Our findings suggest that DP103 could potentially serve as a diagnostic biomarker to identify the patients most likely to benefit from RX-5902 treatment, paving the way for a more precise, personalised approach to treating triple-negative breast cancer,” he said.
“Instead of treating all patients the same, future clinical trials could focus on those whose tumours have high levels of DP103, where the therapy is expected to have the greatest impact,” said Kumar.
First author Cai Wanpei said RX-5902 could prevent beta-catenin, a protein whose mutation is associated with various cancers, from entering the nucleus of human cells and switching off genes that drive cancer growth and spread.
“This slows tumour progression and triggers apoptosis – the natural death of cancer cells,” said Cai, who was a PhD student at the NUS Centre for Cancer Research and NUS Medicine’s pharmacology department during the research.
Study co-author Celestial T. Yap said triple-negative breast cancer remains particularly difficult to treat because conventional treatments such as surgery, chemotherapy and immunotherapy may not work for all patients.
She said DP103 could represent a “biological vulnerability” in the disease.
“This discovery offers new insights that could support more precise patient selection and open the door to better targeted strategies for durable disease control and improved clinical outcomes,” said Yap, an associate professor with the NUS Centre for Cancer Research and NUS Medicine’s physiology department.
The researchers said abnormal Wnt signalling also drives several other cancers, meaning the findings could offer avenues for treating other aggressive cancers.
Their next steps include validating DP103 as a predictive biomarker in larger patient groups and further developing therapies targeting the regulator for clinical testing.
The team will also investigate combining RX-5902 with existing therapies to further improve treatment outcomes.
Australia’s drug advisory committee has recommended wider funding of triptorelin for women with breast cancer or endometriosis.
The recommendation comes after AstraZeneca announced plans to remove Zoladex from the market, risking leaving more than 7,500 women with breast cancer without an alternative treatment.
Both medicines block the release of oestrogen and testosterone and can be used as part of treatment, or for fertility preservation, in some forms of cancer.
The Pharmaceutical Benefits Advisory Committee met urgently in July and recommended making triptorelin unrestricted under the Pharmaceutical Benefits Scheme (PBS), which would mean it was funded for all uses.
The drug has been listed on the PBS for prostate cancer since 2006.
Triptorelin and Zoladex can also be used to treat endometriosis and to block puberty for either precocious puberty or gender-affirming care.
Vicki Durston, director of policy and advocacy at Breast Cancer Network Australia, described the recommendation as “a significant step forward” and said access to the medicine could mean the difference between life and death for some patients.
She said some women had already chosen to have their ovaries removed because of uncertainty over Zoladex supplies.
Marilla Druitt, Victorian state chair of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, said it remained unclear whether triptorelin would work exactly the same way as Zoladex, but the recommendation was likely to be positive for patients with endometriosis and pelvic pain.
She said: “I’m glad we’ve got an alternative.”
“That’s fantastic, and it remains to be seen whether or not it will be as good, but pain is so complex, pain is a really hard thing to study because it’s got so many contributors.”
Druitt said further research would be needed after the medicine was introduced.
If accepted by the federal government, the recommendation would also allow PBS funding of triptorelin for puberty suppression in precocious puberty and gender-affirming care.
This would make gender-affirming care federally funded through the PBS for the first time and would remove a financial barrier for transgender children in Queensland and the Northern Territory.
Stuart Aitken, medical director of Gender Health Australia, said the recommendation had sparked “absolute joy” among his patients.
He said: “It takes away a huge barrier to accessing evidence-based care.”
“It means that the ban has a very limited effect.”
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