The Biomedical Research in Gynaecology group at the Vall d'Hebron Research Institute (VHIR) has observed that combining two drugs with complementary mechanisms of action could improve the treatment of high-risk endometrial cancer. The work, carried out in preclinical models generated from patient tumours and published in the journal Biomedicine & Pharmacotherapy, was conducted jointly together with the Gynaecologic Oncology Unit and the Department of Pathology at Vall d'Hebron University Hospital.

Endometrial cancer is the most common gynaecological cancer in developed countries, with nearly 1,000 cases diagnosed each year in Catalonia and around 7,000 in Spain, and its incidence continues to increase, mainly due to rising life expectancy and obesity. In high-risk tumours, resistance to treatment can limit the available therapeutic options.

A combination of two drugs

In order to find new therapies for patients with endometrial cancer, the VHIR team and the company Byondis S.L. conducted a study combining two drugs that are already independently approved for other oncology indications: SYD985 (a HER2 antibody conjugated to a potent cytotoxic drug) and niraparib.

HER2 is a receptor involved in processes related to cell growth and survival. This receptor is highly expressed in some tumours, such as breast and gastric cancers, and therefore treatments targeting this receptor are already used to selectively attack tumour cells. In endometrial cancer, however, its expression tends to be lower and more variable, which is why these treatments have been little studied as a therapeutic alternative for this type of tumour.

In this study, SYD985, a HER2 antibody conjugated to a cytotoxic drug, was used. The antibody identifies cells expressing HER2 and directs the treatment towards them, while the cytotoxic drug causes damage to HER2-expressing tumour cells as well as to adjacent cells. “Although endometrial cancer does not express HER2 at such high levels, this antibody-drug conjugate allows us to target treatment to the cells that express it and, thanks to the cytotoxic drug, amplify its effect”, explains Dr. Valeria Tubita, a postdoctoral researcher in the Biomedical Research in Gynaecology group at VHIR.

In addition to SYD985, a second drug, niraparib, an inhibitor of DNA damage repair, is administered. By blocking this pathway, tumour cells can accumulate damage that they are unable to repair and eventually die. These treatments are already used in clinical practice and are particularly useful as maintenance therapy in tumours with underlying mutations in the DNA damage repair pathway, such as ovarian cancer.

Two drugs with greater antitumour activity than the individual treatments

The research team conducted the study using fifteen animal models in which different tumour subtypes obtained from patients with endometrial cancer were implanted. These models, known as PDXs, from the English acronym Patient-Derived Xenograft, make it possible to study new treatments in a clinically relevant way because PDX models retain many of the characteristics of the original tumour. For each of the PDX models derived from 15 patients, a preclinical study was conducted to evaluate four conditions: placebo, niraparib alone, HER2-targeted treatment alone, or the combination of both drugs.

The results showed that the combination had a greater antitumour effect than the individual treatments. Specifically, a complete response, meaning the complete disappearance of the tumour, was observed in 60% of the treated models. The individual treatments achieved this in only 7% or 27% of the models. This effect was observed in tumours with diverse molecular characteristics and not only in models with high HER2 expression or mutations classically associated with sensitivity to niraparib.

The team also analysed gene expression in the different tumours to identify molecular characteristics associated with a better response. The results indicate that the models that responded best to the combination displayed characteristics similar to those associated with a response to the two treatments separately. “Understanding the molecular profile of tumours provides deeper knowledge and helps us establish prognosis and predict treatment response”, says Dr- Antonio Gil-Moreno, co-leader of the Biomedical Research in Gynaecology group at VHIR.

Preclinical research continues with the support of the Solidarity Scarf

The results pave the way for further studying this therapeutic strategy in new experimental models in the laboratory, such as organoids—small 3D structures obtained from patient cells that reproduce the structure and function of the original tumour.

The team will investigate the mechanisms that explain the positive results obtained by combining niraparib and the HER2-targeted antibody. For example, they will investigate whether, as previous studies have suggested, niraparib is capable of increasing HER2 levels and therefore makes tumour cells more readily recognised by the antibody.

In addition, organoid models also make it possible to test other drugs that inhibit DNA damage repair and HER2, as well as other potential therapeutic combinations.

“One particularly interesting aspect of this strategy is that the drugs we are testing are already individually approved for clinical use, so we are not starting from scratch. Further preclinical and clinical studies are still needed, but the knowledge we already have about these treatments may facilitate the steps needed to bring them to patients”, highlights Dr. Eva Colás, co-leader of the Biomedical Research in Gynaecology group at VHIR.

This new phase of the research is supported by the Spanish Association Against Cancer, the Dexeus Mujer Foundation, and the Vall d'Hebron and Natura Solidarity Scarf initiative.

Since 2017, the Solidarity Scarf has helped promote research into cancers that specifically affect women. Thanks to the involvement of thousands of people, more than 42,000 units have already been sold, helping to support projects such as this one. If you would like to contribute to research into women's cancer, we encourage you to buy the Solidarity Scarf!

*Institucional Declaration on the use of research animals