GLOBAL NEWS: OVARIAN CANCER RESEARCH

Updated findings from a US Phase 2 trial show that this combination therapy is well tolerated and may become the new standard for treating recurrent low-grade serous ovarian cancer. 

Verastem Oncology in the US recently released encouraging data from their Phase 2 trial, RAMP 201, using a new drug combination for treating recurrent low-grade serous ovarian cancer (LGSOC). LGSOC is a challenging form of ovarian cancer that is difficult to treat and frequently resists chemotherapy. 

The trial tested the effectiveness of avutometinib, combined with defactinib, which are both inhibitors targeting key proteins involved in cancer cell migration, attachment and survival. This unique combination aims to block multiple cancer growth pathways at once, potentially giving a stronger, longer-lasting anti-cancer effect. In this study, 109 patients were treated, and results showed that 31% responded positively to the treatment, with response rates even higher (44%) among patients who had a specific mutation in the gene KRAS, commonly found in LGSOC. 

The combination also proved generally safe, with few patients discontinuing due to side effects. Common side effects included nausea and diaorrhea, and no new safety concerns arose. This is significant as the current standard treatments for LGSOC, like hormone therapy and chemotherapy, are often less effective and have limited targeted options, leaving patients with few reliable choices. The median duration of response was over 30 months for patients with the KRAS mutation, and median progression-free survival extended beyond a year, underscoring the potential durability of this treatment in keeping cancer at bay. 

Verastem Oncology aims to fast-track this new therapy by submitting a New Drug Application (NDA) to the US Food and Drug Administration (FDA), with hopes for approval in 2025 for patients with KRAS-mutant LGSOC. Additionally, they plan to expand the treatment's availability by further testing it in patients without the mutation. The FDA has already granted Breakthrough Therapy and Orphan Drug designations for the avutometinib-defactinib combination, which could accelerate its regulatory review. If approved, this would be the first FDA-sanctioned treatment specifically for recurrent LGSOC, marking a potential new standard of care for this often hard-to-treat cancer. 

Researchers discovered a mechanism that ovarian tumours use to disable immune cells by blocking their energy supply. This could lead to a new immunotherapy approach for ovarian cancer. 

Metastatic ovarian cancer is especially challenging as it is known for weakening the immune system and resisting both standard treatments, such as chemotherapies, as well as immunotherapies. In ovarian tumours, certain immune cells called T cells are trapped in an inactive and non-functional state. These T cells then have poor cancer-fighting abilities that can’t be fixed with typical immune treatments. Researchers are now exploring whether ovarian cancer, in addition to other aggressive cancers, can disrupt an essential pathway called the “FABP5 pathway” which may explain the immune cells’ inability to fight the cancer effectively. The protein “FABP5” plays a crucial role in helping T cells absorb fats and use them to power their energy needs. However, until now, the exact processes controlling how T cells use these fats were not well understood. 

This study discovered that another protein called “TAGLN2” is essential for T cells to effectively absorb fats, generate energy, and attack cancer cells. TAGLN2 works by interacting with the FABP5 pathway to ensure it functions properly on the surface of T cells. However, in ovarian cancer, the stressful environment inside tumours can block the TAGLN2 protein, making T cells less effective at fighting the cancer. 

The researchers found that by restoring the activity TAGLN2 in stressed T cells, they could boost the cells’ ability to absorb fats, produce energy, and kill cancer cells. They also showed that genetically engineered immune cells (CAR-T cells) with extra TAGLN2 protein could overcome stress caused by the tumour environment and successfully fight the cancer pre-clinical metastatic ovarian cancer models. 

In summary, this research identifies the TAGLN2 protein as a key player in T cell energy use and suggests that preserving the TAGLN2–FABP5 pathway could improve cancer immunotherapy, especially for solid tumours like ovarian cancer.