New research advances personalised treatment for low-grade serous ovarian cancer

New research from the University of British Columbia in Canada, led by Professor Mark Carey and in collaboration with OCRF-funded researchers Dr Dane Cheasley and Dr Kathleen Pishas at the Peter MacCallum Cancer Centre in Melbourne, has identified potential biomarkers that could help guide more personalised treatment for low-grade serous ovarian cancer (LGSOC).

The study explored how two targeted therapies, trametinib and palbociclib, work in different biological subtypes of LGSOC, and which cancers may benefit most.

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Image: Dr Dane Cheasley, LGSOC researcher, Peter MacCallum Cancer Centre and the University of Melbourne.

Understanding the challenge of low-grade serous ovarian cancer

Low-grade serous ovarian cancer (LGSOC) is a rare subtype, accounting for only 5-8% of all ovarian cancers. It is typically diagnosed at a younger age (median 45-55 years), and most cases are found at an advanced stage. LGSOCs are typically not responsive to chemotherapies and other standard therapies, and recurrent disease is common (~70%).

While targeted therapies have begun to improve outcomes for some patients, responses vary significantly. There is an urgent need to both identify more effective treatments and determine which patients are most likely to benefit from them.

What this new study investigated

Recently published in the International Journal of Molecular Sciences, the researchers explored whether combining two targeted therapies could improve outcomes in LGSOC.

They focused on:

Trametinib: a MEK inhibitor that blocks part of the MAPK pathway, which helps cancer cells grow and divide.
Palbociclib: a CDK4/6 inhibitor that prevents cancer cells from progressing through the cell cycle, stopping their growth and division.

Together, these drugs target two key growth pathways in cancer cells. Both drugs are already used in other cancer types, such as lung, breast and colorectal cancers, but their combined role in LGSOC and which patients may benefit most remains unclear.

New biomarkers to potentially guide clinical decisions

The researchers analysed tumour samples and laboratory models to examine potential biomarkers that predict response to these therapies.

They found that loss of the cell cycle protein p16 in primary advanced LGSOC tumours (~15% of all cases) was associated with poorer patient survival. Furthermore, loss of p16 (40% of cases) was more common in recurrent disease. While p16 loss or inactivation has shown to predict for sensitivity to palbociclib in other cancers, its role as a predictive biomarker in LGSOC still remains to be established.

The team then examined LGSOC cell models in the laboratory with and without mutations in KRAS and NF1, genes known to drive cancer growth.

They found that the combination of trametinib and palbociclib was synergistic (the drugs work better in combination than alone) LGSOC cells with normal (non-mutated) KRAS/NF1. This effect was not seen in cancer cells with KRAS/NF1 mutations, in which trametinib alone was just as effective as treatment with the palbociclib/trametinib combination.

The researchers also identified diverse biological mechanisms by which LGSOC cells develop resistance to trametinib and palbociclib, providing further insight into why some tumours respond and others do not.

A potential new drug combination regime for low-grade serous ovarian cancer

The drugs were then tested, both individually and in combination, in preclinical models.

The researchers found that low and clinically relevant doses of trametinib combined with palbociclib significantly inhibited tumour growth LGSOC models with normal KRAS/NF1 genes. Importantly, the combination allowed the trametinib dose to be reduced to one-tenth of the standard dose, while achieving comparable tumour growth inhibition to higher-dose trametinib alone.

The combination was also more effective than palbociclib alone.

These findings provide a biological rationale for using tumour biomarkers such as p16 status, Rb levels, and KRAS mutation status to guide the use of MEK and CDK4/6 inhibitors in LGSOC. Additionally, it supports the evaluation of lower drug doses as potential treatments options with reduced side effects.

“The results of this study highlight the importance of using well-characterised (clinically, pathologically and molecularly) research models and clinically-relevant drug doses to obtain laboratory results applicable to future studies in patients”

says Dr. Mark Carey, lead investigator from University of British Columbia, Canada.

Why this research is important

MEK inhibitors are already used in relapsed LGSOC, but response rates remain modest (~26%). Some patients benefit substantially, while others see limited effect. Additionally, the duration of benefit is variable and limited in time (~13 months average).

This study provides evidence that:

Tumour biomarkers like p16 and KRAS may help select and predict which LGSOC patients will benefit from this therapy
Combining MEK and CDK4/6 inhibitors may be particularly beneficial in those LGSOC tumours with normal KRAS/NF1 genes.
Treatment strategies for LGSOC need to be tailored based on tumour biology rather than using a one-size-fits-all approach (known as precision medicine).

For patients with KRAS wild-type disease (i.e. KRAS is not mutated), where existing targeted options like avutometinib and defactinib may be less effective, this research provides support for new therapeutic opportunities using CDK4/6i inhibitor combinations (e.g. MEK inhibitors or hormone therapies).

“Rare disease like low-grade serous ovarian cancer require global collaboration to improve patient outcomes,”

says Dr Dane Cheasley, Peter MacCallum Cancer Centre, Melbourne, Australia.

“By bringing together expertise across Canada and Australia, we’ve been able to generate robust preclinical evidence that strengthens the foundation for future clinical studies.”

What happens next?

These findings are based on laboratory and preclinical models. Further validation and clinical studies are required before this approach becomes standard practice.

However, this research provides an important framework for designing smarter, biomarker-driven clinical trials in LGSOC, moving closer to more personalised treatment options for patients living with this rare ovarian cancer subtype.

“Individuals affected by LGSOC patients deserve equitable treatment opportunities as those individuals suffering from other more common cancer types. While funding support for LGSOC research is very much needed, future success also depends on strong international research collaborations to quickly advance our knowledge and find better treatments,”

says Dr. Mark Carey, University of British Columbia, Canada.

“We are particularly grateful for the research support received from all patient-families and cancer foundations (such as OCRF, Ovarian Cancer Canada and the British Colombia Cancer Foundation), as well as for the research support received from Dr. Cheasley and colleagues over the last 6 years”.

References

Bittner M, Fernandez ML, Hoenisch J, Leung YY, Kim H, Wong NKY, Pishas KI, Chealsey D, Cowley KJ, Simpson KJ, Lin YY, Volik S, Le Bihan S, Collins CC, Köbel M and Carey MS (2026). Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status, International Journal of Molecular Sciences (IJMS), vol. 27, 4, doi: 10.3390/ijms27041774.
Konecny GE, Davidson TM, Lebreton CL, Marsh LA, Chetram DK, Atkinson HJ, Larson MC, Oberg AL, Abdelaal N, Silverstein J, Jatoi A, Washburn A, Burton J, Dowdy S, Zhang L, Hallberg D, Velculescu VE, Slamon DJ, Wahner-Hendrickson AE. Phase II study of the efficacy and safety of palbociclib in patients with recurrent ovarian cancer. Int J Gynecol Cancer. 2025 Oct;35(10):102028. doi: 10.1016/j.ijgc.2025.102028.