Metastatic uveal melanoma (MUM), also referred to as ocular melanoma, is a rare, aggressive form of eye cancer that can become resistant to many treatment options.

MUM tumours commonly spread to the liver; this is seen in 90% of advanced-stage disease. Following metastasis to the liver, the predicted outcome of uveal melanoma is poor, with approximately 50% of patients succumbing to the disease within 10 years of diagnosis.

MUM is a very difficult cancer to treat effectively; a recent clinical trial published in the Open Access journal Cancers investigates a new potential drug combination to treat MUM and provides new insights into its resistance to current cancer treatments.

Metastatic uveal melanoma and treatment evasion

Figure 1: Diagram of the MUM tumours in the eye.

MUM affects melanocytes in the middle layer of the eye, known as the uvea, which is made up of three segments: the iris, ciliary body and choroid. Melanocytes are specialised cells responsible for producing the pigment melanin, which provides protection and improves vision clarity. Moreover, MUM tumours have a low tumour mutation burden. This means the tumours have a low number of genetic mutations, which allows them to go undetected and evade normal immune system checks. The eye and liver are favourable environments for tumour progression, as they actively supress immune responses to prevent severe tissue damage. Various treatment options have been approved for use on MUM tumours including the immunotherapy drug Tebentafusp and Percutaneous hepatic perfusion (PHP). Tebentafusp was approved as it led to a 9% improvement in overall survival, but its use is limited to patients who carry a specific protein in their blood.

Percutaneous hepatic perfusion (PHP) is a minimally invasive procedure that allows chemotherapy to be directly delivered to the liver. It was recently approved to help prevent the metastasis of MUM to the liver. However, its use is only approved for patients who have less than 50% hepatic tumour burden. Although these treatments show promise, patients are still in desperate need of an effective therapy.

Metastatic uveal melanoma mechanism

The lack of therapy options is partially due to the complex mechanism and signalling pathway of MUM, which is still unclear. MUM is initiated by mutations that are activated in genes encoding GNAQ and GNA11 in 80-90% of cases.

GNAQ and GNA11 encode the Gαq and Gα11 alpha subunits of heterotrimeric G proteins, respectively. The Gαq alpha subunit is crucial for complex intracellular signalling for bodily functions, including calcium release and protein phosphorylation. . When mutated, GNAQ and GNA11 can signal to several pathways, including the MEK-ERK1/2 pathway required for tumour cell progression. However, targeting the MEK-ERK1/2 pathway alone has failed to provide clinical benefits in MUM patients.

This has led researchers to explore other pathways using alternative approaches, including a synthetic biology approach and a genome-wide RNAi screen, which revealed that both genes can activate a cascade of pathways associated with the tyrosine kinase FAK. Tyrosine kinase FAK has multiple effects on a cancer cell and its environment,making it often associated with drug resistance.

The authors, therefore, investigated the use of a combination of FAK and RAF/MEK inhibitors, defactinib and avutometinib, for the treatment of MUM.

Using a combined inhibitor approach to treat metastatic uveal melanoma

Defactinib is a small-molecule inhibitor of FAK that may be a promising treatment option, as by blocking FAK phosphorylation, it can interfere with how cancer cells grow, move, and survive. The researchers also investigated the use of avutometinib in combination with defactinib.  Avutometinib is an RAF/MEK inhibitor which traps RAF and MEK proteins together, preventing the phosphorylation of MEK and preventing tumour growth.

The researchers initiated the trial in February 2021 and continued through to January 2023. During this time, 12 patients were given doses of both defactinib and avutometinib. Defactinib (200 mg) was given twice daily, and avutometinib (3.2 mg) was given twice a week. Both drugs were given for 3 weeks on and 1 week off (28-day cycle).

The researchers used disease control rate (DCR) as the primary endpoint of this study as a measure of the proportion of patients who achieve tumour relief and stable disease. Response to the treatment was measured using a range of biochemical analyses and regular scans.

Targeting Gαq pathways for metastatic uveal melanoma treatment

Following two cycles of treatment, 50% of patients saw no change in their condition also referred to as  stable disease, while 50% of patients saw a decline in health and cancer progression .  No patients had a significant reduction in disease progression and therefore enrolment in the trial was halted. Although no benefit of other therapies was observed, it is important to note that the combination of drugs was very tolerable for patients, as there were no patients who required dose reductions.

Taking a closer look at the pre- and post-treatment tumour samples, the authors saw that patients with disease progression had increased levels of an enzyme called ALDH1A3. Furthermore, patients whose disease remained stable tended to have lower levels of ALDH1A3 than those who had progressed. These findings demonstrate that the enzyme ALDH1A3 may have a role in tumour progression and treatment resistance. Dr Seedor, lead author of the study explains the study’s importance:

“Together, the study highlights how moving discoveries from the laboratory into the clinic and then bringing what is learned back to the laboratory is ‘crucial to moving the science forward and developing better therapies,’”

MDPI publishing impactful Open Access research

This study demonstrates the importance of sharing all results openly with the scientific community. Although this particular combination of therapies did not produce the cure the researchers were hoping for, it provides further insight into the complex mechanism of metastatic uveal melanoma drug resistance and helps inform future combination therapy studies.

It is extremely important to openly discuss all scientific findings even if not the intended result as it can inspire future researchers. Open Access allows the continuation of this discussion not just within the researchers’ circle but to a wider audience. This can increase the impact of this study and bring researchers and patients one step closer to new and effective treatment options.

Further research on cancer therapy and clinical trials can be found across MDPI Open Access journals: Cancers, and their dedicated section: Clinical Research in Cancer.  

Alternatively, you can access the full MDPI journal list here.