PI3K/AKT Pathway Potential Target for Treating Brain Mets in Melanoma

Michael Davies, MD

Activation of the PI3K/AKT pathway may play a role in the development of metastases in melanoma, according to a preclinical study published in Cell Report.¹

In the study, researchers found that expression of activated AKT1 resulted in highly metastatic melanomas with lung and brain metastases in 67% and 17% of the mice tested in the study, respectively. Silencing of the tumor suppressor PTEN in BRAF V600 melanomas also contributed to the activation of AKT1, and resulted in decreased tumor latency and the development of lung and brain metastases in nearly 80% of tumor-bearing mice.

In particular, brain metastases mark a significant problem in patients with melanoma, says Michael Davies, MD, an investigator on the Cell Report study.

“Historically, between 40% and 60% of patients with stage IV melanoma will develop CNS involvement at some point in their disease,” says Davies, associate professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “Brain metastasis has been one of the leading causes of death from melanoma, with patients having a survival, on average, of only 4 months from the diagnosis of CNS involvement.”

Research into the connection between the PI3K/AKT pathway and brain metastases may lead to a better understanding of what therapeutic regimens can be used to treat brain and other metastases, says Davies.

“We’ve actually shown that combining a PI3 kinase inhibitor with a BRAF inhibitor markedly improved survival in mice with brain metastasis,” he says. “We believe that this data perhaps sets the stage for clinical trials that, instead of being exclusionary to patients with brain metastases, may actually be specifically designed for patients with brain metastases.”

OncLive: What are the biggest obstacles to treating brain metastases?

In an interview with OncLive, Davies discusses the biggest challenges in treating brain metastases, what is known about the connection to the PI3K/AKT pathway, and what his future plans are for research in this area.Davies: One of the very challenging things about the management of patients with brain metastases is, although there have been many exciting clinical trials over the last decade, patients with brain metastases have been excluded from almost all trials due to their poor outcomes and concern that many agents will not cross the blood-brain barrier.

However, there is growing evidence in melanoma and many other cancers that the molecular biology of a brain metastasis is different from cancers growing elsewhere in the body. In particular, our work—and the work of several other investigators—has implicated activation of the PI3K/AKT pathway in brain metastases in melanoma.

The PI3K/AKT pathway is an oncogenic pathway that has been implicated in multiple tumors. We see activation of this pathway in a subset of melanomas. We have demonstrated that evidence of activation of the PI3K pathway, through loss of the tumor suppresser PTEN, predicts which patients with stage III melanoma will have a much higher risk and a shorter time to the development of brain metastasis.

Additionally, when we compare the molecular characteristics of those tumors to other tumors growing at other sites in the body in patients who have undergone resection of a brain metastasis, the distinguishing feature of the mass is that they have much higher activation of the PI3K/AKT pathway.

What implications could a better understanding of the connection between PI3K/AKT and brain metastases have on future treatment strategies for patients with melanoma?

Most other pathways do not look differentially activated. This suggests that the PI3K/AKT pathway plays a specific role in the pathogenesis of brain metastases and, therefore, may be a good therapeutic target to improve outcomes in patients.One of the things we hope to be able to do is actually identify which patients are at the highest risk for brain metastasis, even with early stages of disease. This could help us prioritize which patients actually need to be monitored, perhaps by an MRI of the brain, as part of their restaging workup after they’ve received potentially curative surgery.

What are the next steps in your research?

If we could detect brain metastasis at an early stage, they could potentially be cured with focal radiation approaches or surgical approaches. For patients who have advanced disease with brain metastases, hopefully an improved understanding of the molecular pathogenesis of these tumors will lead to treatments that are not only rational, but more effective.There are many different ways to target the PI3K pathway, so one of the biggest questions is, “Which of those targets are most likely to be effective?” We are evaluating different strategies to target the pathway and, importantly, we are evaluating different strategies in combination with other therapies, including targeted therapy, immunotherapy, and radiation therapy.

Do you think that combination therapies will be key to successfully targeting the PI3K pathway?

Is a clinical trial investigating the use of PI3K in patients with melanoma who have brain metastases on the horizon?

We know that melanoma is a very complex disease, and the PI3K pathway is equally complex. It can be activated multiple different ways and it can have multiple different effectors. How it intersects with other oncogenic pathways that are clinically significant in this disease, remains an ongoing and important area of research.Absolutely. What we generally see is that the PI3K pathway does not drive tumor growth by itself, but it compliments other pathways to make tumors much more aggressive and resistant to therapies.The challenge with getting a clinical trial up and running is the hesitancy of pharmaceutical companies to include brain metastases in trials. This is something that is slowly changing, as we have now seen clinical trials with both BRAF inhibitors with ipilimumab and PD-1.

However, often trials are done after most of the other clinical testing has been completed. It’s an active area of work for investigators in the field and for patient advocates to try and encourage companies to develop earlier stage clinical trials for patients with brain metastasis. This remains a critical unmet need for patients with this disease.

1. Cho J, Robinson J, Arave R, et al. AKT1 activation promotes the development of melanoma metastases. Cell Rep. 2015;13(5): 898-905.