Associated Project 4

1. Applicant

2. Topic

Inhibition of the PI3K-AKT signaling pathway to overcome therapy resistance in melanoma-derived brain metastasis

3. Short summary

Fig. 1: Melanoma-derived brain metastasis
Fig. 2: Inhibition of the PI3K-AKT signaling pathway

Brain metastases occur in over 70% of patients with metastatic melanoma and are the most common cause of death. Current therapy options are neurosurgery, radiosurgery, whole brain radiation, chemotherapy and supportive care. The median survival time for melanoma patients with brain metastasis ranges from 0.7 to 5 months depending on age and performance status. Therefore, new therapy strategies are mandatory.

In melanoma, activation of the RAF-MEK-ERK and PI3K-AKT-mTOR signal transduction pathways makes a decisive contribution to tumor progression and treatment resistance. Ongoing clinical studies suggest a transient effect of BRAF inhibitors in melanoma brain metastases. We posed the question as to whether blockade of the RAF-MEK-ERK or/and PI3K-AKT-mTOR signalling pathways would be a promising strategy for the treatment of melanoma brain metastases. We blocked RAF-MEK-ERK or/and PI3K-AKT-mTOR signalling pathways at different levels using claasical and new pharmacological inhibitors and investigated the effects on viability/proliferation and survival/apoptosis of newly isolated cell lines derived from melanoma brain metastases. Furthermore, immunohistochemical analyses of brain metastases from melanoma patients including matched extracerebral metastases in the same patients for p-ERK, ERK, AKT and p-AKT were performed. Growth inhibition was most pronounced with PI3K inhibitors achieving growth inhibition rates of up to 80%. Furthermore, PI3K inhibition potently induced apoptosis in cerebral metastatic melanoma cells. Moreover, most melanoma brain metastases were highly positive for activated AKT, whereas matched extracerebral metastases from lung and liver in the same patients were weakly positive or negative for activated AKT.

Together, these findings suggest that activation of AKT is relevant for the survival and growth of melanoma cells in the brain parenchyma suggesting that inhibition of PI3K-AKT signaling may be a suitable strategy to overcome therapy resistance in melanoma brain metastasis. The main goal of this project is to put this hypothesis to test. In particular, we aim to answer the following questions: 1) What are the mechanisms responsible for AKT activation in melanoma brain metastases? 2) Which downstream targets of AKT are relevant to melanoma brain metastasis? 3) Does inhibition of PI3K-AKT signaling or combined inhibition of RAF-MEK and PI3K-AKT signaling inhibit the growth, survival and invasive tumor growth of brain-metastatic melanoma cells?

Thus, the project shall lead to a better understanding of melanoma brain metastasis formation and shall identify new strategies for treatment.