Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma.

INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. CONCLUSION: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

[Systemic treatment of inoperable metastasized malignant melanoma]. / Systemtherapie des inoperabel metastasierten malignen Melanoms.

BACKGROUND: The medical therapy of inoperable malignant melanoma has changed dramatically over the last few years. OBJECTIVES: The purpose of this article is to summarize the current state of systemic medical treatment of malignant melanoma. MATERIALS AND METHODS: Clinical studies and guidelines in the therapy of malignant melanoma are reviewed. RESULTS: Medical therapy of inoperable melanoma changed due to developments in immunotherapies (checkpoint inhibitors) and molecular-targeted therapies (BRAF and MEK inhibitors). Checkpoint inhibitors are antibodies administered as infusions every 2-3 weeks, blocking the checkpoints PD-1 or CTLA-4, thus, preventing downregulation of the immune system. BRAF and MEK inhibitors are small molecules, they are given orally and block a certain signaling pathway in tumor cells. The activation of this pathway has to be demonstrated by molecular analysis of tumor tissue first. This strategy is currently registered for 40-50 % of melanomas harboring a BRAF V600 mutation, while the combination of a BRAF plus MEK inhibitor has been proven more efficient than a BRAF inhibitor alone. DISCUSSION: A fascinating development has started in the melanoma field due to immunotherapeutic and molecular-targeted treatment strategies. The continuation of this development needs further clinical and translational studies. This includes particular clinical studies with the new substances in the adjuvant situation, and sequences and combinations in the metastatic setting. Translational studies are needed to develop biomarkers for response and side effects.

[Melanoma brain metastases : Treatment options]. / Hirnmetastasen des malignen Melanoms : Therapiebesonderheiten.

The majority of patients with metastatic melanoma will develop brain metastases, which are the most common cause of death. Until recently, local therapies (e. g., neurosurgery, radiotherapy) were the only options for brain metastases; however, effective systemic treatment options are now available. Upon suspicion of brain metastases, diagnostic staging with brain MRI and a neurological investigation are indicated. Prognostic factors such as number of cerebral metastases and symptoms, serum lactate dehydrogenase and S­100 levels, extracerebral metastases, and ECOG status are considered during therapeutic planning. Treatment planning and therapeutic interventions should be based on an interdisciplinary and multimodal approach. Established treatments for singular brain metastases are neurosurgical resection and stereotactic radiotherapy, which can prolong survival. In patients with asymptomatic BRAF V600E-mutant brain metastases, the BRAF inhibitors dabrafenib, vemurafenib, and immunotherapy with ipilimumab are used. In the case of multiple symptomatic brain metastases, palliative whole-brain radiotherapy is used for treatment, although it has failed to show an overall survival benefit. Increased intracranial pressure and epileptic seizures are addressed with corticosteroids and anticonvulsants. Current clinical studies for melanoma patients with brain metastases are investigating new treatment options such as PD-1 antibodies, combined ipilimumab and nivolumab, combined BRAF inhibitors and MEK inhibitors, and stereotactic radiation in combination with immunotherapy or targeted therapy.