Screening for novel therapeutic targets in melanoma

• Applicant: Dr. Celia Vogel
• Subject Area: Cell Biology
• Term: from 2011 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 211103201

Malignant melanoma is a highly aggressive skin cancer rising alarmingly in incidence worldwide. Primary melanoma can be cured surgically, but metastatic melanoma is refractory to current treatment regimens. Most cancers activate the MAPK pathway and its downstream component MEK. Melanoma does so mainly via the oncogenic BRafV600E or NRasQ61R mutations. Recent clinical trials with the BRafV600E inhibitor PLX4032 show spectacular remissions, but most patients relapse eventually, demonstrating that targeted therapy of melanoma is possible, but limited at this stage. NRas mutations confer resistance to PLX4032. They occur in treatment-naïve and relapsed PLX4032-treated melanoma. Importantly, there is currently no targeted therapy available for NRas mutant melanoma.Cancer cells frequently depend on activated oncogenes for their proliferation and/or survival, but also on non-oncogenes to cope with the stresses of chronic oncogene activation and mutation load, phenomena known as (non-)oncogene addiction. Successful clinical strategies exploit these addictions by inhibiting (non-)oncogenes.Aims: 1) Identification of genes, which become essential in the context of NRas mutations in the presence or absence of MEK inhibition using NRas mutant cell lines from a unique panel of 41 low passage human metastatic melanoma cell lines that we have extensively characterized. An unbiased functional shRNA screen targeting the kinome can identify both oncogenes and non-oncogenes effectively using next-generation sequencing. 2) Hit validation in a screen of melanoma and control cell lines, followed by tests with additional shRNAs and with kinase inhibitors. 3) Uncovering the mechanism(s) of action of the validated hits with in vitro and in vivo experiments with inducible knockdown systems and drugs.Using state-of-the-art technologies I expect to identify much-needed therapeutic targets for metastatic melanoma.

• DFG Programme: Research Fellowships
• International Connection: Netherlands
• Host: Professor Daniel Peeper, Ph.D.