+ New Era of Melanoma Therapy

Question 1

Melanoma therapy overview:

Answer 1

• Targeted and immunotherapy approaches have largely replaced cytotoxic chemotherapies

Question 2

Features of targeted therapies

Answer 2

• Constitutively activated pathways sustain cancer cell proliferation and survival, and instruct the TME
• Small-molecule drugs inhibit signalling proteins (i.e. kinases), inducing tumour regression
• High initial resistance and relapse limit long-term benefits

Question 3

Features of immunotherapy:

Answer 3

• T cells recognise antigens presented via the MHC to the TCR, but are supressed by inhibitory ligand/receptor interactions
• Antibodies block inhibitory immune checkpoints (PD-1, CTLA-4). activating a cytotoxic immune response
• Durable responses in a subset of patients
• Intrinsic resistance and severe side-effects remain challenging

Question 4

RAFi and MEKi small-molecule rugs

Answer 4

RAFi:

• vemurafenib
• dabrafenib

MEKi:

• cobimetinib
• trametinib
• Study using adjuvant dabrafenib and trametinib showed promising results with 53% reduced risk of relapse in the treatment vs placebo group

Question 5

Example of anti-PD-1 antibody:

Answer 5

• nivolumab
• Focus of first trial discussed in the review -> >50% 3-year overall survival rate for patients with unresectable melanoma

Question 6

+ Further examples of targeted therapies concerning: Activating invasion and metastasis, resisting cell death, deregulating cellular energetics…

Answer 6

• Activation of invasion and metastasis -> Inhibitors of HGF/c-Met
• Resisting cell death -> Pro-apoptotic BH3 mimetics
• Deregulating cellular energetics -> Aerobic glycolysis inhibitors