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![• BR AF is a serine/threonine protein kinase, encoded on chromosome
7q34, that activates the M AP kinase/ERKsignaling pathway. BR AF is
the family member most easily activated by Ras (1)
• In fact , approximately 50 % of melanomas harbor
activating
• BR AF mutations. Among the BRAF mutations observed in
melanoma, over 90 % are at codon 600, and among these,
over 90 % are a single nucleotide mutation resulting in
substitution of glutamic acid for valine (BR AF V600E:
nucleotide 1799 T > A; codon GTG > GAG).
• The second most common mutation is BRAF V600K
substituting lysine for valine, that represent s 5-6 % (GTG
> AAG), followed by BR AF V600R (GTG > AGG), an
infrequent two-nucleotide variation of the predominant
mutation, BR AF V600 ′ E2′(GTG > GAA), and BR AF
V600D (GTG > GAT ) [2].
1.Niault TS, Baccarini M: Targets of Raf in tumorigenesis. Carcinogenesis 2010,31:1165–1174
2.Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF: Prognostic and
clinicopathologic associations of oncogenic BRAF in metastaticmelanoma. J Clin Oncol 2011, 29:1239–1246.](https://image.slidesharecdn.com/melanomafrontlineapproach-150424033123-conversion-gate02/75/Melanoma-frontline-approach-8-2048.jpg)
Uploaded byEreny Samwel
Melanoma frontline approach
This document discusses the treatment of metastatic melanoma with BRAF mutations. It begins by describing a 45-year-old man who presented with widespread melanoma metastases. It then reviews how understanding the biology of melanoma led to two treatment targets - BRAF mutations and the downstream MEK-ERK pathway. Several BRAF and MEK inhibitors are discussed that block these targets, including combinations of BRAF+MEK inhibitors. It also explains that melanoma is an immunogenic tumor and discusses immune checkpoint inhibitors like anti-CTLA4 and anti-PD1 antibodies that help activate the immune system to fight melanoma. The document concludes by mentioning a recent clinical trial combining immunotherapies.
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Melanoma frontline approach
- 1. melanocyte melanoma epidermis dermis Frontline Approachto Metastatic BRAF-Mutant Melanoma Diagnosis, Molecular Evaluation, and Treatment Choice By ErenyS. Poles Ass.lecutrer of clinical oncology , Assuit university
- 2. 45 yo manwith ‘mole’ on his back for years presented with headaches and was found to have widespread (brain, liver, lung, bowel spread) liver biopsy showed metastatic melanoma
- 3. Patients with metastaticmelanoma had few treatment options
- 5. When we beginto understand the biology , it is the real beginning
- 6.
- 7.
- 8. • BR AFis a serine/threonine protein kinase, encoded on chromosome 7q34, that activates the M AP kinase/ERKsignaling pathway. BR AF is the family member most easily activated by Ras (1) • In fact , approximately 50 % of melanomas harbor activating • BR AF mutations. Among the BRAF mutations observed in melanoma, over 90 % are at codon 600, and among these, over 90 % are a single nucleotide mutation resulting in substitution of glutamic acid for valine (BR AF V600E: nucleotide 1799 T > A; codon GTG > GAG). • The second most common mutation is BRAF V600K substituting lysine for valine, that represent s 5-6 % (GTG > AAG), followed by BR AF V600R (GTG > AGG), an infrequent two-nucleotide variation of the predominant mutation, BR AF V600 ′ E2′(GTG > GAA), and BR AF V600D (GTG > GAT ) [2]. 1.Niault TS, Baccarini M: Targets of Raf in tumorigenesis. Carcinogenesis 2010,31:1165–1174 2.Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF: Prognostic and clinicopathologic associations of oncogenic BRAF in metastaticmelanoma. J Clin Oncol 2011, 29:1239–1246.
- 9. BR AFV600E has been implicated in different mechanisms of melanoma progression, and principally the activation of the downstream MEK/ERK pathway, evasion of senescence and apoptosis, unchecked replicative potential, angiogenesis (through MEK- dependent activation of HIF-1α and VEGF)* *Maurer G, Tarkowski B, Baccarini M: Raf kinases in cancer-roles andtherapeutic opportunities. Oncogene 2011, 30:3477–3488.
- 10. The second stepis MEK- ERK
- 11. Now there aretwo targets BRAF mutation V600E MEK – ERK Pathway
- 12. First how toassess BRAF mutation?1-Real-time Polymerase Chain Reaction 2-Next-generation sequencing 3- Immunohistochemistry 4-Circulating tumor-derived DNA Done only for proven metaststic disease
- 13. Therapeutic approach forBRAF mutated metastatic malignant melanoma VEMURAFEN IB
- 16. Dabrafenib : SecondFDA approved BRAF inhibitor
- 18. Do we solvethe problem ? NO
- 20. Now there aretwo targets BRAF mutation V600E MEK – ERK Pathway
- 21. MEK – ERK Pathway(MAPK) Trametinib : A First in Class Oral MEK Inhibitor Approved for Treatment of Metastatic Melanoma With BRAF V600 Mutations. Trametinib (MEKINIST) is a first-in-class, orally administered selective inhibitor of MEK1/2 serine threonine kinase.
- 22. The FDA hasgranted an accelerated approval to the combination of the MEK inhibitor trametinib (Mekinist) and the BRAF inhibitor dabrafenib (Tafinlar) as a treatment for patients with unresectable or metastatic melanoma who harbor a BRAF V600E or V600K mutation. The approval for the combination was based on results from an open-label phase I/II trial, which showed that trametinib combined with dabrafenib nearly doubled the duration of response and significantly improved overall response rates (ORR) when compared with dabrafenib alone.
- 23. Cobimetinib (another MEKinhibitor)
- 24.
- 25.
- 26. Why Melanoma isan immunogeneic tumour 1-The reason underlying the immunogenicity of melanoma is unclear. One hypothesis relates to the high mutation rate seen within melanomas compared with other tumor types. 2- The majority of these mutations are passenger mutations that are non-essential for the survival of the tumor but offer an opportunity for immune recognition. 3- where the mutation rate is higher, the chance of generating a mutation with the capacity to bind major histocompatibility complex could also be higher. Others have argued that the extensive research in melanoma immunology is largely opportunistic and stems from the failure of standard chemotherapeutic
- 27. As melanoma isimmunogenic so it can be eliminated naturally by host immune system Immune escape Tumors utilize a number of pathways to avoid immune detection. 1-Antigen expression and presentation mechanisms may be suppressed through decreased major histocompatibility complex class I expression. 2-Tumors are also able to limit an immune response by releasing immunosuppressive paracrine mediators including adenosine, transforming growth factor- b, vascular endothelial growth factor- A and indoleamine 2,3-dioxygenase (IDO) to suppress T-cell activation.
- 28. 3-Dampening of T-cellactivity also occurs through the regulatory pathways such as upregulation of cytotoxic T- lymphocyte antigen-4 (CTLA)-4 on T cells, or engagement of programmed death-1 (PD-1), an inhibitory T-cell co-receptor, with its ligand, B7-H1 (PD- L1) on tumor cells
- 30. T- lymphocyte antigen4 antibody(CTLA 4)
- 31. Ipilimumab ( CTLA4antibody)
- 32. Anti programmed death1 antibodies (PD-1)antibodies
- 34. Mechanism of actionof anti – PD1
- 36. NOW IS 2015 EMERGING APROACH Asortof permution and combinations
- 38. Participating investigators randomlyassigned patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m every 3 weeks or paclitaxel 175 mg/m combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects
- 40.