What is BRAF, RAS (K RAS, N RAS)?

[Music] what is b raf raz such as k razzin and raz can these genes be mutated are there other mutated genes associated with myeloma and how are gene mutations determined individual genes may have just a single code change a mutation that is a single change in a gene that can now cause that gene to function differently now you'll notice that in this slide i'm showing how common some of these are and look at the top of the list is what's called k ras and nras through research and understanding and testing what these genes do we now understand that the ras genes signal cells to divide and proliferate and it's a normal gene in the normal genome but in myelomas oftentimes that gene is mutated and it's mutated so that that gene functions at a higher level functioning at a higher level means it's signaling that cell to divide and proliferate at a higher level that's what tumor cells do that's what we don't want them to do so there are a couple useful pieces of information here one is we start understanding which genes contribute to the myeloma trait of its proliferation or maybe its migration to the marrow but it also gives us another useful piece of information if i can block that k-ras gene and stop it from overacting i might have an effective therapy so in fact a lot of research at academic institutions and at pharma companies are trying to develop drugs that will specifically target the genes that are mutated in myeloma so that the drug will stop that gene from functioning and so there's a lot of research being done you'll see a gene there called b raf there's actually good therapy drug for the treatment of tumors that have braf mutations so this is also giving us information based on the genetic mutations as to how aggressive the disease might be and what their what effective therapeutics there might be or what targets we should be testing to try to treat this disease that's all research being done at the background of genetic information a lot of what we've talked about has been you know whole chromosome or changes in expression but there are some mutations which don't change the expression of a gene but they change how it functions and the the most famous ones would be k-ras n-ras b-raf and some patients in fact with fgf receptor 3 they'll get a single nucleotide a single amino acid gets changed in that protein and it activates it so that the the gene is like constantly on constantly signaling and it's constantly signaling growth and so it's like putting your foot on the accelerator and it's telling it's giving a signal to the cell that it should divide there's a lot of other cancers we can there are targeted therapies which inhibit these activated proteins called kinase inhibitors and so far there don't seem to be any that are working particularly well in multiple myeloma but it has been a hope that we would find some targeted therapy that would be active against these mutations how would i know if i have one of these gene mutations the only way that you'd find out if you've got a point mutation in almost any any gene in multiple myeloma like k rasa and ras or b raf or p53 would be if you had sequencing done it typically would be next generation sequencing and you would would want to include a variety of genes because you know most the the only a few genes are commonly mutated so nras and k-ras that would be about 20 each but then the other genes are you know 10 or less and so you really need to sequence a lot of genes in order to identify which ones might be mutant in a given individual what is precision medicine and what that means is to take drugs which are active maybe in other cancers against a given mutation and apply them to multiple myeloma patients that share the same mutation those studies are very difficult to do because any given mutation tends to be quite uncommon but they they are being done one study that that's going on nationwide is called my drug from the multiple myeloma research consortium there's a study from the national cancer institute called paper t-a-p-u-r um and these these are very large studies which have brought together a number of different drugs and the patients has their tumor sequenced and then the drug which matches that patient's mutation is used in the clinical trial um but i would say to date the the uh that was that approach um has shown a lot of hurdles a lot of the difficulty in getting it done and it hasn't had a lot of successes uh in multiple myeloma and so i think we really need to um you know we need to do more studies before we can see that's ready for prime time if a myeloma patient has a braf mutation can they be treated with a braf inhibitor that is used in another cancer there's some data from a few case studies where the patient has a transient response but the issue is that the patient who's got a b raft mutation typically that's in a subclone and there's another subclone that doesn't have a b raft mutation and so when you treat with the inhibitor you just allow the other subclone to [Music] grow