Why is myeloma hard to treat? What is meant by a signaling pathway?

[Music] why is myeloma hard to treat and what is meant by a signaling pathway so why is it hard to treat well it's a heterogeneous disease not all myelomas are the same they are tumor cells they grow uncontrolled many cases they proliferate when you kind of wish they didn't they go places you don't want them to go they go to the bone marrow and they often interfere with normal functions so all of those are events that are deregulations of normal cells to become these tumor cells and the fact is we know a lot more about the biology to understand that not every myeloma got there by the same path i often talk to groups and talk about how i can get from minneapolis to chicago there are a lot of roads that will get me from minneapolis to chicago i will get to chicago but i can take a lot of different routes to get there a lot of different paths to get there similarly myeloma gets to a point of proliferation and going to the bone marrow by a lot of different paths in different individuals and it's trying to understand those different paths that will give us a better understanding not just of the biology of myeloma but the unique biology of every individual's myeloma what is a signaling pathway so we've been talking about signaling pathways in multiple myeloma without using that word um when we talk about mutations of nras and k-ras and raf all those proteins they signal that means they typically take a signal that starts from the surface of the cell and eventually goes to the nucleus through a given set of other proteins and that's called a pathway and in that case the pathway is called the map kinase pathway there's another important pathway which is called the nf kappa b pathway um and that's frequently mutated uh in multiple myeloma and that pathway starts from bcma which is on the surface of myeloma cells and we're using it as a target for therapy now but that signals down from the surface to the nucleus through a pathway called nf kappa b and there's a number of mutations that basically can substitute for the presence of nf kappa b for bcma on the surface of the cell to signal to nf kappa b down on the nucleus it doesn't typically go you know straight the signal doesn't go straight from the surface to the nucleus it goes through a number of other proteins to get from the top down to the bottom and any one of those proteins in the pathway can be affected by mutations what are pd-1 and pdl-1 pd1 and pdl-1 are markers in the surface of the cells that signal to each other so that's that's a different kind of it's not signaling from outside to in it's signaling from outside of one cell to outside of another cell those are called checkpoint inhibitors because those signals check the activity of t cells and so if a tumor expresses pd1 the pd the the receptor for that signal is called pdl1 is on the surface of immune cells it it tells them you know don't bother with me i'm i'm not i'm not bad and don't try and kill me and by interfering with those signals there's been a lot of success in the treatment of solid tumors and lymphoma but it has not been very active in multiple myeloma so far what is nyc or mick mick is called the universal amplifier it's a one of the oldest known oncogenes and its function is to amplify whatever a cell is doing and often in a cancer cell that means proliferation um i think in myeloma it amplifies you know other things as well um such as the ability to to make uh and secrete a lot of antibody um but it's really a it's it's a fundamental um gene in in all of cell biology and all of cancer biology unfortunately it's it's not a gene that we can typically um target with a drug because it's located down in the nucleus it's it's not an enzyme like the kinases and so um i think we can however maybe turn off the signals that turn mick on and one of the ways we do that is with drugs like revlimid which inhibit a gene called icarus and icarus is a critical component that turns on mick in myeloma patients that have got [Music] abnormalities that make