Cancer cells almost always defeat drug therapies. Will we ever prevent or overcome drug resistance? I am your host, Dr. Bruce Bloom, and joining us to discuss modeling cancer therapy on an HIV combination therapy model is Dr. Jeffrey Settleman, Director of Center for Molecular Therapeutics and Professor Of Medicine at both Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston.
DR. BRUCE BLOOM:
Dr. Settleman, welcome to ReachMD.
DR. JEFFREY SETTLEMAN:
Good to be here.
DR. BRUCE BLOOM:
DR. JEFFREY SETTLEMAN:
DR. BRUCE BLOOM:
Do the genomics of cancer vary either within a patient?
DR. JEFFREY SETTLEMAN:
DR. BRUCE BLOOM:
DR. JEFFREY SETTLEMAN:
DR. BRUCE BLOOM:
When we talk about cancer cells creating resistance, do they actively do this, in other words; do we think of them as sort of smart cells that are trying to overcome this or is this just a random process that happens because they are so many cells in the body, some of them are likely to be resistant.
DR. JEFFREY SETTLEMAN:
Ya as far as anyone can tell, we think this is really not a purposeful activity of the cancer cell, but rather its an accident of the kind of genetic variation that we all experience and one of the great forces of nature of course being natural selection accounted for and large part by the spontaneous changes in our genome that can contribute to diversity and in the case of a cancer cell, it can lead to drug resistance. So it seems to be just an accident of nature and given the large numbers of tumor cells involved in a typical cancer, there are certainly more than enough opportunity for cells to find what seem like clever ways around the problem of an effective drug.
Dr. BLOOM, DDS:
So what remains to be learned about drug resistance and how are we going to learn that?
DR. JEFFREY SETTLEMAN:
Well, its clear that we have to figure out whether mutations explain some, most, or all of drug resistance, there is an emerging notion that epigenetics or non-mutational mechanisms that relate to the genome, might be playing a role and to learn more about these things, I think its going to be important to dig deeper into the genomic analysis of a large number of clinical specimens, some of that is challenged by the fact that there are fewer and fewer autopsies being performed on cancer patients since we do not have access to material that has tumors essentially that have grown through drug and have experienced resistant mechanisms that we can study. One of the approaches we can use to learn about how cancer cells could overcome effective drugs is to model this in vitro and this is something we are very interested in, that is we take cell lines to arrive from tumors, from human tumors, we grow them in culture, we find drugs that are very effective against these cells, and then we simply keep these cells growing in the presence of drug until most of the cells are killed off, but a few remaining cells, resistant cells, eventually emerge and then by studying those resistant cells, we can learn something about mechanisms that seem to be relevant to humans.
DR. BRUCE BLOOM:
And when you do that in vitro testing, if you give massive amount of drugs right at the beginning do all the cancer cells die?
DR. JEFFREY SETTLEMAN:
DR. BRUCE BLOOM:
So how is drug resistance currently managed?
DR. JEFFREY SETTLEMAN: