G proteins and GPCRs in cancer

Published on November 28, 2019   35 min

Other Talks in the Series: G Protein-Coupled Receptors (GPCRs) Signaling in Health and Disease

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Hi. I'm Silvio Gutkind. I'm professor in the Department of Pharmacology and I'm also the Associate Director of Basic Science at the University of California in the Moores Cancer Center. So the topic of today is G-proteins and G-Protein Coupled Receptors called GPCRs in Cancer.
So G-proteins and G-protein Coupled Receptors are very familiar to everybody involved in drug discovery. So these receptors are the largest family of cell surface molecules involved in signal transmissions, and are the target of more than 30 percent of all drugs in the market, and that includes around 50 percent of the top 200 drugs currently being sold. However, when it comes to cancer with around 14 million new cases of cancer every year resulting in roughly eight million deaths each year worldwide and associated treatment cost of $147 billion, GPCRs are not really very well investigated in the case of cancer. So what I will try to explain today is that GPCR are dysregulated but underexploited particularly in cancer in this new era of precision medicine in immune oncology. What I will try to cover today is very specific areas in G-proteins in GPCRs in cancer, an overview of that topic, and then some new opportunities and there will be a brief discussion of that of targeting GPCRs in this new area of cancer immunotherapies.
So G-Protein Coupled Receptors in cancer has been known for quite some time. So the reality, the first study was published in 1986 in the, should I say old days in which you can take tumors, grind them, isolate DNA, transfer into fibroblasts, and you can isolate oncogenes based on the ability to form what we call foci so the cells pile up one on top of each other, and we can isolate the DNA's in cloned the genes causing transformation. Those genes or oncogenes are usually those were highly represented for example, ras, tyrosine kinases, and so on so forth. So many of these typical oncogenes that we know are quite important in cancer. One of them in the wigglier slab encoded a G-Protein Coupled Receptors. So basically, the sequence revealed that it was likely to encode a G-Protein Coupled Receptor. However, something very interesting is that most of the ones I prefer to for example Ras as a typical oncogene in many cancers, pancreatic cancer, colon cancer and so on and so forth, the majority of these oncogenes have mutations. So it's very easy to grasp the mutations in these molecules may lead to aberrant proliferation in cancer. In the case of the Mas oncogene however, there were no mutations in the coding sequence which to some extent suggested that other the expression itself can cause cancer or we really didn't have at that time a real perspective of how they came about. So in our words, should I say embraced by the community as a very prominent oncogene, and to some extent that may have been neglected for quite some time.