Here is a series of three related papers published by researchers at Johns Hopkins University, led by legendary cancer researcher Bert Vogelstein. It is a significant body of work that is difficult to succinctly summarize, but the linked write-up is a start.
Engineering the immune system to attack tumor cells (immunotherapy) is so effective that it has revolutionized clinical cancer research, but the strategy is limited by the fact that the immune system has a very difficult time “seeing” mutant proteins located in the interior of the cell. Ras and p53 are the two most important genes in all of cancer, albeit for different reasons (Ras promotes tumor development and p53 inhibits tumor development). Both are highly mutated in diverse types of cancer, and both proteins are difficult to target therapeutically, in part because they are located in the interior of the cell where they are hidden from both the immune system and drugs that cannot cross the plasma membrane.
However, these researchers discovered that fragments of mutant p53 and mutant Ras were in fact exposed on the surface of tumor cells, but at very low abundance. Next, the researchers helped the immune system “see” these mutant protein fragments, and then coaxed them to attack the tumor cells using drugs known as bispecific antibodies. In addition to developing a new strategy to attack tumor cells with mutant p53 and/or mutant Ras proteins, this work opens up a new frontier in clinical cancer research because other mutant intracellular proteins may be targeted in a similar manner. Bert Vogelstein Papers
