Adrian Mariño-Enriquez, a surgical pathologist at Brigham and Women’s Hospital at Harvard Medical School, who works closely with his colleague and LRG Research Team Leader Jonathan Fletcher, took time out from his labwork to help explain the significance of a recently published study that will have a big impact on GIST research. Previous reports released by the LRG research team’s referred generally to the molecule that was the focus of this study (CDC37) and its potential as a target for future therapeutic treatments. Now we are able to discuss it in greater detail.
The study, “Genome-wide functional screening identifies CDC37 as a crucial HSP90-cofactor for KIT oncogenic expression in gastrointestinal stromal tumors,” was published in April in Oncogene and co-authored by Adrian, W-B Ou, G. Cowley, B Luo, AH Jonker, M. Mayeda, M. Okamoto, G. Eilers, JT Czaplinski, E. Sicinska, Y Wang, T. Taguchi, George Demetri, DE Root and Dr. Fletcher.
Adrian joined the lab four years ago and his mentor has been Dr. Fletcher.
Here are his answers to some of our questions:
What is the biology behind the study?
It’s important to keep in mind that CDC37 is linked to HSP90 biology. Here is how it works: GIST cells are very dependent on the oncogenic driver KIT. KIT is a very unstable protein. It’s an activated protein, actually very active, which keeps the cells proliferating but also needs a lot of help to do that function. Most of this help is provided by HSP90, which is what we call a protein chaperone. HSP90 is in the cell to support the functions of other proteins. The whole idea here is that HSP90 is helping KIT to accomplish its function. It allows for KIT to be active and keep transmitting signals. So researchers thought that going after HSP90 might be a nice way to target KIT. There was a clinical trial on HSP90 inhibitors, thinking that they’d be an effective way to get rid of the KIT onco-protein.
But HSP90 is like a super-nurse in the cell. It’s taking care of many proteins in tumor and normal cells. So targeting HSP90 turned out to be a little bit too toxic. When we target HSP90 we do get rid of KIT in GIST cells, but also of many other proteins that are necessary for other cells. Hopefully in the future we will be able to find a way to target HSP90 that’s a little more specific.
So where does CDC37 come to play? CDC37 is a partner of HSP90. It helps HSP90 to do its job with kinases. About 10% of the proteins that are taken care of by HSP90 are taken care of with CDC37. And CDC37 is more specific for some kinases. So we think this gives us a more specific target, a window to go for proteins that are more critical for the tumor cells. We would cause less toxicity with a CDC37-targeting strategy.
What is the significance of this for GIST patients?
All the progress in GIST treatment has been made through targeting KIT directly. We have imatinib, sunitinib and now regorafenib—three drugs that target KIT directly. We’ve been talking a lot in recent years about targeting KIT indirectly. We tried HSP90, and it didn’t work as we expected. But this CDC37 study indicates we are on the right track. We just have to get better at it. We can target KIT indirectly and it should work. The problem with targeting KIT directly is that the tumors come back with secondary mutations, one or multiple resistant mutations. KIT keeps evolving and the GIST cells adapt to the treatment.
[box style=”quote”]We think that if we can target KIT indirectly we could take care of all the different KIT-mutant oncoproteins. This can give us a way to destroy GIST independently of the mutations that keep developing. We think this could reduce the chance of the tumor to develop resistance in the long term.[/box]
After resistance emerges, this strategy could provide us with some better ways to treat the tumors. Targeting CDC37 may be a weapon that is useful across the board.
What is the next step?
What we have to find now is good compounds to get the job done. This was a conceptual paper, we found a good target, and now we need good drugs for it. Unfortunately, nobody has a good drug to target CDC37. So now we need to collaborate with chemists, biochemists and pharmacologists to find compounds to target CDC37.
Another aside to this study is that we shouldn’t give up on HSP90 inhibition, even if the initial clinical trial was a bit disappointing. Our results indicate that all the efforts that are put into HSP90 inhibition are worth it.
Was there new technology that made this study possible?
We’ve looked at many genes at once. This study uses a state-of-the-art technology consisting in a library of molecules that target 11,000 genes. It is what we call an unbiased screen, as we start the experiments without any preconceptions. We run the experiment, and just rank the genes according to their relative importance in GIST. CDC37 came out as the first, the most important one, when we checked which genes are essential specifically for the GIST cells. But there’s a lot more data coming from this study that we are still analyzing. This is the first paper, but we have datasets with hundreds and hundreds of genes that we are working on.
We performed this study with the Broad Institute, an institute of genomics established by M.I.T. and Harvard. We collaborate closely with a research group there, which are co-authors of this paper. They developed this technology and we applied it to our GIST models. The only way to do high-quality research is through collaboration. As you can see by the number of authors of this paper, finding new targets in cancer is truly a team effort.
We are very happy with the results of our studies and we have valuable datasets in hand that we keep working on. We’ll hopefully have more exciting advancements to share soon, stay tuned!
Click here to view an abstract of the paper.