A chance discovery in protein dynamics could offer new pathways for the treatment of cancer, suggests research from KAUST. This research finding will benefit from the connections provided by KAUST Smart Health Initiative, a project which links researchers directly with practitioners.
Targeted cancer therapy works by identifying proteins whose overproduction and overactivity causes the uncontrolled cell proliferation that defines the disease. Once such a protein is found, its role in the imbalance needs to be elucidated. Researchers will then try to find smaller molecules, known as ligands, that can selectively bind to and inhibit it.
Computer modeling of the static structure of proteins has been the preferred tool for determining whether they have the “ligandability” needed to target them. However, as bioscientist Łukasz Jaremko has shown, relying on this method can miss a great deal.
With a background in physics, Jaremko uses atomic-level insight to delve deeply into sticking points in medicine to find novel solutions. He has been using NMR to look at some proteins, whose similar structures and flat surfaces should have made them uniformly impermeable to ligands. What he found, in fact, was that one of them was “dancing” in a very interesting way.
“On a molecular timescale, a socket was opening and closing on the protein’s surface, revealing an ideal space for ligands to slot into,” he says. “Simply looking at its 3D structure had not been enough. I realized that in future, understanding the 4D aspect — how proteins moved through time — was going to be just as important.”
“I realized that in future, understanding the 4D aspect — how proteins moved through time — was going to be just as important.”
Some proteins have been identified as potentially useful for targeted therapies. For example, MIZ1 is one such protein that has been found to regulate a very important oncogene known as CMYC. This oncogene plays a central role in 80 percent of cancers, but targeting it directly has been deemed impossible so far.
Not only has MIZ1 offered an indirect means of attacking CMYC, but the protein has also been shown to be highly ligandable. So far Jaremko has discovered more than 100 molecules that will bind to it, giving it “huge therapeutic potential.” By developing some of them, the professor’s team has already reduced the laboratory growth rate of small cell lung cancer tumors by 80 percent.
From bench to bed
With his research still at an academic and preclinical phase, it is an ideal time to partner with medical practitioners. “We understand the mechanisms and we have something that works,” he says. “But we also need cancer cell lines and existing cases. We need clinical data from large cohorts of patients.” However, KAUST has no medical school or teaching hospital attached to it.
The KAUST Smart Health Initiative, which aims to enhance Saudi Arabia’s capabilities in precision medicine, brings together all of these. Firstly, through additional funding, but more importantly, the government program has connected Jaremko to the cancer departments of both the King Faisal Specialist Hospital and Research Centre in Riyadh and the Medical School of Taibah University in Medina.
Jaremko is now working with their specialists to find the best ligands for treating lung and breast cancer, which are the two most common forms of the disease in Saudi Arabia. Once the potency is optimized, clinical trials can begin.
“The KAUST Smart Health Initiative gives a vital opportunity to link results with real patients in hospitals,” says Jaremko. “Most of the doctors I’ve met through this initiative are young and really want to achieve something in their careers. It’s good to see they are as excited about this as I am.”