Cancers are known to “hijack” certain cellular pathways, such as developmental programs or cell death mechanisms to hide from the body’s immune system and continue their unregulated growth. Dr. Behnam Nabet, a new faculty member in the Human Biology Division, thought he might be able to tackle cancer by beating it with its own tricks. To do this, he wondered if he could “hijack the cell’s garbage disposal machinery” to trick cancer cells into degrading the oncogenic proteins that made them cancer cells to begin with, Dr. Nabet explains. Devising strategies to achieve this creative tactic of degrading cancer-driving proteins to combat cancer is one major goal of the Nabet Lab.
After a postdoctoral position at Dana-Farber Cancer Institute and Harvard Medical School, Dr. Nabet joined the Hutch in September of 2021. While Nabet states that setting up his lab was indeed challenging, especially with the ongoing COVID-driven supply chain issues, he was grateful for the help and support from other Hutch faculty members. Sharing a tissue culture room with Dr. Lucas Sullivan and starting joint lab meetings with Dr. Alice Berger were just a few ways the other Human Biology faculty aided in getting the Nabet Lab up and running quickly. This type of support from his colleagues is one of the many reasons that he decided to start his lab at the Hutch. In fact, the first paper from the Nabet Lab was recently published in the European Journal of Medicinal Chemistry. In this publication, the authors took a medicinal chemistry approach to identify an inhibitor for cyclin-dependent kinase 11 (CDK11), an understudied protein with important roles in cell cycle regulation, neuronal function and cell death. Advancing this inhibitor and studying the functions of this understudied protein is just a taste of what is to come from the Nabet Lab.
As a chemical biology lab, the Nabet Lab develops innovative chemical approaches “to answer basic biological questions while also pushing forward their translational potential as new strategies to target different cancer drivers,” Nabet notes. Nabet is focused on developing proximity-based therapeutics that redirect the cell’s own processes for controlling protein levels and activity. For example, they use small molecule protein degraders to destroy cancer-causing proteins. One such class of these protein degraders are known as Proteolysis-Targeting Chimeras (PROTACs). PROTACs are bifunctional molecules that recruit a protein, such as a cancer-driving protein with one end, while the other end recruits the cell’s own garbage disposal machinery to degrade the targeted protein. Remarkably, protein degradation occurs rapidly, in as little as 15-20 minutes. PROTACs have immense translational potential and are already advancing in the clinic for several diseases including cancer. However, Nabet admits that one major limitation to this approach is that it “leverages already available molecules [or chemical tools] that bind or inhibit a protein.” The good news is that many molecules that target potential cancer-drivers already exist and can be used for this approach, but what about novel cancer-drivers that are still being discovered or targets that currently do not have an available targeting molecule? In those cases, new molecules must be discovered or developed, which is feasible but requires significant time and financial investment. For this reason, another wing of the Nabet Lab is focused on tackling this problem. Specifically, Nabet has developed a chemical-genetic technology with similar functionality to PROTACs called the degradation tag (dTAG) system. In this approach, a protein is fused to a universal tag. dTAG molecules bind to this universal tag instead of the protein directly, while also recruiting the cell’s garbage disposal machinery to degrade the tagged protein. This critical tool allows researchers to test whether targeting and degrading any protein of interest is beneficial, before spending the time and energy to develop a molecule to target that protein. The Nabet Lab has been working closely with collaborators to apply this technology to understand functions of several novel drug targets. This team science approach has led to recent ground-breaking publications defining roles of new drug targets in Molecular Cell, Cancer Discovery, Genes & Development and Cell Chemical Biology.
Nabet anticipates that using tools such as dTAG and PROTACs, in addition to developing new technologies to control protein activity, will allow his group to “address biological questions that have been challenging to answer.” He ultimately seeks to find creative approaches for “very difficult to treat cancers, such as pancreatic cancer which lack effective therapies.” He hopes that his science and new technologies will “set precedent for new fields and necessary proof-of-concept for clinical applications.” Importantly, Nabet explains that “as soon as possible, with a team science mentality (one that includes academia and biotech), we aim to push these molecules forward to have an immediate impact in the clinic. The Hutch provides us with the perfect opportunity to join forces with incredible labs, clinicians, and biotech.” Nabet has made headway in creating this team science-driven quest for getting these protein degradation-based therapies from lab to clinic as he has ongoing collaborations with biotech companies and is setting up additional partnerships with the help of the Business Development & Strategy group at Fred Hutch. Nabet also has an open-science mission to make his technologies freely available to researchers worldwide to advance these goals. He has already supported hundreds of labs for applications of the dTAG system and plans to continue this approach with new technologies that his lab develops.
While debating running a lab in academia or biotech, Nabet states that he has “always had a curiosity for science” in addition to a unique “appreciation for academia”. Nabet explains that his parents emigrated from Iran to the US for his father to pursue higher education and a research career. Nabet’s father, now a professor at Drexel University, was pursuing his PhD at the University of Washington in electrical engineering when Nabet was born in Seattle. As such, Nabet grew up in an academic culture. He explains that he watched his parents’ “ongoing commitment towards my father’s education and goals,” while also being “exposed to my father’s commitment to teaching and mentoring. People were always over for events like dissertation defenses, and we spent summers abroad, while my father worked with his collaborators in their labs. His lab and collaborators were like an extended family. Having that exposure early on was certainly a privilege and drew me to the goal of having my own highly collaborative and supportive lab.” Being surrounded by science from a young age, Nabet became “attracted to the complexities of disease and wanting to make an impact in cancers with limited therapies,” which led him on his path towards having his own lab at Fred Hutch. Now, Nabet is back in Seattle with his wife and young son forming a bit of a full circle moment by recreating a similar upbringing for his own son. Nabet describes that when he was young, he would get to visit his father’s office and lab, and now his two-year-old son runs across the courtyard at the Hutch and even knows the way to Nabet’s office. Outside of research, Nabet has been enjoying being back in Seattle, which he says, “has always felt like home” and taking advantage of the outdoor activities including hiking and embracing “my son’s current fascination with all things water, including waterfalls.” He describes Seattle and the Hutch as being scientific and natural paradises. Nabet is looking forward to raising a family here and making impactful scientific discoveries- moving his targeted protein degradation strategies from the lab into the clinic.
If you’re interested in learning more about Dr. Behnam Nabet and his lab, or interested in joining his team, please see more information below.
Recent publications from the Nabet Lab:
Li Z, Ishida R, Liu Y, Wang J, Li Y, Gao Y, Jiang J, Che J, Sheltzer JM, Robers MB, Zhang T, Westover KD, Nabet B#,Gray NS#. Synthesis and Structure–Activity Relationships of Cyclin-Dependent Kinase 11 Inhibitors Based on a Diaminothiazole Scaffold. European Journal of Medicinal Chemistry. 2022 Aug 5;238:114433. (#Co-Corresponding Author)
Ellegast JM, Alexe G, Hamze A, Lin S, Uckelmann HJ, Rauch PJ, Pimkin M, Ross LS, Dharia NV, Robichaud AL, Saur Conway A, Khalid D, Perry JA, Wunderlich M, Benajiba L, Pikman Y, Nabet B, Gray NS, Orkin SH, Stegmaier K. Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts. Cancer Discovery. 2022 Jul 6;12(7):1760-1781.
Olsen SN, Godfrey L, Healy JP, Choi YA, Kay Y, Hatton C, Perner F, Haarer EL, Nabet B, Yuan GC, Armstrong SA. MLL::AF9 degradation induces rapid changes in transcriptional elongation and subsequent loss of an active chromatin landscape. Molecular Cell. 2022. Mar 17;82(6):1140-1155.e11.
Dr. Nabet’s full bibliography: https://pubmed.ncbi.nlm.nih.gov/?term=behnam+nabet&sort=date
Nabet Lab Website: https://research.fredhutch.org/nabet/en.html
The Nabet Lab is supported by funding from the National Cancer Institute, National Center for Advancing Translational Sciences, American Association for Cancer Research, Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium, and Fred Hutchinson Cancer Center.