My Cancer Journey: Perseverance Through Adversity
By: Zachary Blatman
Supervisor: Dr. Aaron Schimmer
In Summer 2018, I received the immense privilege of participating in the Institute of Medical Science’s Summer Undergraduate Research Program under the supervision of Dr. Aaron Schimmer, a senior scientist at Princess Margaret Cancer Centre. As a childhood leukemia survivor, I was particularly looking forward to conducting leukemia research, as it would provide me with the meaningful opportunity to give back to my dedicated care team and pave the way for future advances in this field.
Despite recent improvements in the treatment of certain hematologic malignancies, the pharmacological approach for most patients with acute myeloid leukemia (AML) has remained relatively constant for over 25 years.1 Thus, new treatment strategies for this disease are needed.
Our team studies the ubiquitin-proteasome system, the main mechanism responsible for maintaining homeostasis in cells through degrading excess and misfolded proteins. Proteins destined for degradation are tagged by multiple ubiquitin molecules, which serve as markers for degradation by the proteasome.2 Our lab previously determined that the initiating enzyme in this pathway, ubiquitin-like modifier-activating enzyme 1 (UBA1), is more actively utilized in AML.3 Hence, selectively targeting UBA1 may serve as a novel therapeutic strategy.
Our team recently demonstrated that targeting UBA1 with the small-molecule inhibitor TAK-243 induced strong anti-leukemic effects in cell-based and animal models of AML.4 Subsequently, we conducted a CRISPR screen for genes whose knockout renders AML cells resistant to TAK-243. The top hit from the screen was BEND3, a transcriptional repressor that regulates chromatin accessibility. To validate these results, we knocked out BEND3 and confirmed resistance to TAK-243 by growth and viability assays.
My summer project focuses on determining the mechanism by which BEND3 knockout induces resistance to TAK-243 in AML. This is exciting because I get to act like a cancer detective every day – trying to solve the mystery behind BEND3’s mechanistic activity, one piece of experimental evidence at a time!
I wish my wet lab experience went off without a hitch, and that I achieved my idealistic aspiration of discovering a cure for cancer. However, I struggled initially to master the new experimental techniques – whether it was almost breaking my research facility’s western blot film developer or nearly killing my cells every week. I remained perseverant through adversity by reminding myself why I started this cancer research journey in the first place.
I communicated my discomforts and concerns with my supervisor. With his patience and unwavering support, I conquered this steep learning curve by developing personal learning goals as well as actively seeking feedback from fellow students and senior staff members. By August, I gained expertise in experimental methodology, demonstrating that BEND3 knockout reduces markers of cellular apoptosis and endoplasmic reticulum stress. In the future, physicians can utilize BEND3 expression levels as a potential biomarker to predict AML patients’ response to TAK-243 treatment. This experience demonstrated to me the importance of perseverance and determination when overcoming difficult situations. As well, it strengthened my passion for research and medicine to continue improving the lives of individuals with cancer.
- Škrtić M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z, Hurren R, Jitkova Y, Gronda M, Maclean N, Lai CK. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell. 2011;20(5):674-88. Available from: doi: 10.1016/j.ccr.2011.10.015
- Nandi D, Tahiliani P, Kumar A, Chandu D. The ubiquitin-proteasome system. J Biosci. 2006;31(1):137-55. Available from: doi: 10.1007/BF02705243
- Xu GW, Ali M, Wood TE, Wong D, Maclean N, Wang X, Gronda M, Skrtic M, Li X, Hurren R, Mao X. The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma. Blood. 2010:blood-2009. Available from: doi: 10.1182/blood-2009-07-231191
- Barghout SH, Patel PS, Wang X, Xu GW, Kavanagh S, Halgas O, Zarabi SF, Gronda M, Hurren R, Jeyaraju DV, MacLean N. Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia. Leukemia. 2018:1. Available from: doi: 10.1038/s41375-018-0167-0