The importance and magnitude of your work in the lab is never as profound as when the disease you study strikes your family.
As a scientist, dissemination of our research findings among our peers and members of the wider community is an essential aspect of our job, and thus we spend quite a bit of time attending seminars and conferences. And while in the latter half of the 20th century and certainly in the last 20 years many previously incurable cancers now have vastly improved outcomes, there are some, such as the blood cancer acute myeloid leukaemia (or AML, which is my area of expertise) that have not seen marked improvements for decades. Inevitably, in many of these seminars, the opening slide usually contains a variation of the phrase “Cancer XYZ is a devastating disease, characterised by poor prognosis and long-term survival”. You are always cognisant of the fact that the disease you study is all these things, but seeing it manifest in person, and in a family member no less, brings added perspective. In 2017, the year I started my PhD, my uncle was diagnosed with AML. Being a close-knit family, I was able to witness the toll intense chemotherapy took on him; the jubilation of his first remission; and the devastation of his inevitable relapse. AML is an insidious creature in that practically every patient relapses – and relapsed and refractory disease is largely resistant to further chemotherapy. Unfortunately, despite several novel drugs having come to market in recent years, many of these work only in certain contexts and most patients end up on a clinical trial as there just aren’t any second options. Sadly, my uncle eventually succumbed to his disease. But one thing I will never forget is the fact that each of the drugs he was treated with during his clinical trials had close relationships with several of the cancer hospitals in Melbourne; either the clinical trials were hosted from that hospital, or significant basic science was performed that enabled greater understanding of how these therapies worked. The short of it is – basic bench to patient bedside science is pivotal – and the work you do in the lab has the potential to make real, measurable improvements in patient’s lives and their cancer experience.
The primary focus of the work during my PhD was to deeply examine and understand what biological effects mutations in a gene called FLT3 had on AML cells (FLT3 mutations are among the most common in AML). What I discovered was evidence of a metabolic “switch” in leukaemia cells that carried this mutation. When FLT3 was mutated in AML cells, they shuttled a greater proportion of glucose, the primary energy source of the cell, down a pathway that generated an amino acid (or metabolite) called serine (1). It turns out that serine is essential for many biological functions that allow cancer cells to rapidly divide, such as nucleotide (or DNA) synthesis. Usually, cells are able to address amino acid requirements by bringing it in externally from the blood or extracellular space – but having the capacity to generate more serine endogenously makes the process of cell proliferation much easier. Indeed, we’ve known for a long time that FLT3 mutations result in highly aggressive leukaemias – my findings may be one potential mechanistic explanation as to why. While we had some ideas on the broader implications of these findings clinically, as is often the case, your lab findings may shed light on old clinical observations after the fact. We’ve recently seen some evidence arise that suggests my findings could help explain why FLT3 mutant leukaemias have a greater tendency to infiltrate the central nervous system (or CNS) (2). It turns out that cerebrospinal fluid, which cushions the brain and spinal cord, has very low levels of serine (3). Because FLT3 mutant AML cells are able to generate serine endogenously, they would have much less reliance on external serine in the cerebrospinal fluid, and thus would hypothetically be able to better survive in this otherwise inhospitable environment. Whilst we still have some work to do to prove this, this is tantalising evidence that work I have performed in the lab may shed some light on why this subset of disease behaves in a certain way in real patients.
After finishing my PhD, I started a Postdoc position under the supervision of Dr Kristin Brown and Prof Ricky Johnstone in the Cancer Biology and Therapeutics Program at the Peter Mac (both were instrumental in the work I did in my PhD). The idea of metabolic reprogramming in cancer has stuck with me. I find it fascinating that a cell might re-tune its intrinsic metabolism to address a certain metabolite deficiency, while concurrently becoming absolutely reliant on another pathway that can then be therapeutically exploited. As I work towards developing my own independent research interests, this is an area I’m actively hoping to investigate. Some of the oldest chemotherapy regimens block cellular metabolic pathways, and I hope to one day discover a new modality which we can then translate to the clinic – thus giving hope as a “second option” to patients suffering from these terrible diseases.
Figure Legend: Simplified representation of mutant FLT3-induced reprogramming of serine metabolism. FLT3 drives de novo serine metabolism via the mTORC1/ATF4 pathway; one biological consequence of increased serine metabolism is enhanced nucleotide biosynthesis.
References
- Bjelosevic S, Gruber E, Newbold A, Shembrey C, Devlin JR, Hogg SJ, et al. Serine Biosynthesis Is a Metabolic Vulnerability in FLT3-ITD-Driven Acute Myeloid Leukemia. Cancer Discov. 2021 Jun;11(6):1582–99.
- Jabbour E, Guastad Daver N, Short NJ, Huang X, Chen H-C, Maiti A, et al. Factors associated with risk of central nervous system relapse in patients with non-core binding factor acute myeloid leukemia. Am J Hematol. 2017 Sep;92(9):924–8.
- Ngo B, Kim E, Osorio-Vasquez V, Doll S, Bustraan S, Liang RJ, et al. Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition. Cancer Discov. 2020 Jun;10(9):CD-19-1228.
Dr Stefan Bjelosevic is a Cancer Council Victoria (CCV) Postdoctoral Fellow working in the Brown and Johnstone Laboratories at the Peter MacCallum Cancer Centre. Stefan obtained his PhD in 2021 under the supervision of Prof Ricky Johnstone and Dr Gareth Gregory at the Peter MacCallum Cancer Centre and University of Melbourne. His current work attempts to identify metabolic reprogramming events in cancer cells that can be exploited for therapeutic gain. His PhD work was recently published in the top cancer journal Cancer Discovery, and he was the 2020 recipient of the VCCC Picchi Award for Excellence in Cancer Research. He serves as the Ambassador to Australia for the YoungEHA branch of the European Haematology Association (EHA).
Dr Bjelosevic can be contacted by:
Email: [email protected]
Twitter: @StefBPhD
ORCID: https://orcid.org/0000-0002-3012-9273
Linkedin: https://www.linkedin.com/in/stefanbjelosevic/
