Dr. Hirbe's Mission
In the Hirbe Lab we are focused on using omic data (genomic, proteomic, and metabolomic) to help patients at risk for developing bone and soft tissue sarcomas through early cancer detection as well as to identify better therapeutic options for those patients suffering from bone and soft tissue sarcomas.
With many collaborators, both within Washington University in St. Louis and around the country, we leverage omic data from patient samples and use this information to target approaches for molecular manipulation in preclinical models of sarcoma. Our goal is to understand the underlying biology with the hope of discovering therapeutic targets to improve patient survival.
Dr. Hirbe's Research
As a practicing medical oncologist who treats sarcoma, my research focuses on utilization of omic information from sarcomas to better understand the pathogenesis of these tumors and to identify biomarkers and therapeutic targets for these aggressive cancers.
After completing my undergraduate degree, I entered into the MD/PhD program at Washington University School of Medicine. My graduate research was performed in the laboratory of Dr. Katherine Weilbaecher, where I focused on understanding the role of a chemokine receptor, CXCR4, in osteoclast biology and bone metastasis.
I then joined the Physician Scientist Training Program at Washington University and completed residency and fellowship training in Internal Medicine and Oncology. During fellowship, I chose the Sarcoma Program as my continuity clinic during my post-doctoral years of fellowship (years 2-4) and trained clinically with Dr. Brian Van Tine. For my post-doctoral research, I worked in the laboratory of Dr. David Gutmann to study the molecular mechanisms of transformation and metastasis in Neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs), the type of sarcoma that I first studied as a teenager when I was accepted into a research program when I was in high school.
In 2016, I launched my independent research career. The focus of my laboratory is to utilize omic information from human sarcoma samples to better understand the development and progression of these tumors to aid in early cancer detection as well as improved therapeutics. I mentor a dedicated and busy group of students, post-doctoral fellows and research staff.
In the clinical setting, I care for patients with sarcomas as well as patients with genetic predisposition syndromes that put them at risk for developing sarcomas. My primary clinical interests are in the management and treatment of patients with Neurofibromatosis Type 1, Li Fraumeni Syndrome, Adolescent Young Adult sarcoma patients, MPNSTs and precursor plexiform neurofibromas, bone tumors, and desmoid fibromatosis.
In Loving Memory
Brian Andrew Van Tine, M.D., Ph.D. was a Professor of Medicine and Pediatrics at Washington University in St Louis, Missouri, where he was the Sarcoma Program Director at the Alvin J. Siteman Cancer Center. Dr. Van Tine received his Bachelor of Science degree from the Departments of Chemistry and Biochemistry at The University of Arizona in 1995. Dr. Van Tine completed his M.D. and Ph.D. degrees at the University of Alabama at Birmingham in 2005. His thesis research mainly focused on the role of Human Papilloma Virus (HPV) in the development of cervical cancer with Profs. Louis T. Chow and Thomas R. Broker. After completing his M.D., Ph.D., Dr. Van Tine went to Washington University in St. Louis/Barnes Jewish Hospital where he did his Internal Medicine Residency and Medical Oncology Fellowship. Working to understand the intricate chemical reactions of molecules occurring in various types of cancerous tumors for therapeutic translation into new drugs and treatments is the overall goal of the Van Tine laboratory.
Dr. Van Tine's Research
Dr. Van Tine’s laboratory identified a common defect in sarcoma; the loss of ASS1 (argininosuccinate synthetase 1) gene expression. Cells require arginine, an amino acid, to survive. A normal copy of the ASS1 gene is required to make the enzyme argininosuccinate synthetase 1, which helps make arginine in cells. His team was the first to report that this gene was silenced in ~90% of sarcomas. Sarcoma cancer cells are vulnerable to death if they are deprived of arginine and glutaminase, since they can’t make their own arginine due to this genetic mutation. His team identified the changes that occur when arginine is depleted from ASS1-deficient cells using global metabolomics, which investigates all of the chemicals in a cell sample. This led to identification of the first dual metabolic therapy for sarcoma using an enzyme that breaks down arginine and a glutaminase inhibitor.
In addition, his team identified that arginine starvation could be used to increase the transport of the chemotherapy drug gemcitabine via transporter protein SLC7A11, a concept currently being tested in a Phase II clinical trial (NCT03449901). The clinical trials associated with this research will lead to new treatments, transforming the clinical care of patients with sarcoma.
In parallel, Van Tine’s team was the first to identify 3-phosphoglycerate dehydrogenase (PHGDH), an enzyme that helps make the important amino acid serine out of glucose, as a therapeutic target in osteosarcoma. Too much PHGDH in osteosarcoma correlates with poor survival. Inhibiting PHGDH slows or stops osteosarcoma cell reproduction, but this leads to the activation of the pro-survival mTor pathway. Combining PHGDH inhibitors with mTor pathway inhibitors to eliminate the cancer cells could be the first dual or triple metabolism-based combination therapy for osteosarcoma.
Finally, the team found that synovial sarcoma is missing a key protein, malic enzyme 1 (ME1), which forces synovial sarcoma tumors to rely on a different metabolic pathway. This makes it uniquely vulnerable to the inhibition of that alternate pathway. The drug ACXT-3102 interferes with this alternate route. The interference causes volatile waste to build up inside the cancer cells. When enough waste builds up inside, the cancer cells die.
Publications
https://pubmed.ncbi.nlm.nih.gov/?term=Hirbe+A
Sundby RT, Szymanski JJ, Pan AC, Jones PA, Mahmood SZ, Reid OH, Srihari D, Armstrong AE, Chamberlain S, Burgic S, Weekley K, Murray B, Patel S, Qaium F, Lucas AN, Fagan M, Dufek A, Meyer CF, Collins NB, Pratilas CA, Dombi E, Gross AM, Kim A, Chrisinger JSA, Dehner CA, Widemann BC, Hirbe AC, Chaudhuri AA, Shern JF.Clin Cancer Res. 2024 Oct 1;30(19):4363-4376. doi: 10.1158/1078-0432.CCR-24-0797.
Loss of Chromosome 3q Is a Prognostic Marker in Fusion-Negative Rhabdomyosarcoma.
Dehner CA, Bell RC, Cao Y, He K, Chrisinger JSA, Armstrong AE, Yohe M, Shern J, Hirbe AC.JCO Precis Oncol. 2023 Sep;7:e2300037. doi: 10.1200/PO.23.00037.
Chromosome 8 gain is associated with high-grade transformation in MPNST.
Dehner C, Moon CI, Zhang X, Zhou Z, Miller C, Xu H, Wan X, Yang K, Mashl J, Gosline SJ, Wang Y, Zhang X, Godec A, Jones PA, Dahiya S, Bhatia H, Primeau T, Li S, Pollard K, Rodriguez FJ, Ding L, Pratilas CA, Shern JF, Hirbe AC.JCI Insight. 2021 Mar 22;6(6):e146351. doi: 10.1172/jci.insight.146351.
Zhang X, Borcherding DC, Zhang M, Lyu Y, Wang G, He K, Oztosun G, Sachdeva I, Yang L, Yang K, Yuen A, DiBenedetto H, Tsai A, Huang A, Maxwell JP, Cottrell KM, Briggs KJ, Hirbe AC.Clin Cancer Res. 2025 Nov 14;31(22):4779-4789. doi: 10.1158/1078-0432.CCR-24-3610.
https://medicine.wustl.edu/news/some-sarcoma-patients-improve-with-t-cell-immunotherapy/