Targeting STAT5 oligomerization in leukemia
Led by Anna Orlova, PhD
Cancer is a prevalent disease with high mortality. Progress in therapy towards prolonged survival and life quality of the patients has been made . However, due to the common drug resistance development and severe side effects, it is crucial to develop novel targeted anti-cancer therapies that are safer and more efficient. The most common reasons for the severe side effects of cancer therapeutics are that they are either untargeted, such as chemotherapy, or that the targeted therapy is not specific for cancerous cells but hits many healthy essential cell types as well.
Previous work has shown that oligomerization of oncogenic STAT5 transcription factors occurs in leukemic cells but not in healthy cell types. Furthermore, genetic approaches validated the efficacy of blocking STAT5 oligomerization as a vulnerable node to normalize excessive oncogene transcription.
Our objective, therefore, is to target this cancer-specific oligomerization and design novel therapeutics for the treatment of hematopoietic cancers with acute myeloid leukemia (AML) as primary indication.
For the identification of efficacious small molecule inhibitors, we developed a unique phenotypic screening system. With this innovative system, we have recently identified several hits from different chemotypes that show direct interaction with STAT5 and revealed promising potency. With the support of the FFG Spin-off Fellowship, we aim at further biological validation of the therapeutic concept and the generation of highly resolved target/ligand 3D structure. This would eventually enable us to pursue a sound structure-based lead compound development program in the prospective spin-off company and generate a lean portfolio of composition of matter patents around the most promising compounds generated. The ultimate beneficiary of our product is the patient suffering from leukemia or other types of cancer who is being provided with a safe and efficacious novel targeted therapy.
Dr. Anna Orlova is an early career researcher who joined the research team of Richard Moriggl in 2016 as a PhD student, funded through the FFG project entitled “STAT3/5 inhibitors”. She graduated with her doctorate degree in 2019 with distinction. Anna has strong expertise in molecular biology, biochemistry, drug targeting, and mouse model analyses. Previous to her PhD studies, Anna completed her MSc in molecular biology and molecular medicine at the University of Vienna, and her BSc in biology and biochemistry at the Taras Shevchenko National University of Kyiv, Ukraine. Her solid background in biochemistry and molecular biology and a keen interest in applied and translational studies prompted Anna to explore drug development for targeting of leukemia.
Dr. Orlova is currently supported by FFG Spin-off Fellowship, which enabled her to establish her own group within the Moriggl lab as a part of the entrepreneurial Vetmeduni.
- American Association for Cancer Research (AACR)
- Austrian Association of Molecular Life Sciences and Biotechnology (ÖGMBT)