Deciphering the Molecular Mechanisms of Cancer and Developing Precision Therapeutics

In my doctoral studies, I worked on two approaches to further advance our understanding of cancer development: identifying attractive pharmaceutical targets and taking initial steps toward developing new drugs. Acute myeloid leukemia (AML) is a hematological malignancy distinguished by the aberrant proliferation and accumulation of immature myeloid cells within the bone marrow. In this context, inflammation plays a pivotal role in advancing AML. However, overactivation can also induce cell death. IRF2BP2 is a chromatin regulator linked to AML pathogenesis, but its purpose is still being investigated. We demonstrated that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2 in AML, which is likewise involved in regulating inflammatory pathways. We showed that the ATF/JDP2 dimer recruits IRF2BP2 to chromatin, where IRF2BP2 repressed its gene-activating role. Loss of IRF2BP2 triggered overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our investigation revealed that a fine-tuned balance between activating and repressive transcriptional mechanisms contributes to the development of a pro-oncogenic inflammatory environment within AML cells. The regulatory axis involving ATF7/JDP2 and IRF2BP2 emerges as a probable central player in orchestrating this phenomenon, potentially offering an attractive target for therapeutic intervention in AML. Our study highlights potential mechanisms contributing to AML and uncovers a possible avenue for future AML treatment strategies. In the second project, we chose a more global approach by developing an inhibitor for ELOB/C and testing its success in hindering cancer cell growth. We developed a new method aimed at disrupting protein-protein interactions (PPIs) by utilizing specifically designed peptides to target the biological functions of proteins. The focal point of this approach was the Elongin BC heterodimer (ELOB/C), a contributor to cancer cell growth due to its interaction with BC-box motif-containing proteins. We synthesized a peptide to closely mimic the high-affinity BC-box observed in the PRC2-associated protein EPOP. Remarkably, this synthetic peptide demonstrated a robust binding capability to the ELOB/C dimer (KD: 0.46 ± 0.02 nM), leading to the block of the association between ELOB/C and its partner proteins in vitro and the cellular environment. Further investigation revealed the significant impact of the peptide inhibitor on cancer cells. Following treatment, notable outcomes included reduced cell viability, increased apoptosis, and disruption of gene expression. These observations collectively suggest that obstructing the BC-box binding site on ELOB/C could serve as a feasible avenue to hinder its functionality, thereby limiting the expansion of cancer cells. Crucially, our peptide inhibitor not only improves our understanding of the ELOB/C dimer's function but also offers a promising foundation for developing potential therapies that target ELOB/C dysfunction.