Targeting mitochondrial dynamics in venetoclax-resistant acute myeloid leukemia
Christina Glytsou
PhDNew York University School of Medicine
Project Term: July 1, 2021 - June 30, 2023
Although new targeted therapies have been discovered and approved for the treatment of various types of leukemia, in many cases patients do not respond or develop resistance to treatments. My LLS-funded studies shed light on the mitochondria adaptations which enable cancer cells escape cell death induced by the treatments, while suggesting novel therapeutic strategies.
Acute Myeloid Leukemia (AML) is the second most common cancer of the blood in adults. AML is associated with dismal prognosis and high mortality, with an only 28% overall five-year survival rate. For the past three decades, AML treatment has largely remained unchanged for many patients using conventional chemotherapy that often fail to achieve complete remission. The disease relapse is frequently fatal (~66%) and bone marrow transplantation is applicable to only a few select AML patients, highlighting the need for novel targeted treatments. In 2018, the FDA approved a new drug, Venetoclax, for the treatment of newly-diagnosed elderly AML patients in combination with hypomethylating agents or chemotherapy. However, despite promising early responses to venetoclax-based therapies, approximately 30% of patients with AML do not respond and many patients still develop resistance while on treatment, limiting the long-term success of this approach. With this in mind, a deep understanding of the molecular mechanisms underpinning Venetoclax resistance is required in order to rationally devise more efficacious targeted treatment strategies for AML. Venetoclax selectively targets the regulation of cellular survival. Under normal circumstances, damaged cells activate their suicidal program -apoptosis- in order to prevent the propagation of defects in the organism. Cancer cells violate this cell death program to evade apoptosis and become “immortal”. Venetoclax specifically targets this apoptotic process, promoting the death of leukemic cells. The apoptotic pathway is tightly regulated by small, dynamic, cellular organelles called mitochondria. Recently, we discovered that mitochondria alter their shape as a response to Venetoclax treatment or upon acquisition of drug resistance, suggesting that Venetoclax-resistant AML cells actively modify their mitochondrial architecture and function to resist induced cell death. We are using state-of-the-art super-resolution microscopy to achieve detailed imaging of the dynamic mitochondrial adaptations occurring in drug resistant human AML. Our experiments will uncover the molecular details of the mitochondrial processes that contribute to the gain of Venetoclax-resistance. Importantly, a novel chemical compound targeting mitochondrial structure will be tested by others for the first time in human cancers and our experiments will address its anti-leukemic efficacy and synergism with Venetoclax in AML models. Our overall goal is to propose a novel combinational targeted therapy for this devastating blood cancer.