Dario C. Altieri, M.D.

The Altieri laboratory is credited with the discovery and characterization of the survivin gene. With over 10,500 citations currently in PubMed, survivin is recognized as a fundamental cancer gene, a pleiotropic molecular hub for multiple pathways of cell survival, mitosis, adaptation to stress and metabolic reprogramming, as well as a validated therapeutic target in the clinic. Altieri’s contributions in this field have run the gamut from the discovery of survivin to the characterization of its unique role at the interface between cell death and mitosis in cancer, to clinical validation as a therapeutic target and predictive/prognostic disease biomarker.

Over the past decade, the Altieri lab’s work uncovered a novel role of protein folding quality control in mitochondria as a key driver of tumor progression. These studies elucidated mechanisms of protein homeostasis, or proteostasis maintained by Heat Shock Protein-90 (Hsp90) chaperones as well as AAA+ proteases in mitochondria, characterized their role in adaptive regulation of apoptosis, metabolic reprogramming and retrograde gene expression, and identified novel mechanisms of tumor adaptation to microenvironment stress stimuli, including hypoxia or exposure to molecular therapy.

How tumors that switch to an inefficient glycolytic metabolism, i.e. the Warburg effect, manage to accomplish highly energy-demanding tasks of cell motility and invasion has long remained elusive. Altieri’s work demonstrated that mitochondrial oxidative phosphorylation is required to fuel membrane dynamics of cell motility, resulting in increased tumor chemotaxis, invasion and metastasis. Mechanistically, Altieri showed that this pathway involves the redistribution of energetically active mitochondria to the peripheral cytoskeleton of tumor cells, where they provide a concentrated, spatiotemporal energy source to power membrane lamellipodia dynamics, turnover of focal adhesion complexes, and sustained phosphorylation of cell motility kinases.

Recent findings from the Altieri group have demonstrated that mitochondrial reprogramming is a universal cancer trait that imparts unique plasticity to a full spectrum of tumor responses, from early-stage malignant transformation to full blown tumor growth, to regulation of go-or-grow decisions, the dynamic and reversible switch between cell proliferation and cell migration states. The Altieri lab showed that mitochondrial control of tumor plasticity involves panoply of signaling pathways, including generation of ROS, exosome-dependent intercellular communication, and stabilization of HIF1 resulting in a transcriptionally-active, pseudo-hypoxic state.

The Altieri laboratory has pioneered the concept of targeting mitochondrial reprogramming for novel cancer therapeutics. The group uses a combination of mitochondrial-targeted peptidomimetic antagonists and small molecule ATPase inhibitors to disrupt mitochondrial Hsp90-directed protein folding, inhibit oxidative bioenergetics and abolish MFF cytoprotection at the mitochondrial outer membrane. In preclinical studies, these first-in-class mitochondrial-targeted agents (Shepherdin, Gamitrinib, MFF 8-11) were well-tolerated, demonstrated a unique “mitochondriotoxic” mechanism of action, and delivered potent, cytotoxic anticancer activity alone or in combination with molecular therapies in localized and disseminated tumor models, in vivo.