Mitochondria serve as a hub for multiple signaling pathways at the intersection of energy production, survival control, and oxidative stress. The central role of mitochondria in malignant transformation, impacting tumor progression, metastasis, and response to treatment (Cell 2016;166(3):P555-56616) is the subject of an intense field of research, and mitochondrial reprogramming in cancer, although in its infancy, is being explored as a potential therapeutic target in the clinic (Cancer Res 2016;76(20):5914-5920; Nat Rev Drug Discov 2010;9(6):447-464).
Yet, it is still poorly understood how mitochondrial functions are exploited in cancer to sustain aberrant energy production and survival, especially in conditions of metabolic and oxidative stress. The characterization of these pathways has recently become an urgent priority to identify new, druggable targets in genetically disparate tumors.
Our recent work identified mitochondrial fission factor (MFF), a molecule implicated in the control of mitochondrial size and shape, also called mitochondrial dynamics, as a novel transcriptional target of the Myc oncogene. As a result, MFF becomes overexpressed in primary and metastatic prostate and lung cancer and multiple myeloma compared to normal tissues. Biochemically, we found that MFF isoforms MFF1 and MFF2 associate with the Voltage-Dependent Anion Channel 1 (VDAC1), a key effector in multiple forms of cell death at the mitochondrial outer membrane (EBioMedicine 2019;48:353-363).
This interaction turned out functionally important. We found that disruption of the MFF-VDAC complex by silencing MFF induced a general collapse of mitochondrial integrity, with loss of inner membrane potential, bioenergetics defects and activation of cell death pathways. This translated into inhibition of tumor cell proliferation, suppression of colony formation in vitro, and reduced tumor growth in xenograft mouse models (EBioMedicine 2019;48:353-363). Overall, this study points to a novel crosstalk between different mitochondrial pathways that are almost invariably reprogrammed in cancer, resulting in inhibition of cell death and sustained tumor growth-mitochondrial cell death and mitochondrial dynamics.
A Novel Mitochondrial Therapeutic Target
Can we target the MFF-VDAC1 interaction for novel cancer therapeutics? To answer this question, we produced a cell-permeable molecule that mimics MFF and competes with it to bind to VDAC1. Using biochemical approaches, we demonstrated that this peptidomimetic molecule effectively disrupted the MFF-VDAC1 complex, inducing acute mitochondrial dysfunction and, as a consequence, tumor cell death (Cancer Res 2019; doi: 10.1158/0008-5472.CAN-19-1982).
When tested in multiple preclinical models of tumorigenesis, the MFF peptidomimetic delivered potent anticancer activity, inducing acute cell death in 3D organoids of patient-derived lung and breast cancer and in glioblastoma neurospheres; and inhibition of prostate cancer and drug-resistant melanoma growth in mouse xenografts. Importantly, this novel type of treatment was well-tolerated in mice, with no overt signs of toxicity (Cancer Res 2019; doi: 10.1158/0008-5472.CAN-19-1982).
Our results suggest that MFF inhibitors represent promising candidates for clinical development. Of note, targeting protein-protein interactions similar to the MFF-VDAC complex at the mitochondrial outer membrane is a validated therapeutic strategy in cancer, as venetoclax and other inhibitors that disrupt the interaction between pro- and anti-survival Bcl-2 molecules are currently used in clinical practice as cell death-modifying drugs, especially in hematologic malignancies (Cell Death Differ 2018;25(1):27-36).
Importantly, because the MFF peptidomimetic inhibitor causes general mitochondrial dysfunction that involves several cell death pathways, it may bypass the onset of drug resistance and offer broader efficacy in multiple malignancies.
Based on these promising results, future experiments will aim at refining the potency and drug-like properties of novel MFF inhibitors, further characterize their spectrum of anticancer activity, and test their potential efficacy in combination with conventional and molecular therapies.
DARIO C. ALTIERI, MD, is President and Chief Executive Officer of The Wistar Institute.