Abstract BS3-2: Targeting mitochrondria with FDA-approved antibiotics may be a new therapeutic strategy to eliminate cancer stem cells

Abstract

Abstract Our recent studies indicate that cancer stem cells (CSCs) have increased mitochondrial mass, which directly reflects an increase in mitochondrial biogenesis and OXPHOS capacity. Thus, we believe that more effective anti-cancer therapy would involve the strategic targeting of CSC mitochondria, to prevent or reverse tumor recurrence, metastasis and drug-resistance. Interestingly, mitochondria are originally derived from aerobic bacteria that were engulfed by eukaryotic cells and adapted over millions of years of evolution. This is known as the 'Endo-symbiotic Theory of Mitochondrial Evolution'. As a consequence, certain antibiotics target mitochondrial protein translation as a manageable side effect. We have recently proposed to harness this side effect and to re-purpose it as a therapeutic effect to target breast CSCs. In accordance with this strategy, we have already experimentally identified 4 to 5 different class of mitochondrial-targeted antibiotics that could be used halt the proliferation and eradicate breast CSCs. These antibiotics included azithromycin and doxycycline, among others. Importantly, these antibiotics showed anti-CSC activity in 12 different cell lines, across 8 different cancer types, that were originally derived from breast, DCIS, ovarian, prostate, pancreatic and lung carcinomas, as well as glioblastoma and melanoma. In this context, doxycycline appeared to be one of the most promising agents, as human clinical trials in MALT lymphoma have already shown very positive results. Similarly, clinical trials with azithromycin in lung cancer patients have also shown positive results. Thus, targeting mitochondrial protein translation, with FDA-approved antibiotics, may be a safe effective strategy for inhibiting mitochondrial function in CSCs, regardless of the tumor type or site of origin. For further information on this topic, please see the following references: Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease. Lamb R, Ozsvari B, Lisanti CL, Tanowitz HB, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Oncotarget. 2015 Mar 10;6(7):4569-84. Drug therapy: Can the mitochondrial adverse effects of antibiotics be exploited to target cancer metabolism? Killock D. Nat Rev Clin Oncol. 2015 Apr;12(4):190. High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant. Farnie G, Sotgia F, Lisanti MP. Oncotarget. 2015 Sep 30. [Epub ahead of print] PMID: 26421710 http://www.ncbi.nlm.nih.gov/pubmed/26421710 Mitochondrial mass, a new metabolic biomarker for stem-like cancer cells: Understanding WNT/FGF-driven anabolic signaling. Lamb R, Bonuccelli G, Ozsvari B, Peiris-Pages M, Fiorillo M, Smith DL, Bevilacqua G, Mazzanti CM, McDonnell LA, Naccarato AG, Chiu M, Wynne L, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Oncotarget. 2015 Sep 28. [Epub ahead of print] PMID: 26421711 http://www.ncbi.nlm.nih.gov/pubmed/26421711 Citation Format: Lisanti MP. Targeting mitochrondria with FDA-approved antibiotics may be a new therapeutic strategy to eliminate cancer stem cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr BS3-2.