A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

Abstract

Here, we wish to propose a new systematic approach to cancer therapy, based on the targeting of mitochondrial metabolism, especially in cancer stem cells (CSCs). In the future, we envision that anti-mitochondrial therapy would ultimately be practiced as an add-on to more conventional therapy, largely for the prevention of tumor recurrence and cancer metastasis. This mitochondrial based oncology platform would require a panel of FDA-approved therapeutics (e.g. Doxycycline) that can safely be used to inhibit mitochondrial OXPHOS and/or biogenesis in CSCs. In addition, new therapeutics that target mitochondria could also be developed, to optimize their ability to eradicate CSCs. Finally, in this context, mitochondrial-based biomarkers (i.e. “Mito-signatures”) could be utilized as companion diagnostics, to identify high-risk cancer patients at diagnosis, facilitating the early detection of tumor recurrence and the prevention of treatment failure. In summary, we suggest that new clinical trials are warranted to test and possibly implement this emerging treatment strategy, in a variety of human cancer types. This general approach, using FDA-approved antibiotics to target mitochondria, was effective in killing CSCs originating from many different cancer types, including DCIS, breast (ER(+) and ER(-)), prostate, ovarian, lung and pancreatic cancers, as well as melanoma and glioblastoma, among others. Thus, we propose the term MITO-ONC-RX, to describe this anti-mitochondrial platform for targeting CSCs. The use of re-purposed FDA-approved drugs will undoubtedly help to accelerate the clinical evaluation of this approach, as these drugs can move directly into Phase II clinical trials, saving considerable amounts of time (10–15 y) and billions in financial resources.

Mitochondrial Fission Factor (MFF) Inhibits Mitochondrial Metabolism and Reduces Breast Cancer Stem Cell (CSC) Activity

“…We previously established that within the heterogeneous tumor mass, cancer cells exhibiting stemness features are also characterized by an elevated level of mitochondrial function (5,6,28). On the other hand, strategies aimed at targeting mitochondria have proven to be beneficial in halting CSCs, both in pre-clinical and clinical studies (9,12,29,30). Based on these observations, we investigated whether aberrant mitochondrial fission may affect CSC propagation, together with the impairment of mitochondrial function.…”

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

“…Increases in reactive species suppress the proportions of cancer stem-cells [ 73 , 87 , 88 , 89 ] and contribute to cytostasis [ 40 , 45 ]. Very likely, the metabolic alterations also contribute to cytostasis and to suppressing cancer stem cells [ 73 , 74 , 90 ].…”

Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities

“…The homology existing between mammalian mitochondrial ribosomes and prokaryotic ribosomes is well established, for this reason it is possible to use a wide variety of antibiotics already approved by the FDA [52]. Ribosomes are targeted by the two main families of antibiotics, tetracycline and macrolide [53,54]. Among the wide range of antibiotics, tested by Lamb et al doxycycline was found to inhibit mammosphere formation in breast cancer and many different tumor types [52].…”