Abstract: High ATP production by the mitochondrial ATP-synthase is a new therapeutic target for anti-cancer therapy, especially for preventing tumor progression. A mitochondrial-related gene signature for metastasis is described, which features the gamma-subunit of the mitochondrial ATP-synthase (ATP5F1C). Knock-down of ATP5F1C expression significantly reduces ATP-production, 3D anchorage-independent growth and cell migration. Administration of the Bedaquiline, or a Bedaquiline derivative with a fatty acid moiety, down-regulates ATP5F1C expression in vitro and prevents spontaneous metastasis in vivo. Mitochondrial ATP5F1C is a promising new biomarker and molecular target for future drug development, for the prevention of metastatic disease progression.

Abstract: This disclosure describes the characteristics of the “energetic” cancer stem cell (e-CSC) phenotype. This distinct sub-population of cancer stem cells (CSCs) has a unique energetic profile compared to bulk CSCs, being more glycolitic, having higher mitochondrial mass and elevated oxidative metabolism. e-CSCs also show an increased capacity to undergo cell cycle progression, enhanced anchorage-independent growth, and ALDH-positivity. The e-CSC phenotype presents new targets for cancer therapeutics, and in particular the anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis of e-CSCs makes them highly susceptible to mitochondrial inhibitors that target e-CSC anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis. Gene products for e-CSCs are disclosed, as well as classes of mitochondrial inhibiting therapeutic agents. Also disclosed are methods for identifying and separating e-CSCs front bulk cell populations.

Abstract: High mitochondrial ATP is a metabolic trait that confers hyper-proliferation, sternness, anchorage-independence, anti-oxidant capacity and multi-drug resistance in cancer cells. Under the present approach, intracellular ATP levels may be used as a metabolic biomarker to identify, separate, and purify an aggressive and hyper-proliferative cancer stem cell (“CSC”) phenotype. Further, ATP may be combined with other CSC markers, e.g., CD44 or ALDH-activity, to beneficially fractionate the CSC population into sub-populations. For example, ATP-high/ CD44-high CSC sub-populations showed twice the level of anchorage-independent growth compared to ATP-low/CD44-high CSC sub-populations. Also disclosed are complementary bioinformatic data that implicate mitochondrial ATP synthesis in stemness, metastasis, and the detection of circulating tumor cells (“CTCs”), and a five-member, ATP-related metastasis gene-signature (ABCA2, ATP5F1C, COX20, NDUFA2 and UQCRB).

Abstract: This disclosure describes the characteristics of the “energetic” cancer stem cell (e-CSC) phenotype. This distinct sub-population of cancer stem cells (CSCs) has a unique energetic profile compared to bulk CSCs, being more glycolytic, having higher mitochondrial mass and elevated oxidative metabolism. e-CSCs also show an increased capacity to undergo cell cycle progression, enhanced anchorage-independent growth, and ALDH-positivity. The e-CSC phenotype presents new targets for cancer therapeutics, and in particular the anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis of e-CSCs makes them highly susceptible to mitochondrial inhibitors that target e-CSC anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis. Gene products for e-CSCs are disclosed, as well as classes of mitochondrial inhibiting therapeutic agents. Also disclosed are methods for identifying and separating e-CSCs from bulk cell populations.

Abstract: Cancer stem cells (CSCs) may be eradicated through a novel therapeutic strategy involving, in some embodiments, FDA-approved antibiotics and dietary supplements. The present approach effectively results in the synergistic eradication of CSCs through inhibiting mitochondrial biogenesis in CSCs during induced mitochondrial oxidative stress, without inhibiting normal cells. Embodiments may include a therapeutic agent that inhibits mitochondrial biogenesis and targets the large mitochondrial ribosome, a therapeutic agent that inhibits mitochondrial biogenesis and targets the small mitochondrial ribosome, and a therapeutic agent that behaves as a pro-oxidant or induces mitochondrial oxidative stress. Compositions according to the present approach inhibited CSC propagation by ˜90% in MCF7 ER(+) cell lines during preliminary studies, with confirmed reduction in mitochondrial oxygen consumption and ATP production.

Abstract: This disclosure describes the characteristics of the “energetic” cancer stem cell (e-CSC) phenotype. This distinct sub-population of cancer stem cells (CSCs) has a unique energetic profile compared to bulk CSCs, being more glycolytic, having higher mitochondrial mass and elevated oxidative metabolism. e-CSCs also show an increased capacity to undergo cell cycle progression, enhanced anchorage-independent growth, and ALDH-positivity. The e-CSC phenotype presents new targets for cancer therapeutics, and in particular the anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis of e-CSCs makes them highly susceptible to mitochondrial inhibitors that target e-CSC anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis. Gene products for e-CSCs are disclosed, as well as classes of mitochondrial inhibiting therapeutic agents. Also disclosed are methods for identifying and separating e-CSCs from bulk cell populations.

Abstract: Cancer cells can develop resistance to endocrine therapies, such as Tamoxifen, through acquisition of the Y537S mutation. Cells transfected with the Y537S mutation showed significant increases in mitochondrial mass and membrane potential, consistent with an increase in mitochondrial biogenesis. Certain biomarkers are identified that have prognostic value of endocrine therapy resistance. The mechanism resulting in this resistance, however, leaves these treatment-resistant cells vulnerable to therapeutics that inhibit mitochondrial biogenesis. Numerous mitochondrial biogenesis inhibitors are disclosed, as well as methods for reducing or eliminating endocrine treatment resistance, improving the effectiveness of an endocrine therapy, and for treating cancer.