Lunella Biotech, Inc.

Marco Fiorillo

Michael P Lisanti

Federica Sotgia

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.

Biomarkers and therapeutics for endocrine therapy resistance

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.

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Manchester, United Kingdom

Marco Fiorillo