The ideal treatments for cancer achieve a therapeutic index by exploiting the differences between cancerous and normal cells. Here we describe an approach to develop targeted cancer therapies that relies on selective activation of a pro-drug by specific cytochrome P450 (CYP) enzymes. Compared to normal cells, many cancers express higher levels of CYP enzymes, which metabolize xenobiotics. We seek to exploit the high expression of CYP enzymes to locally convert an inert molecule into a cytotoxin within the tumor through metabolic activation. In the Preliminary Results section we describe tumor-targeted inhibitors of stearoyl CoA desaturase (SCD). This enzyme catalyzes the introduction of unsaturation into fatty acids. Tumor cells require high levels of unsaturated fatty acids and are therefore sensitive to SCD inhibitors. They exist in a nutrient poor environment and require de novo synthesis of unsaturated fatty acids to synthesize membranes, maintain membrane fluidity, and buffer the cell from the toxic effects of saturated fatty acids and free cholesterol. Indeed, our SCD inhibitors display low nM toxicity towards cultured human cancer cells. While inhibition of SCD in the liver is non-toxic, and inhibition of SCD within tumors arrests their growth, inhibition of SCD in the skin results in toxicity that presents an obstacle to the clinical development of conventional SCD inhibitors. Specifically, mice treated with known inhibitors suffer atrophy of sebocytes. These skin cells require SCD to synthesize sebum, which contains esters of fatty acids and fatty alcohols. Sebum is excreted onto the skin by hair follicles to reduce heat loss and onto the eyes and eyelids for lubrication. As a result of sebocyte atrophy, mice treated with SCD inhibitors suffer from dry eye, dry skin and hypothermia. In summary, SCD activity is critical for tumor growth, dispensable in the liver, but also required in the skin. An ideal anti-cancer treatment would therefore inhibit SCD in the tumor but not skin cells. Here we demonstrate the discovery of such tumor-targeted agents. We show that they are inert in their pro-drug form, but low nM inhibitors of SCD in their active form. Furthermore, we show that they are activated in tumors, but not in skin. Initial in vivo experiments demonstrate both tumor growth inhibition and an improved therapeutic index relative to non-targeted inhibitors of SCD. We describe plans to characterize the inhibitors' interactions with SCD, optimize them for in vivo utility, and fully evaluate their therapeutic potential as anti-cancer agents in rodent models of lung and liver cancer. The proposed studies should identify an optimized, targeted inhibitor of SCD suitable for advanced pre- clinical development including IND-enabling toxicology, formulation and manufacturing (not proposed). If successful, we will have identified an approach to targeted cancer therapies that exploits a metabolic weakness of cancer cells. While not proposed here, we recognize that this strategy could be tuned to exploit other over-expressed CYP isoforms and/or other classes of cytotoxins.
We describe a targeted cancer therapy that exploits metabolic differences between cancer and normal cells to activate a pro-drug within tumors. Specifically, we describe inhibitors of stearoyl CoA desaturase (SCD) that are activated by specific cytochrome P450 enzymes that are expressed in tumors. Conventional SCD inhibitors are systemically active, and therefore result in toxicity to skin cells. Our data shows that tumor-targeted SCD inhibitors minimize toxicity to the skin, resulting in a higher therapeutic index.
