Numerous studies have revealed that in contrast to normal tissue, high mortality cancers such as prostate carcinomas (PCa), glioblastomas, and small cell lung carcinomas are critically dependent on the uptake of the non-essential amino acid L-cysteine (L-Cys) and its oxidized form L-cystine (CSSC) for proliferation and survival. Cancer specific metabolic defects such as L-Cys dependence are unique therapeutic opportunities that can be exploited by introducing into circulation pharmacologically optimized enzymes that degrade the amino acid upon which the tumor critically relies. We hypothesized that enzyme-mediated systemic depletion of the serum L-Cys/CSSC pool would constitute a powerful and completely novel cancer therapeutic approach as a cancer monotherapy and as a mechanistically synergistic agent with existing chemotherapeutic modalities. Indeed in an initial protein engineering campaign exploring this hypothesis we engineered and pharmacologically optimized a prototype human L-Cys/CSSC degrading enzyme (Cyst(e)inase) and found that bi-weekly administration to mice results in near complete depletion of the serum L-Cys/CSSC pool; (ii) mediates sustained and complete cessation of PCa tumor growth with cancer cells experiencing cell cycle arrest accompanied by increased oxidative stress and autophagy and (iii) importantly treatment for over a month was very well tolerated with no weight loss or gross toxicities.

Human therapeutic enzyme specifically sabotages tumor metabolism by an engineered cystine/cysteine degrading activity

249th National Meeting (2015)

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