Engineering and Preclinical Development of a Human Enzyme for Cancer Therapy Via the Depletion of the Serum L-Cysteine Pool

Extensive studies have revealed that several high mortality cancers including prostate carcinomas (PCa), glioblastomas, and chronic lymphocytic leukemia (CLL) are critically dependent on the uptake of the non-essential amino acid L-cysteine (CYS) (and its oxidized form L-cystine (CSSC)) for proliferation, survival, and even resistance to many standard of care chemotherapeutics. The observation that relative to non-malignant tissues a tumor’s excessive requirement for CYS/CSSC is a critical metabolic vulnerability, led us to exploit this tumor deficit by developing a novel therapeutic that systemically depletes CYS and CSSC. An important point is that most if not all normal tissue can make CYS from the essential amino acid L-Methionine, thus tumors are selectively impacted when CYS is unavailable.

We engineered and developed a human enzyme with the requisite kinetic and pharmacological properties that can (i) deplete the serum pool of CYS/CSSC to near completion, (ii) selectively and potently kill cancer cells through increased ROS production and (iii) mediate a sustained cessation of tumor growth without any weight loss or apparent toxicities.

The outstanding results from this approach have accelerated our efforts towards bringing this therapeutic to the clinic. We discuss the many studies currently ongoing and highlight the engineering, pharmacological studies, efficacy studies, biological mechanisms and IND enabling work in mice and non-human primates. Having a pharmacological tool to non-toxically manipulate the major extracellular redox buffer (CYS/CSSC) in living mammals and revoke a tumors ability to cope with its own reactive oxygen species is an unprecedented advance for oncology.