More than 80 years ago, Nobel laureate Otto Heinrich Warburg pointed to a difference in mitochondrial energy metabolism between tumour cells and normal healthy cells. This observation led to significant advances in cancer imaging using positron emission tomography (PET) and, because the altered energy metabolism is common to many types of cancer cells but not normal cells, it is also an attractive target for therapy. Now, Cornerstone Pharmaceuticals has announced the start of a clinical trial with a ‘thioctan’, CPI-613, the first example of an altered energy metabolism-directed (AEMD) compound.
In laboratory tumour models and animal studies, the new class of compounds were effective, even against difficult to treat tumours such as those of the lung, colon and pancreas, and showed very few adverse effects.
The AEMD technology platform being developed by Cornerstone is based upon the research of Paul M. Bingham, Ph.D. and Zuzana Zachar, Ph.D., Stony Brook University, Stony Brook, NY. These scientists disclosed ‘Lipoic acid derivatives and their use in treatment of disease’ in a patent filed in 1999.
The inventors describe key differences between metabolism in normal cells compared to that in cancerous cells:
The vast majority of normal cells utilize a single metabolic pathway to metabolize their food. The first step in this metabolic pathway is the partial degradation of glucose molecules to pyruvate in a process known as glycolysis or glycolytic cycle. The pyruvate is further degraded in the mitochondrion by a process known as the tricarboxylic acid (TCA) cycle to water and carbon dioxide, which is then eliminated. The critical link between these two processes is a large multi-subunit enzyme complex known as the pyruvate dehydrogenase (“PDH”) complex (“PDC”). PDC functions as a catalyst which funnels the pyruvate from the glycolytic cycle to the TCA cycle.
Most cancers display profound perturbation of energy metabolism. This change in energy metabolism represents one of the most robust and well-documented correlates of malignant transformation.
Because tumor cells degrade glucose largely glycolytically, i.e. without the TCA cycle, large amounts of pyruvate must be disposed of in several alternate ways. One major pathway used for disposal of excess pyruvate involves the joining of two pyruvate molecules to form the neutral compound acetoin. This generation of acetoin is catalyzed by a tumor-specific form of PDC. Although the TCA cycle still functions in cancer cells, the tumor cell TCA cycle is a variant cycle which depends on glutamine as the primary energy source. Tumor-specific PDC plays a regulatory role in this variant TCA cycle. Thus, inhibition or inactivation of a single enzyme, namely tumor-specific PDC, can block large scale generation of ATP and reducing potential in tumor cells.