Researchers at the University of Texas MD Anderson Cancer Center’s Cancer Biology Program, recently published results from a study in which they discovered an antibody drug conjugate (ADC) based on alpha-amanatin, a toxin found in “death cap” mushrooms, that when used in gene-targeting therapy is highly effective in treating colon cancer (CC) in mouse models. The study entitled “TP53 loss creates therapeutic vulnerability in colorectal cancer” was published in the latest edition of Nature.
Cancer researchers have known for some time that the death cap mushroom’s toxin had potential tumor suppressing properties, but the drawback was the damage alpha-amanatin caused to the liver of experimental animal models.
In this study Dr. Xiongbin Lu, PhD, Associate Professor, Department of Cancer Biology, MD Anderson CC, and his collaborators tried an approach that would circumvent the damaging side-effects to the liver that alpha-amanatin induced. The team combined alpha-amanatin with an engineered antibody (ADC) that specifically targets cancer cells that have a single copy of the gene POLR2A, which is essential for cell survival; and a well-known tumor suppressor gene, TP53.
The results showed that 53% of CCs, 62% of breast cancers and 75% of ovarian cancers, can be attributed to cancer cells that have a single copy of both POLR2A and TP53. A normal, non-cancerous cell has two copies of each gene.
In a University press release Dr. Lu, stated, “A tremendous effort has been made to restore TP53 activity in cancer therapies. However, no TP53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of TP53 signaling. POLR2A encodes an enzyme that is inhibited by alpha-amanatin. We found that suppression of POLR2A with low-dose alpha-amanatin stopped cancer cell growth and reduced toxicity.” He continued, “We anticipate that inhibiting POLR2A will be a novel therapeutic approach for human cancers harboring such common genomic alterations.”