A toxin called alpha-amanatin, derived from “death cap” mushrooms was considered for some time as a potential treatment for colorectal cancer. But since the toxin is known to cause liver toxicity, there have been limitations to enable its use as a potential effective therapy.
In a recent study published in Nature, a team of researchers at The University of Texas MD Anderson Cancer Center led by Xiongbin Lu, Ph.D., associate professor of Cancer Biology investigated the alpha-amanatin derived antibody drug conjugates (ADCs) as one potential solution.
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 mouse model of CC the ADC caused complete tumor regression while sparing liver tissues and greatly reducing toxicity. These findings show that ADCs allow an improved targeting of cancer cells, resulting in less impact on healthy cells.
“POLR2A is an essential gene for cell survival, including cancer cells,” said Dr. Lu. “Because there is only one copy, the cancer cells are more susceptible to suppression of this gene. A tremendous effort has been made to restore TP53 activity in cancer therapies,” the researcher continued. “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.”
“We anticipate that inhibiting POLR2A will be a novel therapeutic approach for human cancers harboring such common genomic alterations,” Dr. Lu added.