The "death cap" mushrooms, scientists reveal, is a possible cure to treating colorectal cancer. Though cancer scientists have considered toxin, alpha-amanatin derived from the fungus, as a possible cancer treatment, due to its penchant for causing liver toxicity, its potential as an effective therapy has been limited.
Now, researchers at The University of Texas MD Anderson Cancer Center looked at antibody drug conjugates (ADCs) based on alpha-amanatin as one solution. They found that ADCs, when aimed at a gene called POLR2A, are highly effective in mouse studies in treating colorectal cancer. The drug caused complete tumor regression and greatly reduced toxicity. ADCs allow for improved targeting of cancer cells, resulting in less impact on healthy cells.
The study by Xiongbin Lu, Ph.D., associate professor of Cancer Biology, observed that when the common tumor suppressor gene, TP53 is deleted resulting in cancer growth, another nearby gene, POLR2A is also deleted. Normal cells have two copies of POLR2A and TP53 genes. Lu targeted cancers that had a single copy of both genes, representing 53 percent of colorectal cancers, 62 percent of breast cancers and 75 percent of ovarian cancers.
Lu said that POLR2A was an essential gene for cell survival, including cancer cells. Because there was only one copy, the cancer cells become more susceptible to suppression of this gene.
Discovering that POLR2A is deleted at the same time as TP53 meant that therapies could more narrowly target the genetic processes allowing cancer cells to thrive.
Understanding that one copy of POLR2A could allow cancer to grow gives researchers a new target to hit. As it turned out, it could be suppressed by an ADC based on the mushroom toxin. Lu's team tested the drug, alpha-amanatin as it was believed that it specifically inhibited POLR2A.
Lu said they found that suppression of POLR2A with low-dose alpha-amanatin stopped cancer cell growth and reduced toxicity.
The study was published in Nature.