For some time, cancer researchers have considered alpha-amanitin, the toxin derived from “death cap” mushrooms, as a possible cancer treatment. However, because of its penchant for causing liver toxicity, its potential as an effective therapy has been limited.
MD Anderson scientists looked at antibody-drug conjugates (ADCs) based on alpha-amanitin 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 combine powerful anticancer toxins linked to antibodies that allow for improved targeting of cancer cells, resulting in less impact on healthy cells.
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, also is deleted. Normal cells have two copies of POLR2A and TP53 genes. Lu’s study targeted cancers that had a single copy of both genes, representing 53% of colorectal cancers, 62% of breast cancers and 75% of ovarian cancers.
“POLR2A is an essential gene for cell survival, including cancer cells,” said Lu. “Because there’s only one copy, the cancer cells are more susceptible to suppression of this gene.”
Lu’s study was published in Nature.
The discovery that POLR2A is deleted at the same time as TP53 means that therapies can more specifically target the genetic processes that allow cancer cells to thrive. Understanding that one copy of POLR2A can allow cancer to grow gives researchers a new target to hit. As it turns out, it can be suppressed by an ADC based on the mushroom toxin. Lu’s team tested alpha-amanitin because it was believed to specifically inhibit POLR2A.