A recent study by researchers at the University of Texas MD Anderson Cancer Center (TX, USA) has demonstrated the efficacy of antibody drug conjugates (ADCs) based on mushroom toxins in mouse models of colorectal cancer.
The study, recently published in Nature, reports full tumor regression and decreased toxicity, attributable to the improved targeting of cancerous cells enabled by ADCs.
The specific toxin tested, alpha-amanatin, is derived from the Amanita phalloides mushroom, commonly referred to as the ‘death cap’ mushroom due to the potent toxins it contains. Alpha-amanitin has previously been considered as a potential candidate for cancer therapies; however its ability to cause fatal liver damage has hindered progress.
The research team, led by Xiongbin Lu (MD Anderson Cancer Center), focused their work on ADCs based on alpha-amanatin, which were then targeted at the POLR2A gene. It was observed that when the tumor suppressor gene, TP53, is deleted, the nearby POLR2A was also deleted. Although normal cells possess two copies of both of these genes Lu’s team focused on cancers that contain one copy of each. This included 53% of colorectal cancers, 62% of breast cancers and 75% of ovarian cancers.
“POLR2A is an essential gene for cell survival, including cancer cells,” commented 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,” explained Lu. “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,” added Lu.