CANCER DIGEST – April 22, 2015 – For some time cancer scientists have considered the toxin found in “death cap” mushrooms, called alpha-amanatin, as a possible colorectal cancer treatment. While it has been shown to kill cancer cells, its drawback has been the unacceptable damage it causes to the liver.
In a study published April 22, 2015 in the journal Nature, researchers led by Xiongbin Lu, PhD at The University of Texas MD Anderson Cancer Center may have found a way to limit the liver toxicity of alpha-amanatin.
In a two-pronged approach, Lu’s team combined alpha-amanatin with an engineered antibody that specifically targets cancer cells that have a single copy of the gene POLR2A.
Many cell types contain two copies of a tumor suppressor gene, called TP53 and two copies of the gene POLR2A. It has been known for some time that when TP53 is deleted cells can become cancerous, growing out of control. While many researchers searched for cancer therapies that would reactivate TP53, Lu observed that where TP53 is deleted a nearby copy of POLR2A is also deleted, making the cells vulnerable.
Lu’s team looked at an antibody drug that combines alpha-amanatin with an antibody, called an antibody drug conjugate, or ADC, that targets cancers with a single copy of both genes, representing 53 percent of colorectal cancers, 62 percent of breast cancers and 75 percent of ovarian cancers.
They found that ADCs that targeted POLR2A are highly effective in mouse studies. The drug caused complete tumor regression while sparing liver tissues greatly reducing toxicity.
“We anticipate that inhibiting POLR2A will be a novel therapeutic approach for human cancers harboring such common genomic alterations,” said Lu.
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