The Secret of Deleted DNA – Activating the Immune System Against Tumours
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A University of Texas research team reports that a new drug candidate developed from a biological discovery improves the ability of immune cells to fight cancer. Melanoma, bladder cancer, leukaemia and colon cancer mouse models showed that the experimental drug could slow tumour growth and extend survival. This notable study was published on 28 September 2023 in Cancer Cell.
Many cancers delete the region called 9p21 in their DNA. This is the most common genetic alteration involving DNA deletion, occurring in 25-50% of certain cancers, such as melanoma, bladder cancer, mesothelioma and some brain cancers. Scientists have long known that cancers with 9p21 deletion mean poorer patient outcomes and resistance to immunotherapies.
The deletion acts in part by encouraging cancer to pump out a toxic compound called MTA. MTA prevents immune detection and destruction of cancer cells and also impairs the effectiveness of immunotherapies.
The Study’s 4 Key Findings
- Loss of the gene encoding the enzyme MTAP, also called MTAP, increases MTA levels and immunotherapy failure in melanoma and urinary tract cancers.
- In the tumour microenvironment, excess MTA impairs T cells.
- Administering the experimentally developed PEG-MTAP enzyme to tumours with MTAP gene deletion controls tumour growth in a T-cell-dependent manner.
- Combining the MTAP enzyme with immunotherapy may be effective in treating MTAP-deficient cancers.
Oncologist Dr Everett Stone, who led the research, explains: “In animal models, our drug brings MTA down to normal levels and immune activity returns. We see many more T cells around the tumour, and they are in attack mode. T cells are an important type of immune cell that can recognise tumour cells and fill them with enzymes that break them apart from the inside out.”
Dr Stone envisions using the drug alongside immunotherapies.
Deletion of 9p21 causes the loss of several key genes in cancer cells. For example, a pair of genes producing cell-cycle regulators is lost. These proteins allow healthy cells to grow and divide slowly and steadily. Without these genes, cells can grow uncontrollably, potentially triggering cancer. Another gene producing an enzyme that breaks down the MTA toxin is also deleted. According to Dr Stone, this loss enables cancer cells to disable the immune system.
“When cancer loses these two genes, it loses the brakes that normally stop it from growing uncontrollably. At the same time, it disarms the body’s police force, becoming a much more aggressive and malignant cancer.” says Dr Stone.
To create the drug candidate, Stone and his colleagues began with the naturally produced enzyme that helps break down MTA and then added flexible polymers.
Dr Stone says, “It is already a very good enzyme, but we needed to optimise it to last longer in the body. Simply injecting the natural enzyme would lead to its elimination within a few hours. In mice, our modified version remained in circulation for days, suggesting it could last even longer in humans.”
The researchers plan further safety testing of their drug, PEG-MTAP, and are seeking funding to take it into human clinical trials.
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