Blocking tumor evolution to halt cancer drug resistance

Researchers have synthesized short, chemically modified oligonucleotides that target specific immune system enzymes used by cancers to form treatment-resistant strains. (La Jolla Institute)

Cancer and its progression have always mirrored evolution: As tumor cells develop different genetic mutations, some acquire traits that allow them to evade the body’s immune system and anticancer drugs, while others do not. This selection process and its survivors contribute to proliferation and treatment resistance.

But now, researchers at Massey University and the Maurice Wilkins Centre for Molecular Biodiscovery in New Zealand are developing a new class of drug that could put the brakes on these evolutionary processes by targeting a less-essential immune system enzyme that triggers some of the initial mutations of tumor DNA.

Normally, the APOBEC3 family of seven proteins helps the innate immune system fight off retroviruses and other infectious pathogens by mutating cytosine to uracil in foreign pieces of single-stranded DNA to effectively disarm them.

But cancer hijacks one member of this family, APOBEC-3B, to promote the progression of tumors and drug-resistant cell strains. APOBEC-3B has been identified as major source of genetic mutations in multiple breast, bladder, cervical, lung, ovarian and head and neck cancers, according to co-corresponding author Vyacheslav Filichev, a professor at Massey University.

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Compared to the rest of its family, APOBEC-3B is not vital to wider immune responses, and selective inhibitors could help avoid unwanted side effects—while also extending the life of existing cancer therapies by giving them more time to do their work within the body.

“We established that we can selectively inhibit the APOBEC-3B enzyme using chemically modified DNA molecules,” said Filichev. “We think that it will be possible to use our modified DNA molecules to target APOBEC-3B in cancer cells. But in order to do so, we need more powerful inhibitors to be developed.”

The study, published in the journal Organic & Biomolecular Chemistry, details the work of Filichev’s team in synthesizing short oligonucleotides toward a treatment that targets specific APOBEC3 enzymes.

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Following these first steps, Filichev estimates that it may take five to 10 years before a potential therapy reaches clinical trials. “Drug resistance is a big problem in cancer therapy and targeting cancer evolution will be a key part in solving this problem,” he said.

“Cancer cells change over time and so treating cancer is like hitting a moving target,” said Helen Rippon, chief executive of Worldwide Cancer Research, which helped fund the study. “If you could pin it down and stop it changing it should be easier to deliver a knockout blow, but until now we have had no practical idea how to do that.”