A possible route around a cancer therapy’s built-in defense
Researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center have identified a potential way to counter one mechanism that can blunt the effect of DNA methyltransferase inhibitors, a class of cancer medicines designed to restore activity in genes silenced by tumors.
In laboratory models, the team found that triptolide, a natural compound derived from the plant Tripterygium wilfordii, or thunder god vine, blocked an enzyme called DCTPP1. Cancer cells can use DCTPP1 to break down DNA methyltransferase inhibitors before the drugs can fully act. Pairing triptolide or related compounds with the DNMT inhibitor decitabine increased the drug’s ability to reactivate tumor-suppressor genes and kill cancer cells in those models.
The findings were published in Nature Communications. They do not establish a treatment for patients, but they point to a strategy for investigating why some tumors evade epigenetic medicines and how that resistance might be overcome.
Why DNA methylation matters in cancer
DNA methylation is an epigenetic process that helps cells control which genes are active. DNA methyltransferases, or DNMTs, add chemical tags known as methyl groups to DNA. Those tags are part of the system cells use to regulate whether particular genes are turned on or off.
Cancer cells can exploit that process. Abnormal DNA methylation can shut down genes that would normally help restrain uncontrolled growth. DNMT inhibitors, including decitabine and azacitidine, are intended to remove abnormal methylation and allow cancer-fighting genes to become active again.
These drugs have shown value in certain blood cancers, including myelodysplastic syndromes and leukemia. Their record in solid tumors has been more limited, in part because tumors can have defenses that neutralize the therapy before it begins to work effectively. The Johns Hopkins work focuses on one such defense.
Targeting the enzyme that breaks down the medicine
The researchers screened chemical libraries for compounds that could interfere with resistance to DNMT inhibitors. Their results identified triptolide as a compound that blocks DCTPP1, an enzyme that can degrade this category of drug.
That mechanism matters because the effectiveness of a medicine depends not only on its intended biological target, but also on whether enough active drug remains available to reach it. If cancer cells can dismantle a DNMT inhibitor early, they may prevent the treatment from producing the gene-reactivating effect it was designed to deliver.
When the team combined triptolide or related compounds with decitabine, they observed stronger reactivation of tumor-suppressor genes and increased cancer-cell killing in laboratory models. Senior study author Vasan Yegnasubramanian said the work offers a potential way to remove a barrier that prevents these drugs from working effectively in many cancers.
An early-stage result, not a clinical recommendation
The study is a mechanistic and preclinical finding. The supplied report describes laboratory models, not results from human clinical trials. It therefore cannot show that triptolide plus decitabine is safe, effective, or appropriate for people with cancer.
That distinction is especially important because a compound’s biological activity is not the same thing as a validated medicine. The next questions include whether the combination can be delivered at useful doses, whether it affects healthy tissue, which tumor types might be susceptible, and whether its activity persists in more complex models and clinical testing.
Still, the work provides a defined hypothesis for further research: inhibiting DCTPP1 may preserve the activity of DNMT inhibitors long enough to restore tumor-suppressor gene function. If that hypothesis holds up, it could broaden investigation of epigenetic therapies beyond the settings in which they have already had their clearest success.
What the finding changes now
For now, the immediate contribution is a clearer view of a resistance pathway. Rather than treating limited DNMT-inhibitor activity in solid tumors as a single, undifferentiated problem, the research identifies an enzyme that may be a tractable point of intervention.
It also illustrates a wider approach in cancer-drug development: pairing an established therapy with a second agent that disables a tumor’s protective mechanism. In this case, the established therapy is decitabine, and the proposed supporting role is played by a compound that prevents enzymatic breakdown of the drug.
Whether that approach can become a practical therapy remains an open question. But the evidence reported by the Johns Hopkins team gives researchers a specific target, DCTPP1, and a molecular lead, triptolide, for testing how epigenetic cancer medicines might be made more effective against resistant disease.
This article is based on reporting by Medical Xpress. Read the original article.
Originally published on medicalxpress.com
