VHIO scientists reveal novel drug-target to strangle sleeping cancer cells

• Latest discovery promises new weaponry against dormant tumor cells to counteract resistance and prevent disease relapse.
• Findings show epigenetic enzyme TET2 as an orchestrator of the control and survival of these cells as promoters of cancer recurrence.
• TET2 inhibition proposed as an effective approach to prevent their seeding of metastasis.
• Novel biomarker identified for DTC detection and to more precisely predict those patients at risk of recurrence.

Research spearhead by first author Isabel Puig, Post-Doctoral Fellow of the Vall d´Hebron Institute of Oncology's (VHIO) Stem Cells & Cancer Group, directed by Principal Investigator Héctor G. Palmer, has culminated in the discovery of a biomarker to identify dormant tumor cells (DTC), also known as slow-cycling cancer cells (SCCC), that, in their sleepy and silent state, go undetected by current treatments that have mostly been designed to target rapidly dividing tumor cells.

Having travelled undetected and settled in other parts of the body, when these DTC awake - the alarm clock trigger yet unknown - they behave like cancer stem cells, regenerate the original tumor and drive metastatic cell spread in patients thought to be cured.

Findings reported ahead of print today in the Journal of Clinical Investigation, reveal that a novel drug-target, the TET2 epigenetic enzyme, shows promise as a strategy to eliminate these sleeper yet murderous cells. Additionally, authors show that 5-Hydroxymethylcytosine (5hmC), generated by TET2, can be utilized as a biomarker for chemoresistant DTC detection and predictor of worse survival.

Fully equipped with the myriad of acquired alterations in cancer to go forth and multiply uncontrollably, this population of highly aggressive cells have the ability to sleep 'on the job'. While they slumber, they go undetected by powerful anti-cancer medicines since they currently only hone in on proliferating tumor cells. This enables DTC to travel to - and settle in - other organs and tissues in the body incognito, until they eventually wake up.

"In the current era of transformative medicine against cancer, we are increasingly delivering on the true promise of precision medicine in oncology. Two major challenges that hamper our collective efforts aimed at improving outcomes for our patients, are resistance to therapy and disease relapse. Concerning the latter, we need to move faster and get smarter in targeting and blasting these dormant cells as the seeders of tumors and metastatic cell spread," observes Héctor G. Palmer, corresponding author of this study.

Since dormant cancer cells are also notoriously difficult to detect among the army of normal cells in the body, the key to the team's research was finely-tuning their method of detecting and isolating them. He continues, "This was an essential element in the mix that enabled us to analyze these cells as known drivers of disease regression in patients thought to have been cured, as well as discover more about their molecular makeup."

The study showed that TET2 epigenetic enzyme activity, previously described as a tumor suppressor and downregulated in many tumor types, is increased in a small, stem-like cancer population and that elevated TET action is associated with chemoresitance. With the capacity to send these cancer cells to sleep, without sacrificing their potential malignant status, TET2 is a major orchestrator of their latent state.

"From the moment we identified TET2 as the Achilles heel of dormant tumor cells we have been focusing our efforts on developing novel inhibitors to block this enzyme activity. This new anti-cancer armory promises to counteract resistance and prevent relapse in some of our patients," observes Isabel Puig, first author of the paper.

Importantly, the researchers also identified a biomarker for the identification of this tricky-to-track and treatment-resistant population of cancer cells. Higher TET activity correlates with elevated levels of 5hmC as well as a greater risk of resistance to therapies and cancer recurrence.

"By detecting cells with 5hmC we can more precisely predict which patients are most likely to develop resistance to anti-cancer medicines as well as identify those who may suffer from relapse earlier on. Having seen that DTC are present across several tumor types including colon, breast and lung cancers as well as glioblastoma and melanoma, our findings could offer fresh hope for an important number of patients with advanced disease," she concludes.

Having driven precious insights into the molecular intricacies of these cells and expanded understanding surrounding their distinctive behavior, the team will seek to translate these two important findings into the clinic toward potentiating cancer therapeutics, preventing cancer relapse and extending survival of patients.

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Incorporating leading scientists from several other VHIO groups, in collaboration with colleagues from other research centers of excellence across Spain and Switzerland, this multidisciplinary decade-long study was in part supported by the Spanish Association against Cancer (AECC), FERO Foundation, Instituto de Salud Carlos III (ISCIII), CIBERONC Network, and the CELLEX Foundation.

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