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Telomeres as target of potential breakthrough therapy for 10-15 % of intractable tumors


IFOM's laboratories have identified a potential therapeutic opportunity to treat ALT tumors, which include, for example, glioblastoma and osteosarcoma and against which chemotherapy and radiotherapy are ineffective. It involves an Antisense Oligonucletide-based therapy that targets RNAs that allow the survival of cancer cells of this tumore type. The study, recently published in Nature Communications, was supported by AIRC Foundation.

A study conducted at IFOM in Milan has identified a new therapeutic approach for the treatment of ALT tumors, an acronym that stands for Alternative Lengthening of Telomeres. These tumors, little known outside of the scientific community, account for about 10 to 15 percent of all cancers and almost all of some cancers of the central nervous system, such as glioblastoma, and bone tissues, such as osteosarcoma.

"ALT tumors represent a considerable challenge in the field of oncology," illustrates Fabrizio d'Adda di Fagagna, head of the DNA Damage Response and Cellular Senescence Laboratory at IFOM in Milan and CNR Director of Research, "since currently there is no specific, effective therapy for patients affected by them. In addition, conventional therapies such as chemotherapy and radiotherapy seem to be rather ineffective, suggesting the urgency of finding new approaches with therapeutic potential for their treatment. This is a significant portion of cancer patients, and an effort by the scientific community in this direction is therefore due."

"Therefore, in our laboratory we pursued," continued d'Adda di Fagagna, "the identification of a novel approach for the treatment of ALT tumors, and we are grateful to AIRC for believing in our working hypothesis and funding this study, the results of which have just been published in Nature Communications and indicate a real opportunity with potential benefits for patients. What are ALT tumors characterized by? "What distinguishes these tumors," continues d'Adda di Fagagna, "is a survival mechanism of the cancer cell that relies on a peculiar strategy of maintaining telomeres, our chromosome ends that play a crucial role on the longevity of cells, including cancer cells."

Fabrizio d'Adda's laboratory in Fagagna has been working on the role of telomeres in maintaining the proliferative capacity of cells for 20 years. Their function is now known to have a wide impact in the maintenance of human health: altered telomere function is linked to aging processes, as well as to genetic disorders or to the increased likelihood of developing cancer.

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"Telomeres themselves," the researcher points out, "are subject to wear and tear and damage, and in recent times we discovered a family of telomeric RNAs that had never been characterized before, which proved to be crucial in safeguarding them. And it is this RNA that we are now leveraging to develop innovative therapeutic strategies for ALT tumors." Indeed, ALT cancer cells are characterized by constantly damaged telomeres, and the study that we published in Nature Communications revealed that this RNA is essential for their maintenance and, consequently, their uncontrolled proliferation and survival. "This evidence," stressed d'Adda di Fagagna, "has allowed us to identify these telomeric RNAs as a new molecular target that can be selectively targeted with novel approaches to induce selective ALT cancer cell death."

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The therapeutic solution IFOM researchers have adopted is an innovative technology that is being successfully established on various advanced research and clinical fronts: antisense oligonucleotides, also known as ASOs. ASO is a new class of drugs, consisting of short synthetic sequences , similar to DNA, designed and synthesized to complementarily bind aand inhibit a specific target, in this case a pathological RNA. "We have therefore designed," explains d'Adda di Fagagna, "a highly selective ASO that is complementary to ALT telomeric RNA necessary for the survival of ALT tumor cells and, to our great satisfaction, we observed in vitro that ALT cells from brain and bone tumors treated with ASOs underwent cell death, while the impact on healthy cells was negligible." These results were also obtained thanks to the contribution of IFOM's experimental therapies unit led by Ciro Mercurio. "Our next endeavor," the researcher concludes, "will be to bring this therapeutic approach closer and closer to its clinical use, also by verifying the potential for synergy with other molecules that could further increase its efficacy."

This research, conducted by researchers Ilaria Rosso and Corey Jones-Weinert, under the coordination of Fabrizio d'Adda di Fagagna and the experimental supervision of Francesca Rossiello, would not have been possible without the contribution of a grant from the Italian Association for Cancer Research (AIRC) (Investigator Grant), and a European Research Council (ERC) Advanced Grant ("TeloRNAging").

    last update: 29/11/23