Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?

Abstract

Telomeres are specialized nucleoprotein structures responsible for protecting chromosome ends in order to prevent the loss of genomic information. Telomere maintenance is required for achieving immortality by neoplastic cells. While most cancer cells rely on telomerase re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10–15%) employs telomerase-independent strategies, collectively referred to as Alternative Lengthening of Telomeres (ALT). ALT mechanisms involve different types of homology-directed telomere recombination and synthesis. These processes are facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture. Although the functional consequences of telomerase and ALT up-regulation are similar in that they both prevent overall telomere shortening in tumors, these telomere maintenance mechanisms (TMMs) differ in several aspects which may account for their differential prognostic significance and response to therapy in various tumor types. Therefore, reliable methods for detecting telomerase activity and ALT are likely to become an important pre-requisite for the use of treatments targeting one or other of these mechanisms. However, the question whether ALT presence can confer sensitivity to rationally designed anti-cancer therapies is still open. Here we review the latest discoveries in terms of mechanisms of ALT activation and maintenance in human tumors, methods for ALT identification in cell lines and human tissues and biomarkers validation. Then, original results on sensitivity to rational based pre-clinical and clinical anti-tumor drugs in ALT vs hTERT positive cells will be presented.

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

“…In addition, the evidence that (i) ALT may operate as a backup mechanism when telomerase is inhibited (Table 2 and Figure 2), (ii) ALT-positive cells are characterized by higher levels of telomeric DNA damage than telomerase-positive cells [9], and (iii) different factors involved in DNA damage repair are required to promote ALT activity in immortalized cell lines [60], which suggests that ALT may dictate the sensitivity of tumor cells not only to telomerase inhibitors but also to radiation [14] and DNA damaging agents [61].…”

Expression of tert Prevents ALT in Zebrafish Brain Tumors

“…Despite the established impact of telomere biology in cancer and the recent advancements on the role of chromatin structure and TERRA in TMMs in cancer, the molecular events that trigger ALT in a developing tumor remain unclear. The study of ALT in cancer has mostly relied on ALT sarcoma cell lines (Heaphy et al, 2011) and their telomerase positive counterparts, and only recently TMMs started to be evaluated in primary cancers (Pompili et al, 2017). Mouse models have been used extensively to study telomere biology (Goytisolo and Blasco, 2002) and have enabled essential progresses in the field.…”

ALT: A Multi-Faceted Phenomenon

“…Trabectedin is a marine alkaloid that covalently binds the minor groove of the DNA double helix, eventually triggering a response from DSB repair pathways [89]. ALT cells have been shown to be more sensitive to Trabectedin than telomerase positive cells [90] but the reason for this selective toxicity is unknown. Nonetheless, it must be said that Trabectedin has already been approved for use in soft tissue sarcomas [91], which, along with osteosarcomas, are known to have a higher prevalence of ALT than other tumors.…”