Key result
Trabectedin shows greater cytotoxicity in ALT-positive versus ALT-negative cancer cells, correlating with c-circles expression.
Why the study?
The question whether ALT presence can confer sensitivity to rationally designed anti-cancer therapies remains open, necessitating review of ALT mechanisms and treatment responses.
Does Trabectedin or other anti-cancer therapies show differential sensitivity in ALT versus hTERT positive cells?
Does Trabectedin or other anti-cancer therapies show differential sensitivity in ALT versus hTERT positive cells?
This paper reviews ALT mechanisms and presents data on the sensitivity of ALT-positive versus telomerase-positive cells to therapies like Trabectedin.
Answers are grounded in this paper and cite their sources.
Trabectedin may preferentially target ALT-positive cells; leaves open clinical translation in ALT-driven cancers.
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.
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Pompili et al. (2017) conducted a review in Alternative Lengthening of Telomeres (ALT) positive tumors. Trabectedin vs. ALT-negative cell lines was evaluated on IC50 dose for cell viability (p=<0.005). Trabectedin demonstrated significantly higher cytotoxicity in ALT-positive cancer cells compared to ALT-negative cells (p<0.005), which correlated with c-circles expression.
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