In a study lately published in Cancer Research, a journal of the American Association for Cancer Research, a platoon of experimenters led byC. Patrick Reynolds,M.D.,Ph.D., director for the Texas Tech University Health lores Center( TTUHSC) School of Medicine Cancer Center, sought to expand upon his lab’s former exploration that showed ALT excrescences linked by a biomarker known as C- circles partake a common biology that confers vulnerabilities to be exploited for cancer remedy.
Reynolds and his platoon of collaborators, all combined with the TTUHSC School of Medicine Cancer Center, included Shawn Macha, Balakrishna Koneru, TrevorA. Burrow, Charles Zhu, Dzmitry Savitski, RakhshandaL. Rahman,M.D., CatherineA. Ronaghan,M.D., Jonas Nance, Kristyn McCoy and Cody Eslinger. The Cancer Prevention & Research Institute of Texas, the National Cancer Institute and Alex’s Lemonade Stand Foundation funded the design.
A subset of cancers live that yield generally poor issues because their cells employ a medium known as indispensable stretching of telomeres( ALT) to maintain telomere length so they can continue to grow and multiply. Telomeres are caps on the end of chromosomes that serve as defenders for the inheritable information contained within the cell.
To continue growing and multiplying, cancer cells must maintain their telomeres using telomere conservation mechanisms( TMM). Without TMM, telomeres begin to erode and the cancer cell dies. The most common TMM uses a cell enzyme known as telomerase that has the capability to add DNA to the ends of chromosomes.
still, some cancer cells are suitable to grow continuously without turning on telomerase. rather, they grow by using an alternate stretching of telomeres( ALT) medium that can repair telomeres without telomerase. The presence of ALT has been set up to be expansive in high- threat neuroblastoma and certain sarcomas, and ALT cancers are a major clinical challenge that warrant targeted remedial approaches.
To conduct their study, the Reynolds platoon employed the C- circle assay to estimate a variety of nonage and adult cancers. They set up ALT positivity in pediatric cancers( neuroblastoma and sarcoma) and in adult cancers( bone, colon and lung cancers). The frequence of ALT ranged from 10 to 78, depending on the type of cancer.
Anyhow of the cancer type, the platoon showed that ALT cancer cell lines parade high resistance to DNA damaging agents in comparison to telomerase-positive cancers.
” ALT cancers have dysfunctional telomeres, which provides unique vulnerabilities that can serve as new remedial targets,” Reynolds said.” An important aspect of targeting ALT in cancer remedy is that, unlike telomerase, ALT is only set up in cancer cells.”
The Reynolds platoon demonstrated that ALT cancer cells have high quantities of actuated ATM( ataxia- telangiectasia shifted) kinase, which promotes chemotherapy resistance in ALT cancers. A kinase is an enzyme that causes the transfer of phosphate groups from high- energy, phosphate- giving motes to specific substrates in a process known as phosphorylation. ATM is a protein kinase that phosphorylates, and therefore activates several crucial proteins that initiate DNA damage that can lead to cell cycle arrest, DNA form or apoptosis( cell death).
To survive having high actuated ATM, cancer cells must inactivate a excrescence protein known as p53. numerous ALT cancers have mutant p53, which Reynolds described as an essential vulnerability because the high ATM activation needed by ALT cancer cells also make those cells largely sensitive to active p53.
” We concentrated on using the ATM kinase activation to which ALT cancers are addicted,” Reynolds said.” Because this requires ALT cancers to have inactivated p53, frequently by mutation, a major element of this study was testing the capability of APR- 246, a medicine that reactivates p53, against ALT cancers and also developing optimal medicine combinations to use with APR- 246.”
Reynolds said his platoon hypothecated that ALT cancers are suitable to tolerate ATM activation due to dysfunctional p53, and that ATM activates p53 that’s restored to functionality by APR- 246.
” We demonstrated that APR- 246, in combination with irinotecan, is widely cytotoxic to ALT cancer cell lines and xenografts relative to cancer cell lines and xenografts that are positive for telomerase,” Reynolds said.” In addition, the study demonstrates that the unique vulnerability conferred by the dependence of ALT cancers cells on ATM kinase is common to ALT cancers across a range of cancer histologies set up in pediatric cancers similar as neuroblastoma, rhabdomyosarcoma and osteosarcoma, and adult cancers similar as triadic negative bone cancer, colon cancer and soft towel sarcomas.”
Reynolds said data from this design can be an aid in developing clinical trials for cases whose ALT cancer is readily identifiable with the C- circle biomarker.
” We’ve now shown that it isn’t just a neuroblastoma, but that ATM activation in ALT is set up in numerous other types of cancers, and that’s likely what makes those cancers resistant to chemotherapy,” Reynolds said.” The alternate thing is that understanding how ALT works and how to target it’ll enable clinical trials to be developed in the future that may profit cases with excrescences that depend on the ALT medium.”
Macha SJ, Koneru B, Burrow TA, Zhu C, Savitski D, Rahman RL, Ronaghan CA, Nance J, McCoy K, Eslinger C, Reynolds CP.
Alternative Lengthening of Telomeres in Cancer Confers a Vulnerability to Reactivation of p53 Function.
Cancer Res. 2022 Aug 10:OF1-OF14. doi: 10.1158/0008-5472.CAN-22-0125.