Research identifies unique vulnerabilities in ALT cancers that may serve as new therapeutic targets

In a study recently published in Research against cancer, a journal of the American Association for Cancer Research, a team of researchers led by C. Patrick Reynolds, MD, Ph.D., director of the Texas Tech University Health Sciences Center (TTUHSC) School of Medicine Cancer Center, sought to expand on previous research from his lab that showed that ALT tumors identified by a biomarker known as C-rings share a common biology that confers vulnerabilities to be exploited for cancer treatment. The article is titled “Alternative telomere elongation in cancer confers vulnerability to reactivation of p53 function”.

Reynolds and his team of collaborators, all affiliated with the TTUHSC School of Medicine Cancer Center, included Shawn Macha, Balakrishna Koneru, Trevor A. Burrow, Charles Zhu, Dzmitry Savitski, Rakhshanda L. Rahman, MD, Catherine A. Ronaghan, MD, 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 project.

There is a subset of cancers that primarily produce poor outcomes because their cells use a mechanism known as alternative telomere elongation (ALT) to maintain telomere length so they can continue to grow and develop. multiply. Telomeres are caps at the end of chromosomes that serve as protectors for the genetic information contained in the cell.

To continue to grow and multiply, cancer cells must maintain their telomeres using telomere maintenance mechanisms (TMMs). Without TMM, the telomeres begin to erode and the cancer cell dies. The most common MMT uses a cellular enzyme known as telomerase which has the ability to add DNA to the ends of chromosomes.

However, some cancer cells are able to grow continuously without activating telomerase. Instead, they grow using an alternative telomere elongation (ALT) mechanism that can repair telomeres without telomerase. The presence of ALT has been shown to be important in high-risk neuroblastomas and some sarcomas, and ALT cancers are a major clinical challenge that lacks targeted therapeutic approaches.

To conduct their study, Reynolds’ team used the C-circle test to assess a variety of childhood and adult cancers. They found ALT positivity in pediatric cancers (neuroblastoma and sarcoma) and in adult cancers (breast, colon and lung cancers). The frequency of ALT varied from 10% to 78%, depending on the type of cancer.

Regardless of the type of cancer, the team showed that ALT cancer cell lines show high resistance to DNA-damaging agents compared to telomerase-positive cancers.

ALT cancers have dysfunctional telomeres, which provide unique vulnerabilities that may serve as new therapeutic targets. An important aspect of targeting ALT in cancer therapy is that, unlike telomerase, ALT is only found in cancer cells.”


C. Patrick Reynolds, MD, Ph.D., Director, Texas Tech University Health Sciences Center (TTUHSC) School of Medicine Cancer Center

Reynolds’ team demonstrated that ALT cancer cells contain large amounts of activated ATM (ataxia-telangiectasia mutated) kinase, which promotes resistance to chemotherapy in ALT cancers. A kinase is an enzyme that causes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates in a process known as phosphorylation. ATM is a protein kinase that phosphorylates and thereby activates several key proteins that initiate DNA damage that can lead to cell cycle arrest, DNA repair or apoptosis (cell death).

To survive with highly activated ATM, cancer cells must inactivate a tumor protein known as p53. Many ALT cancers have mutant p53, which Reynolds described as an inherent vulnerability, because the high ATM activation required by ALT cancer cells also makes these cells very sensitive to active p53.

“We focused on exploiting ATM kinase activation that ALT cancers are dependent on,” said Reynolds. “Because this requires ALT cancers to have inactivated p53, often by mutation, a major component of this study was to test the ability of APR-246, a drug that reactivates p53, against ALT cancers, and then to develop combinations of optimal drugs to use with APR-246.”

Reynolds said his team hypothesized that ALT cancers are able to tolerate ATM activation due to p53 dysfunction, and that ATM activates p53 which is restored to functionality by APR. -246.

“We demonstrated that APR-246, in combination with irinotecan, is selectively cytotoxic to ALT cancer cell lines and xenografts compared to cancer cell lines and telomerase-positive xenografts,” said Reynolds. “Furthermore, the study demonstrates that the unique vulnerability conferred by dependence of ALT cancer cells on ATM kinase is common to ALT cancers across a range of cancer histologies found in childhood cancers such as neuroblastoma, rhabdomyosarcoma and osteosarcoma, and adult cancers such as triple negative breast cancer, colon cancer and soft tissue sarcomas.”

Reynolds said the data from this project can help in the development of clinical trials for patients whose ALT cancer is easily identified with the C-circle biomarker.

“We have now shown that it is not just a neuroblastoma, but that ATM activation in ALT is found in many other types of cancers, and that is probably what makes these chemo-resistant cancers,” Reynolds said. “The second thing is that understanding how ALT works and how to target it will allow the development of future clinical trials that could benefit patients with tumors that are dependent on the mechanism of ALT.”

Source:

Texas Tech University Health Sciences Center

Journal reference:

Masha, SJ, et al. (2022) Alternative telomere elongation in cancer confers vulnerability to reactivation of p53 function. Research against cancer. doi.org/10.1158/0008-5472.CAN-22-0125.

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