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Researchers Identify Potential Treatment Targeting Proliferation Pathway in Some Aggressive Tumors

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Key Points

  • A potential new treatment of ALT-positive cancers has been identified by molecularly blocking a protein in the ALT pathway.
  • Researchers used the ATR inhibitors VE-821 and AZ20 to selectively eliminate ALT-positive osteosarcoma and glioblastoma cells from panels of cancer cell lines.
  • Targeted treatments like these could preserve surrounding tissue and minimize harsh side effects in cancer treatment.

Researchers from the Massachusetts General Hospital (MGH) Cancer Center and Boston University School of Medicine (BUSM) have identified a potential treatment targeting a pathway by which several aggressive tumors maintain their ability to proliferate, according to a study by Flynn et al published in Science. Treatment with a small molecule that blocks a key step in that pathway—the alternative lengthening of telomeres (ALT) pathway—was able to inhibit the growth and survival of ALT-positive tumor cells.

“Identification of genetic markers that predict cancer cell vulnerabilities and new drugs to exploit such vulnerabilities is a focal point of cancer research today,” said Lee Zou, PhD, Associate Scientific Director of the MGH Cancer Center, and senior and co-corresponding author. “Cancer cells must rely on either the telomerase enzyme or the ALT pathway to bypass the normal processes of cell aging and death. Our findings may provide a new direction for the treatment of ALT-positive cancers, which include osteosarcoma, glioblastoma, and certain pancreatic tumors.”

Study Details

In their investigations, the researchers studied how the action and expression of several key proteins is altered in cancer cells that use the ALT pathway. Focusing on a protein called ATR, a master regulator of DNA repair and recombination, the investigators verified that the protein also plays a crucial role in regulating the ALT pathway. They found that the ATR inhibitors VE-821 and AZ20 selectively eliminated ALT-positive osteosarcoma and glioblastoma cells from panels of cancer cell lines, suppressing their ability to extend their telomeres though recombination and leading to the cells’ death.

Co-corresponding and lead author Rachel Flynn, PhD, Assistant Professor of Pharmacology & Experimental Therapeutics and Medicine at BUSM, explained, “This study suggests that inhibiting ATR may be a novel and important strategy in treating cancers that rely on the ALT pathway, including up to 60% of osteosarcomas and 40% to 60% of glioblastomas. Such targeted treatments would only affect cancer cells and have little effect on the surrounding healthy tissue, potentially minimizing the harsh and debilitating side effects experienced with traditional cancer therapies.”

While clinical trials of telomerase inhibitors for the treatment of cancer are currently underway, the up to 10% of tumors that do not use the telomerase pathway would not respond to such drugs. “Testing tumors for their use of telomerase or the ALT pathway is not yet routine,” Dr. Flynn said. “If VE-821 or other ATR inhibitors are clinically successful, it would support such testing and may lead to more personalized and targeted therapeutic regimens for several cancers refractory to traditional chemotherapeutics.”

Dr. Zou and Dr. Flynn are the corresponding authors for the Science article.

The study was supported by a Wellcome Trust grant and two National Institute of Health grants. Dr. Flynn is supported by the Karin Grunebaum Cancer Research Foundation and the Foster Foundation, and Dr. Zou is a Jim and Ann Orr Massachusetts General Hospital Research Scholar and a Senior Scholar of the Ellison Medical Foundation. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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