Targeted Telomere-Disrupting Oligonucleotide for Acute Myeloid Leukemia Therapy
Abstract
The immune system has the ability to detect and eliminate cancer cells, but it is often overwhelmed by rapidly progressing tumors and fails to attack. Over 90% of human cancers rely on telomerase, an enzyme that makes cancer cells immortal and able to proliferate indefinitely. Telomerase is commonly activated in hematologic malignancies with high proliferative rate, such as acute myeloid leukemia (AML). High telomerase activation correlates with more aggressive, treatment-resistant, and relapsing leukemia. Telomerase is long recognized as an attractive but challenging therapeutic target. Its activity is also necessary for production of normal blood cells and activity of certain immune cells such as T cells. The first generation of broadly acting telomerase inhibitors had limited antitumor efficacy with slow onset of cancer cell killing, toxicity to blood cells, and many side effects. Recent strategies used new tactics. Modified DNA building blocks, such as 6tdG, can trick telomerase into adding them into chromosome ends, thereby causing DNA damage and cancer cell death. While promising in preclinical studies, the nucleoside analogs are not cancer-cell selective and affect also nonmalignant cells. We previously showed that it is possible to use short synthetic DNA molecules (oligonucleotides) to deliver therapeutic molecules with high efficiency and precision into target cancer cells without need for any additional reagents and formulations. Based on these studies, we generated DNA drugs (CpG-6tdGOs) with ability to deliver multiple 6tdG molecules to telomerase-positive leukemic cells but not into T cells or healthy tissues. CpG-6tdGOs induced death of telomerase-positive human and mouse AML cells at low dosing. We further optimized these molecules chemically to protect them from degradation in human blood for several days but to enable release of 6tdG molecules once inside the cell. In addition, CpG-6tdGOs were equipped with immunostimulatory properties to activate antitumor immunity. Our initial studies confirmed that intravenously injected CpG-6tdGOs induced regression of mouse and also patient’s derived AML models in mice. The multiple, repeated CpG-6tdGOs treatments were well tolerated and have not induced adverse effects or toxicities typical for earlier telomerase inhibitors. Here, we propose studies with a goal to develop a novel, bifunctional oligonucleotide therapy to treat currently incurable resistant and relapsed AML. We believe that the combination of rapid and direct CpG6tdGO-induced AML cell death with the activation of immune system will maximize therapeutic efficacy of this strategy. First, we plan to characterize the two-pronged mode-of-action of CpG-6tdGOs on telomerase-positive AML cells and on the leukemia-associated immune cells in mice. These studies in human and mouse AML models should identify molecular mechanisms and potential clinical biomarkers of oligonucleotide activity. Next, we will assess the efficacy of CpG-6tdGOs alone or in combination with clinically relevant strategies for therapy of human AML. These studies will provide us with information on the CpG-6tdGOs activity, which will be later used to design a clinical trial in AML patients in collaboration with Dr. Guido Marcucci (City of Hope), a renowned expert in leukemia biology and therapy. AML remains a rare cancer with high mortality rate and poor survival in the United States. Once relapsed after initial treatment, only 5% of AML patients survive for 5 years. The new targeted therapies for AML are by no means curative, while the development of novel, antibody- or CAR T cell-based immunotherapies for myeloid leukemia were met with challenges. Two-pronged and cell-selective CpG-6tdGOs utilizes the potential of targeting AML cells while avoiding toxicities to non-malignant cells. The proposed studies will address two of the Overarching Challenges for the fiscal year 2022 Rare Cancers Research Program, na
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310857
Entities
People
- Marcin Kortylewski
Organizations
- Beckman Research Institute of City of Hope
- United States Army