Rebecsinib reverses ADAR1-induced cancer stem cell cloning capacity

Cancer stem cells (CSCs) are a subpopulation of cells within a tumor that possess stem cell-like properties and are believed to play a crucial role in the initiation, progression, and metastasis of cancer. These cells have the ability to self-renew and differentiate into different cell types, making them a key component of tumor heterogeneity. CSCs were first identified in leukemia in the late 1990s, and since then, they have been found in a wide range of solid tumors, including breast, brain, colon, lung, and prostate cancer. Unlike normal stem cells, which play important roles in tissue homeostasis and repair, CSCs are thought to be responsible for tumor initiation and growth, as well as for the development of drug resistance and disease recurrence. One of the hallmarks of CSCs is their ability to evade conventional cancer therapies such as chemotherapy and radiation, which target rapidly dividing cells but often spare the slower-dividing CSC population. This is thought to contribute to the high rates of relapse and treatment failure seen in many cancers. In recent years, there has been growing interest in developing therapies that specifically target CSCs, with the goal of eradicating these cells and preventing tumor recurrence. Strategies under investigation include targeting CSC-specific surface markers, inhibiting signaling pathways that regulate stemness, and disrupting the tumor microenvironment that supports CSC growth. While the development of CSC-targeted therapies is still in its early stages, there is growing evidence that these approaches may hold promise for improving cancer treatment outcomes and reducing disease recurrence.

Human innate immune responses against retroviruses rely on adenosine-to-inosine (A-to-I) RNA base editing (BE) by the adenosine deaminase acting on RNA1 (ADAR1) p150 isoform, which plays a critical role in preventing retroviral infections. However, recent studies have revealed that ADAR1-mediated A-to-I editing deregulation is a primary driver of CSC generation and is implicated in the progression of 20 different hematologic malignancies and solid tumor types.

In this context, the development of non-invasive detection and selective inhibition of ADAR1 A-to-I BE activation has become a pressing need. To address this issue, a team of researchers has developed a lentiviral nanoluciferase-GFP (ADAR1 nanoluc-GFP) reporter that enables real-time, non-invasive detection of ADAR1-specific A-to-I RNA editing in human stem and progenitor cells. Additionally, they have developed a lentiviral dual-fluorescence (GFP/RFP) splicing reporter, RNA-seq GRCh38-aligned computational bioinformatics platforms, and a flow cytometric assay for quantifying stem and progenitor cell ADAR1p150 protein expression levels.

Researchers at University of California San Diego School of Medicine, Sanford Stem Cell Institute and Moores Cancer Center led by Professor Catriona Jamieson report that a late-stage, pre-clinical small molecule inhibitor, rebecsinib, reverses malignant hyper-editing by an inflammation-induced protein isoform, known as ADAR1 p150. This malignant protein isoform of ADAR1 promotes immune silencing, metastasis and therapeutic resistance in 20 different cancer types. The findings are published in Cell Stem Cell. The research team developed the selective small-molecule inhibitor of splicing-mediated ADAR1 activation, Rebecsinib (17S-FD-895), which prevents ADAR1p150-splice isoform expression and malignant A-to-I editing-mediated LSC self-renewal in pre-investigational new drug  studies. The doses of Rebecsinib that spare normal HSPCs are well-tolerated in rat, rabbit, and non-human primate pre-IND toxicokinetic, pharmacokinetic, and pharmacodynamic studies.

Clinical development of Rebecsinib may offer a potential solution to A-to-I-editing-driven therapeutic resistance and reduce relapse-related mortality rates in acute myeloid leukemia (AML) and 20 therapeutically recalcitrant, ADAR1p150-overexpressing malignancies. In summary, the development of non-invasive detection and selective inhibition of ADAR1 A-to-I BE activation represents a significant advance in our understanding of cancer biology and may have a significant impact on the development of novel therapeutic strategies for treating cancer.