Breakthrough in Uncoverment of Non-Druggable Cancer Target
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Nature: Breakthrough in Uncoverment of Non-Druggable Cancer Target After Six Years of Research Using CRISPR Screening
Immunotherapy, exemplified by molecules like PD-1/PD-L1 and CTLA-4, has revolutionized the field of cancer treatment in recent years, fundamentally altering the landscape of cancer therapy. However, the effectiveness of this therapy varies greatly among different cancer patients, with a majority showing no response and a lower long-term benefit ratio. Hence, there is a need to develop new therapies to overcome resistance issues.
Tyrosine phosphatases PTPN2 and PTPN1 play central roles in inflammation. A study published in Nature in 2017 demonstrated that their loss can enhance anti-tumor immunity, making them potential targets for cancer immunotherapy. However, phosphatases fall under the category of “non-druggable targets,” making it highly challenging to develop drugs targeting them.
On October 4, 2023, researchers from AbbVie, the Broad Institute, and Calico Life Sciences collaborated to publish a study in the journal Nature titled “The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.”
The study reveals that ABBV-CLS-484 is a potential first-in-class oral dual inhibitor of PTPN2/PTPN1 phosphatases, which enhances anti-tumor immunity and suppresses tumor growth. Research data supports further development of ABBV-CLS-484 as a promising strategy for cancer immunotherapy.
Currently, ABBV-CLS-484 has entered a Phase 1 clinical trial for solid tumors, marking the first active-site phosphatase inhibitor to enter clinical trials as a cancer treatment drug.
Back in 2017, Robert Manguso and colleagues published a paper in Nature that identified PTPN2 and its closely related PTPN1 as new targets for cancer immunotherapy through in vivo CRISPR screening. Knocking out PTPN2 was shown to enhance interferon-gamma (IFN-γ)-mediated antigen presentation and growth inhibition, thereby improving the effectiveness of tumor immunotherapy.
However, the challenge lay in the fact that these were considered “non-druggable targets” in the traditional sense. In this new study, AbbVie researchers overcame this challenge by employing structure-based drug design and optimizing drug-like properties, leading to the discovery of the PTPN2/PTPN1 dual inhibitor ABBV-CLS-484. Researchers from AbbVie, the Broad Institute, and Calico further elucidated the biological and mechanistic actions of ABBV-CLS-484.
Preclinical study results showed that ABBV-CLS-484 treatment amplified the tumor’s inherent response to interferons and increased the activation and function of several immune cell subsets, promoting cellular pathways, including JAK-STAT signaling, in mouse models.
In mouse tumor models resistant to PD-1 monoclonal antibody therapy, monotherapy with ABBV-CLS-484 demonstrated powerful anti-tumor immune effects. Through in vivo studies and single-cell transcriptome analysis of tumor-infiltrating lymphocytes from mice treated with ABBV-CLS-484, the research team found that ABBV-CLS-484 induced inflammation in the tumor microenvironment, promoting NK cell and CD8+ T cell function. In T cells, ABBV-CLS-484 induced epigenetic and metabolic changes, resulting in a unique functional state that increased T cell cytotoxicity while reducing T cell exhaustion and dysfunction.
Dr. Christina Baumgartner, the lead author of the paper and Senior Chief Research Scientist at AbbVie, stated that immunotherapies like PD-1 blockade have transformed cancer treatment, but many cancer patients do not respond well to them. Thanks to the exceptional efforts of AbbVie’s medicinal chemistry team, we now have a potential first-in-class PTPN2/PTPN1 inhibitor. We are excited to share its biology and mechanism and look forward to further evaluation in clinical settings.
Marcia Paddock, the lead author of the paper and Head of Tumor New Target Development at Calico, emphasized the strength of this research in demonstrating how collaboration across various expertise areas can advance our understanding of disease biology and lead to the discovery of new treatment strategies for cancer patients. She expressed pride in partnering with AbbVie and the Broad Institute and looked forward to sharing further progress on this novel immunotherapy in clinical research.
ABBV-CLS-484 is the first active-site phosphatase inhibitor to enter clinical trials as a cancer treatment drug and is currently in Phase 1 clinical trials for solid tumors, led by AbbVie and Calico (NCT04777994).
Professor Robert Manguso, the corresponding author of the paper, emphasized that this presents an unprecedented opportunity to evaluate how the immune response functions and underscores the importance of further exploring the capabilities of this signaling pathway in clinical research.
Links to the paper:
Breakthrough in Uncoverment of Non-Druggable Cancer Target After Six Years of Research Using CRISPR Screening
(source:internet, reference only)
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