SRA737 and low dose hydroxyurea1 Mar 2024 15:46
Just found this new combo research - https://nwm.covr.be/cmPortal/searchable/eai24/config/normal#!abstractdetails/0000998790
Introduction
Replication stress is a common feature of solid cancers, and drugs targeting replication stress such as Checkpoint kinase 1 inhibitors (CHK1i) have demonstrated significant preclinical activity although this has not translated into an effective clinical treatment, primarily due to high normal tissue toxicity. We have demonstrated that a combination of CHK1i with a subclinical dose of hydroxyurea selectively targets a range of tumour types, importantly with little normal tissue toxicity. The CHK1i combination also promotes a pro-inflammatory response and immunogenic cell death. In vivo, this drug combination induces tumour regression which is dependent on an adaptive immune response. Here we report the immune responses triggered by this combination in mouse models and demonstrate that this response is suppressed by tumour-associated myeloid cells.
Material and Methods
Syngeneic mouse melanoma and ovarian cancer models were treated in vivo with the combination of CHK1i SRA737 and low dose hydroxyurea. The tumour immune microenvironment and peripheral immune cell responses were assessed by expression analysis and immune cell marker multiparameter flow cytometry.
Results and Discussions
In the panel of cancer models tested in syngeneic mice, the CHK1i combination controlled tumour growth. Immune responses were elicited by the CHK1i combination in all tumours but found different types of immune cell responses in the different models and cancers investigated. The combination enhanced immune responses independent of the initial tumour immune microenvironment, including in tumours that were immunologically "cold". The common features of the immune responses in all the models are increased cytolytic activity and reduced immune suppression in the tumour microenvironment. The responses were dependent on CD8+ T cells with a contribution from NK cells. Myeloid cells in the tumour microenvironment were immunosuppressive and this could be reversed by depletion with CSF-1R antibody or reducing tumour CSF-1 expression.
Conclusion
This demonstrates the CHK1i combination is highly selective with minimal normal tissue toxicity, does not adversely affect immune responses, and can trigger an effective anti-tumour immune response in range of tumour settings. Reducing tumour associated myeloid number or activity was associated with enhanced anti-tumour immune responses. This work suggests that the myeloid component of tumours may significantly alter treatment responses by suppressing anti-tumour immune activity.
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