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PAD4 inhibition in neutrophils halts cancer progression and metastasis


Division of cancer cells. Author: Wistar Institute

Researchers in the laboratory of Yulia Nefedova, MD, of the Wistar Institute and employees of Jubilant Therapeutics Inc. have discovered a new mechanism by which protein arginine deiminase 4 (PAD4) in neutrophils promotes cancer progression. The paper also found that inhibiting this function of PAD4 reduced primary tumor growth and metastases and enhanced treatment with checkpoint inhibitors. Jubilant Therapeutics Inc. is developing a novel small molecule PAD4 inhibitor that directly targets this mechanism. The findings appear in Cancer research.

“The development of metastases remains the leading cause of death from cancer. Tumor-associated neutrophils have long been implicated in cancer progression. Understanding the mechanisms by which these cells promote tumor growth and spread of metastases is critical to the development of new therapies,” shares Yulia Nefedova, MD, Associate Professor, Immunology, Microenvironment, and Metastasis Program, Ellen and Ronald Cancer Center Chaplain of the Wistar Institute.

This study showed the importance of PAD4 protein in neutrophil migration, spec leukocytes which serve as the first line of immune defense in the body, directly affecting the main ones tumor growth and spread of secondary malignancy. Both genetic deletion of PAD4 and pharmacologic inhibition of PAD4 using a novel inhibitor from Jubilant Therapeutic Inc that dramatically downregulates the chemokine CXCR2, reduces immunosuppressive polymorphonuclear myeloid suppressor cells (PMN-MDSC) at tumor and metastatic sites, activates T cells, and synergizes with immune checkpoint blockade.

All results indicate a potent antitumor effect of PAD4 inhibition on PMN-MDSCs in the tumor microenvironment. This finding is further investigated in Nefedov’s Wistar laboratory.

“These results highlight the potential of PAD4 inhibition as a novel approach to cancer treatment in addition to the previously established role of this pathway in autoimmune diseases” said Luca Rastelli, Ph.D., Chief Scientific Officer of Jubilant Therapeutics Inc. “We are developing several highly selective oral PAD4 inhibitors with the goal of applying this novel mechanism in the clinic as potential therapeutic agents for the treatment of tumor metastases. in rectal and pancreatic cancer, patients with liver metastases, and acute and chronic autoimmune/inflammatory diseases.”

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Additional information:
Yulia Nefedova et al., Regulation of Tumor Progression by PAD4-Mediated Neutrophil Migration and Its Targeting by the Novel Selective Inhibitor JBI-589, Cancer research (2022). DOI: 10.1000/CAN-21-4045R1

Citation: PAD4 inhibition in neutrophils halts cancer progression and metastasis (2022, September 7) Retrieved September 7, 2022, from https://medicalxpress.com/news/2022-09-pad4-inhibition-neutrophils-halts-cancer.html

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