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Tag: Nefedova

Wistar Scientists Study Ferroptosis to Improve Cancer Treatments

What clues can a cell’s death reveal for immunotherapies for treating cancer and other diseases?

Wistar scientists Dr. Yulia Nefedova, associate professor in the Immunology, Microenvironment & Metastasis Program in the Ellen and Ronald Caplan Cancer Center, and Dr. Maureen Murphy, Ira Brind Professor and program leader of the Molecular & Cellular Oncogenesis Program in the Ellen and Ronald Caplan Cancer Center, are studying a recently identified form of cell death called ferroptosis and how to harness this knowledge to improve care for cancer patients.

Ferroptosis cloaks cancer from the immune system

In a recently published Nature paper, Dr. Nefedova and collaborators reported that ferroptosis occurs in immune cells called neutrophils in the tumor microenvironment. Ferroptosis of neutrophils suppress the immune system and actually aid cancer cells in escaping death. Specifically, neutrophils dying from ferroptosis inhibit one of the most powerful natural enemies cancer has – T cells. T cells are a critical line of defense in the human immune system because they are programmed to attack cancer cells.

“Understanding the mechanisms that mediate immune suppressive activity of neutrophils in the tumor microenvironment is critical to improve the anti-tumor response and efficacy of immunotherapies,” explained Nefedova.

The study demonstrated that systemically or selectively blocking ferroptosis in neutrophils significantly delayed tumor growth and increased host sensitivity to a type of cancer treatment called immune checkpoint inhibitors. Nefedova shared, “Our study identified a new therapeutic approach that could be further explored as a treatment option for cancer patients – especially those who are poorly responding to the existing immunotherapies.”

Ferroptosis could be used to kill cancer cells

“Most cell death pathways occur more in tumor cells than normal cells, so we try to exploit them for cancer therapy,” explained Dr. Murphy regarding her recent paper published in the Journal of Biological Chemistry. Some cancer cells have an increased sensitivity to ferroptosis, and this research uncovered not only why, but how these findings can be translated to improve clinical care of cancer patients.

The Murphy lab studies genetic variants of p53, a critical suppressor of cancer that regulates a protein called PLTP (phospholipid transfer protein). In the study, Murphy and team identified that PLTP can control ferroptosis in cells by controlling the ability of cells to sequester lipids into “lipid droplets”. If a cell isolates toxic lipids into droplets, it can prevent these lipids from penetrating the cell membrane and causing cell death by ferroptosis.

“By identifying lipid droplets as critical for ferroptosis, we identify a whole series of drugs that regulate lipid droplets that can now be exploited to combat cancer,” said Murphy. “We are now exploring the possibility that immune cells use ferroptosis to kill cancer cells. This would help identify people who might be less suited to use immunotherapy to combat their cancers and might have to use extended treatment or a different form of therapy.”

The Wistar Institute and Jubilant Therapeutics Inc. Find PAD4 Inhibition in Neutrophils Halts Cancer Progression and Metastasis

PHILADELPHIA — (Sept. 7, 2022) — Researchers in the laboratory of Yulia Nefedova, M.D., Ph.D., at The Wistar Institute and collaborators at Jubilant Therapeutics Inc. have uncovered a novel mechanism by which protein arginine deiminase 4 (PAD4) in neutrophils promotes cancer progression. The paper also found that inhibition of this function of PAD4 reduces primary tumor growth and metastasis and enhances checkpoint inhibitor treatments. Jubilant Therapeutics Inc. is developing a novel small molecule PAD4 inhibitor that directly targets this mechanism. The findings appear in Cancer Research, a journal of the American Association for Cancer Research.

“Development of metastases remains a 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 metastatic spread is critically important for the development of new treatments,” shares Yulia Nefedova, M.D., Ph.D., associate professor, Immunology, Microenvironment & Metastasis Program, Ellen and Ronald Caplan Cancer Center of The Wistar Institute.

This research revealed the importance of PAD4 protein in the migration of neutrophils, specialized white blood cells that serve as the first line of immune defense in the body, directly impacting both primary tumor growth and secondary malignant tumor spread. Both genetic deletion of PAD4 and pharmacological inhibition of PAD4 using Jubilant Therapeutic Inc’s novel inhibitor dramatically down-regulated chemokine CXCR2, reduced immune suppressive polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) at tumor and metastatic sites, activated T cells, and synergized with immune checkpoint blockade.

All results point to a potent anti-tumor effect of PAD4 inhibition to target PMN-MDSCs in the tumor microenvironment. This finding is being further investigated in Wistar’s Nefedova laboratory.

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

These findings were only made possible through the supportive collaboration between Wistar, a Philadelphia based nonprofit biomedical research institute, and Jubilant Therapeutics Inc., a clinical-stage precision therapy company developing new therapies to treat oncology and autoimmune disease.

“Only working together are we able to efficiently translate our fundamental research discoveries into clinical realities,” states Heather Steinman, Ph.D., MBA, The Wistar Institute vice president for Business Development & executive director of Technology Transfer.

Co-authors: Hui Deng, Cindy Lin, Laura Garcia-Gerique, Shuyu Fu, Zachary Cruz, Erin Bonner Matthew Rosenwasser, Sridharan Rajagopal, M. Naveen Sadhu, Chandru Gajendran, Mohd Zainuddin, Ramachandraiah Gosu, Dhanalakshmi Sivanandhan, Miriam A. Shelef, Brian Nam, Dan T. Vogl, and Dmitry I. Gabrilovich.

Publication Information: Regulation of tumor progression by PAD4-mediated neutrophil migration and its targeting with a novel selective inhibitor JBI-589. Cancer Research, 2022. Online publication.


The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. Wistar’s Business Development Team is dedicated to advancing Wistar Science and Technology Development through creative partnerships.

Jubilant Therapeutics Inc. is a clinical stage precision therapeutics company advancing potent and selective small molecule modulators to address unmet medical needs in oncology and autoimmune diseases. Its advanced discovery engine integrates structure-based design and computational algorithms to discover and develop novel, precision therapeutics against both first-in-class and validated but intractable targets in genetically defined patient populations. The Company’s advanced pipeline consists of a first in class dual epigenetic modifier, JBI-802, currently in a Phase I/II clinical trial to treat solid tumors, a novel brain-penetrant modulator of PRMT5 for which an IND has been accepted, a brain penetrant PDL1 inhibitor, as well as PAD4 inhibitors for oncology and inflammatory indications. The Company is headquartered in Bedminster, New Jersey and guided by globally renowned key opinion leaders and scientific advisory board members. For more: