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University of Illinois Cancer Center member Sandeep Kumar, PhD, is the Principal Investigator on a $709,000 U.S. Department of Defense (DoD) Breast Cancer Research Program award, along with fellow Cancer Center member co-investigators Kent Hoskins, MD, and Kiwook Kim, PhD.

The three-year grant brings together researchers from the Cancer Center Translational Oncology (Kumar and Hoskins) and Cancer Biology (Kim) research programs. Their project, “Targeting Triple-Negative Breast Cancer (TNBC) Tumors and Immunosuppressive Tumor Microenvironment: Potential Role of MLK1,” includes an additional collaborator at the University of Pittsburgh. 

Their work aims to provide valuable insights into the role of the protein MLK1 in tumors and its correlation with disease progression and patient mortality, establishing it as a potential biomarker for the progression TNBC, an aggressive cancer.  

All three Cancer Center members are part of the College of Medicine at UIC. Kumar (pictured center) is Assistant Professor in the Department of Surgery; Hoskins (pictured left) is Professor in the Division of Hematology and Oncology, as well as a breast oncologist and Oncology Service Line Medical Director at UI Health; and Kim (pictured right) is Assistant Professor in the Department of Pharmacology and Regenerative Medicine.

Kumar said Translational Oncology Research Program co-leader Ajay Rana, PhD, Endowed Professor in the Department of Surgery, has been instrumental in his career growth, and Hoskins has been a source of consistent support. He is also thankful to Cancer Center member Enrico Benedetti, MD, Chair, Professor and Department Head in Surgery, for the departmental support.

Read the project abstract excerpted below.

The lack or negligible presence of therapeutic targets (ER, PR, and HER2), immunosuppressive tumor microenvironment (TME), and inadequate host’s anti-tumor immune response present a clinical challenge in treating patients with TNBC. Therefore, identifying pathway(s) and agents that can effectively prevent TNBC progression, reshape TME, and increase T cell cytotoxicity with no/minimal side effects should significantly impact TNBC patients' therapeutic outcomes. The Mixed Lineage Kinase (MLK) family member MLK1 is overexpressed in TNBC tumors and positively correlated with patients' mortality. Interestingly, MLK1 is directly involved in regulating tumor progression and the infiltration of tumor-associated macrophages (TAMs). MLK1 regulates VISTA-expressing TAMs, which might have a significant role in TAM-mediated TNBC progression. The therapeutic-grade siMLK1-loaded nanocarrier (siMLK1-NPs) efficiently inhibits MLK1 protein expression under both in vitro and in vivo conditions, resulting in tumor regression and downregulation of TAM signaling. The inhibition of MLK1 has failed to enhance the tumor infiltration of cytotoxic T cells (CTLs); however, it increases galectin 3 (Gal3) mRNA and protein expression in TNBC tumors, which can be targeted to boost CTL infiltration and function. Interestingly, the combined blockade of the MLK1-Gal3 axis increases the number of CTLs in TNBC preclinical models. Based on our preclinical data, we anticipate that the successful completion of this project will provide valuable insights into the role of MLK1 in tumors and its correlation with disease progression and patient mortality, establishing it as a potential biomarker for the progression of TNBC.