The first $25,000 awards were announced to fund inaugural proposals for new cancer drug discovery in a joint effort by the University of Illinois Cancer Center and UICentre, the campus-wide drug discovery enterprise at the University of Illinois Chicago.

The two awarded projects stem from a Request for Applications (RFA) entitled “U2D2” launched last year by the Cancer Center and UICentre. Cancer Center members are investigators on the projects.

The project, “Identification of Glioblastoma Subtype Specific Small Molecule Inhibitors for Therapeutics Development,” is led by Principal Investigator (PI) Zilai Wang, PhD, and co-Investigator Lijun Rong, PhD, both part of the Cancer Center’s Translational Oncology research program and the Department of Microbiology and Immunology in the University of Illinois College of Medicine Chicago, plus co-Investigator Yuwei Jiang, PhD, of the Department of Physiology and Biophysics in the College of Medicine.

The project, “Bioassay Development to Discover Lipid-Src Interaction Inhibitors; Potential Therapeutics for Triple-Negative Breast Cancer,” is led by Cancer Center member and PI Wonhwa Cho, PhD, Distinguished Professor and Head of the Department of Chemistry, Liberal Arts & Sciences, at UIC.

PI Wang described their project this way:

Glioblastoma (GBM) is the most lethal primary brain tumor in adults with no cure, characterized by vast variations of tumor properties within a single tumor and between different tumors.

To better understand GBM development, we have created mouse models of two distinct GBM subtypes by targeting two different stem/progenitor cell types in the brain, and established a cell lineage-based GBM classification strategy from mice to humans, which has facilitated the identification of human Type I and Type II GBM and their starkly differential susceptibility to anti-cancer therapies. These findings have established a solid foundation we can take advantage of to identify subtype-specific small molecule inhibitors targeting Type I or Type II GBM for therapeutic development.

In the Cancer Center and UICentre Drug Discovery Program (U2D2) application, we proposed to perform a cell-based, high-throughput screening (HTS) to identify and characterize small molecule inhibitors specifically targeting Type I and/or Type II GBM in cell cultures as well as in mice with tumor transplantation in their brains.

Our research will not only identify GBM subtype-specific small molecule inhibitors, but may also reveal subtype-specific signaling mechanisms and develop new therapeutics for GBM with more potency and precision in the near future.

PI Cho described his project this way:

Lipids play key regulatory roles in diverse biological processes, including cell signaling, through lipid-protein interaction (LPI). Recently, the Cho Group demonstrated that LPI inhibitors offer major advantages over conventional targeted therapy agents in terms of potency, specificity, and safety. Mounting evidence indicates that cholesterol is involved in cancer pathogenesis.

The Cho group recently discovered that the level of cholesterol in the inner leaflet of the plasma membrane (IPM) is elevated in cancer cells, which constitutively activates signaling proteins and thereby orchestrates cell-intrinsic oncogenic signaling networks in a cancer cell type-specific manner. As these stimulus- and mutation-independent signaling pathways lead to cancer progression and drug resistance, they present new actionable targets for targeted therapy.

Triple negative breast cancer (TNBC) is a highly aggressive and lethal breast cancer subtype currently lacking effective targeted therapy. In TNBC cells, elevated IPM cholesterol constitutively activates Src which orchestrates the complex oncogenic signaling network.

The Cho Group has hypothesized that selective inhibitors of the cholesterol-Src interaction could form the basis of a new therapeutic modality for TNBC.  With support from U2D2, UICentre will work closely with the Cho group to optimize biochemical and cellular assays to identify inhibitors of the cholesterol-Src interaction.

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