Targeting leucine-rich alpha-2-glycoprotein-1 (LRG1) and the LRG1-cytochrome c-Apaf-1 axis in cancer therapy

Leucine-rich alpha-2-glycoprotein-1 (LRG1) has received much attention as a prognostic indicator in cancer therapy where high serum levels generally predict a poor outcome. Recently, it has been shown to play an active role in cancer progression and is being pursued as a novel target in cancer therapy. LRG1 acts in neovascularization of tumors resulting in weakened blood vessels and ineffective delivery of chemotherapeutic drugs. A monoclonal antibody (mAb) against LRG1 has shown efficacy in blocking this function of LRG1, normalizing the vasculature, and improving drug delivery in mice. Extracellular LRG1 is also anti-apoptotic and promotes cell proliferation and metastasis, all through epidermal growth factor receptor family signaling. In mice, anti-LRG1 antibody therapy has been shown to inhibit these effects of extracellular LRG1 and to enhance the anti-cancer effect of immune checkpoint blockade (ICB) therapy in mice. Pre-clinical testing of the humanized version of the LRG1 mAb is underway in the United Kingdom. Intracellular LRG1 has been reported to inhibit apoptosis by blocking the binding of Cyt c to apoptotic protease activating factor1 (Apaf-1) and to have other cytoplasmic functions. A nanoscale proteolysis targeting chimera (nano-PROTAC) with improved cytoplasmic delivery has been developed which enhanced apoptosis in tumors of mice. Targeting LRG1 in the aberrant angiogenesis of endothelial cells and the LRG1-Cyt c-Apaf-1 axis in cancer cells, along with other putative intracellular interactions of LRG1, show potential as supplementary, if not alternative, approaches to cancer therapy.