Therapeutic peptide for hepatocellular carcinoma Niranjan B. Pandey, Ph.D. ? PI Aleksander S. Popel, Ph.D. ? Co-I Jordan J. Green Ph.D. ? Co-I Phuoc T. Tran M.D., Ph.D. ? PI of subcontract Project Summary: There are very limited options currently available for the treatment of hepatocellular carcinoma (HCC), the most common type of liver cancer. HCC, like most forms of cancer, is dependent on angiogenesis, the growth of blood vessels. These and other tumors use VEGF and Ang2 to induce angiogenesis. The tumor also uses these factors to suppress the immune system. Anti-VEGF agents inhibit angiogenesis and also allow some activation of the immune system but they induce hypoxia which is itself immune suppressive. We have identified a peptide that simultaneously inhibits VEGF and activates Tie2, the receptor for Ang2. This peptide, AXT201, thus inhibits angiogenesis but promotes normalization of the remaining vasculature thus avoiding hypoxia and immune suppression. In addition by inhibiting VEGF and activating Tie2, AXT201 could make the immune system more anti-tumorigenic by allowing more dendritic cell maturation, more T-cell proliferation and infiltration into the tumor, and reduced number of regulatory T cells in the tumor. Checkpoint inhibitors are promising therapies for cancer but they have challenges with toxicity and also they only work in a minority of patients. The efficacy of these immunotherapies is minimized by an immune system kept suppressed by tumors. We hypothesize that AXT201 will enhance the efficacy of an anti-PD-1 antibody by making the immune system more anti-tumorigenic. Here we propose to determine if the combination of AXT201 and anti-PD-1 antibody increase survival of mice with lethal, autochthonous HCC tumors compared to anti-PD-1 or AXT201 alone. We will also test for evidence of immune system activation by AXT201. Finally we propose studies to facilitate translation of AXT201 into the clinic. Successful completion of the project will result in the creation of a powerful, new therapeutic for the treatment of hepatocellular carcinoma and also help AsclepiX Therapeutics reach a critical milestone.
Project Terms: Ablation; angiogenesis; Angiogenesis Inhibitors; Angiopoietin-2; Anti-PD-1; anti-PD1 antibodies; base; BAY 54-9085; bevacizumab; Blood Vessels; cancer therapy; cancer type; Cell Maturation; Cessation of life; Chemoembolization; chemotherapy; Clinic; Combined Modality Therapy; comparative efficacy; Data; Dendritic Cells; design; Development; Diagnosis; Distant; Doctor of Medicine; Doctor of Philosophy; Drug or chemical Tissue Distribution; efficacy testing; EGF gene; Excision; experimental study; Growth; HepG2; Hypoxia; Immune; immune activation; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapy; Infiltration; intraperitoneal; Jordan; KDR gene; liver transplantation; Malignant neoplasm of liver; Malignant Neoplasms; Mass Spectrum Analysis; medical schools; MEKs; Minority; Modeling; mortality; mouse model; multimodality; Mus; Neoplasm Metastasis; novel therapeutics; Operative Surgical Procedures; Pathway interactions; Patients; peptide drug; Peptides; Pharmaceutical Preparations; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Primary carcinoma of the liver cells; Radiofrequency Interstitial Ablation; Regulatory T-Lymphocyte; Signal Pathway; Site; subcutaneous; Survival Rate; T-Cell Proliferation; Testing; Therapeutic; therapy resistant; TIE-2 Receptor; Tissues; Toxic effect; Translations; tumor; tumor growth; tumor microenvironment; tumorigenic; Vascular Endothelial Growth Factors; Work; World Health Organization; Xenograft procedure;
