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Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and available therapies, including immunotherapies, are ineffective for many patients. HCC is characterized by intratumoral hypoxia, and increased expression of hypoxia-inducible factor 1α (HIF-1α) in diagnostic biopsies is associated with patient mortality. Here we report the development of 32-134D, a low-molecular-weight compound that effectively inhibits gene expression mediated by HIF-1 and HIF-2 in HCC cells, and blocks human and mouse HCC tumor growth. In immunocompetent mice bearing Hepa1-6 HCC tumors, addition of 32-134D to anti-PD1 therapy increased the rate of tumor eradication from 25% to 67%. Treated mice showed no changes in appearance, behavior, body weight, hemoglobin, or hematocrit. Compound 32-134D altered the expression of a large battery of genes encoding proteins that mediate angiogenesis, glycolytic metabolism, and responses to innate and adaptive immunity. This altered gene expression led to significant changes in the tumor immune microenvironment, including a decreased percentage of tumor-associated macrophages and myeloid-derived suppressor cells, which mediate immune evasion, and an increased percentage of CD8+ T cells and natural killer cells, which mediate antitumor immunity. Taken together, these preclinical findings suggest that combining 32-134D with immune checkpoint blockade may represent a breakthrough therapy for HCC.
Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and incidence in the United States has tripled over the last 2 decades (1-3). At the time of diagnosis, more than two-thirds of HCC patients have advanced disease, which is often intractable to available therapies and has a 5-year survival of less than 15% (3). The first approved drug for advanced HCC, which was the tyrosine kinase inhibitor (TKI) sorafenib, provided only a modest survival benefit of 2 to 3 months with low response rates, high toxicity often requiring dose reduction or treatment interruption, and frequent development of resistance, and was followed by several other TKIs (lenvatinib, regorafenib, cabozantinib) and ramucirumab, an antibody against vascular endothelial growth factor A (VEGFA) receptor 2 (4-6).
Immune checkpoint blockade with antibodies that target programmed death 1 (PD1) or PD1 ligand 1 (PDL1) has revolutionized the treatment of advanced melanoma, non-small cell lung cancer, and renal cell carcinoma (RCC) (7-9). PDL1, which is expressed on tumor and stromal cells, binds to PD1 on T cells...