TY - JOUR
T1 - HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy
AU - Salman, Shaima
AU - Meyers, David J.
AU - Wicks, Elizabeth E.
AU - Lee, Sophia N.
AU - Datan, Emmanuel
AU - Thomas, Aline M.
AU - Anders, Nicole
AU - Hwang, Yousang
AU - Lyu, Yajing
AU - Yang, Yongkang
AU - Jackson, Walter
AU - Dordai, Dominic
AU - Rudek, Michelle
AU - Semenza, Gregg L.
N1 - Funding Information:
We thank Laura Kasch-Semenza and David Mohr in the Genetics Resources Core Facility for RNA library preparation and sequencing. We are grateful to Samantha Garcia and Rachel Geisler at Novus Biologicals for providing antibodies listed in Supplemental Table 6. DJM acknowledges funding from Flight Attendant Medical Research Institute and the JHU Institute for Clinical and Translational Research. EEW was supported by the Sarnoff Cardiovascular Research Foundation. NMA and MR were supported by grants from NIH (for the Analytical Pharmacology Shared Resource of the Sidney Kimmel Comprehensive Cancer Center) and the National Center for Advancing Translational Sciences. We thank Akrit Sodhi and Semenza lab members for helpful discussions. GLS is an American Cancer Society Research Professor and the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine. This work was supported by grants from the American Cancer Society and the Armstrong Family Foundation.
Publisher Copyright:
2022, Salman et al.
PY - 2022/5/2
Y1 - 2022/5/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI156774
DO - 10.1172/JCI156774
M3 - Article
C2 - 35499076
AN - SCOPUS:85129599312
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
M1 - e156774
ER -