June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
HIF-inhibitor 64B induces necrosis and suppresses proliferation, metastasis and YAP1 expression in mouse model of uveal melanoma
Author Affiliations & Notes
  • Hua Yang
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Hans E Grossniklaus
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Yutao Yan
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Margaret Offermann
    OncoSpherix, Inc, Georgia, United States
  • Erwin Van Meir
    University of Alabama at Birmingham, Alabama, United States
  • Footnotes
    Commercial Relationships   Hua Yang None; Hans Grossniklaus None; Yutao Yan None; Margaret Offermann OncoSpherix, Inc, Code O (Owner); Erwin Van Meir None
  • Footnotes
    Support  Georgia Research Alliance, NEI P30 03630
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2362 – A0031. doi:
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      Hua Yang, Hans E Grossniklaus, Yutao Yan, Margaret Offermann, Erwin Van Meir; HIF-inhibitor 64B induces necrosis and suppresses proliferation, metastasis and YAP1 expression in mouse model of uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2362 – A0031.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Our previous studies have demonstrated the importance of hypoxia in uveal melanoma (UM) growth and have identified that a hypoxia-inducible factor (HIF) inhibitor 64B reduces primary tumor growth and metastasis in an intraocular melanoma mouse model. Here, we further observe the longitudinal growth of UM in a heterotopic UM animal model treated by 64B and identify a potential new mechanism of action.

Methods : The HIF inhibitor 64B was provided by OncoSpherix, Inc. MTT and crystal violet assays were performed to determine cell viability in response to varying concentrations of 64B in cultured human UM cell lines 92.1 and Mel202. Athymic nude mice (Jackson laboratory) implanted with human UM cells 92.1 subcutaneously were divided to the vehicle control and 64B group (10 mice per group). 120 mg/kg 64B by intraperitoneal injection, once per day, started at a tumor size larger than 80 mm3. Tumor size and mice weight were monitored weekly. Tumor necrosis and liver metastases were quantitated by histology. Immunohistochemistry of Ki67/MIB1 and Yes-associated protein (YAP1) were performed.

Results : Cell viability assays demonstrated that 64B killed 92.1 and Mel202 cells after 3 days of 64B treatment when 64B was at or exceeded the concentration of 2µM. In mouse studies, 64B regressed s.c. 92.1 UM with clear evidence of necrosis and decreased numbers and sizes of liver metastasis compared to the control group. Furthermore, there was a reduction in the percentage of mice that had detectable lung metastasis from 50% in the control group to 20% in mice treated with 64B. The tumor proliferation marker Ki67/MIB1 expression in the 64B groups was significantly less than the control group in the primary tumors, and YAP1 expression associated with hypoxia was suppressed by 64B.

Conclusions : The HIF inhibitor 64B inhibits primary UM growth as well as liver and lung metastasis in a heterotopic mouse model. In addition to the inhibition of HIF function by 64B, the inhibition of the expression of the transcription factor YAP1 might contribute to the antitumor effect of 64B by blocking the ability of YAP1 to promote cancer cell proliferation, chemoresistance, and invasion.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.


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