A Potential Molecular Target for the Treatment of Uveal Melanoma

1. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 A Potential Molecular Target for the Treatment of Uveal Melanoma Jae Hyuk Yoo, PhD Department of Internal Medicine University of Utah Molecular Medicine (U2M2) Program

2. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Before Starting; - Please, please, please interrupt me at any time, ask questions http://cutelovelypics.blogspot.com

3. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 http://www.kellogg.umich.edu/theeyeshaveit • Most common primary ocular malignancy • Half of patients will develop metastases, usually to the liver • No effective treatments for metastatic UM • Mutations in Gαq genes GNAQ or GNA11 in ~90% of cases • Genetic landscape of UM recently characterized Uveal Melanoma (UM)

4. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 https://1bgubiologylcv.wordpress.com/2018/01/09/the-central-dogma-of-molecular- biology-and-gene-regulation/ Robertson et al., Cancer Cell, 2017

5. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Oncogene (accelerator) and Tumor suppressor (brake) Normal cellCancer cell Example in UM: Oncogene: GNAQ/GNA11

6. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 https://www.mycancergenome.org/content/gene/gnaq/ GNAQ/GNA11 - Gq alpha subunit, GTPase protein, and oncogene

7. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 http://tbl.med.yale.edu/cell_communication/reading.php The GTPase protein regulatory cycle Activating mutations in GNAQ or GNA11 – constitutively active GNAQ or GNA11

8. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Signal Pathway (transduction) Signal Pathway is the process by which a chemical or physical signal is transmitted through a series of molecular events in a cell

9. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Targeted Therapy in UM Yang et al., Ther Adv Med Oncol., 2018 PLC-PKC MAPKYAP

10. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 GTPase-activating proteins (GAPs) Guanine exchange proteins (GEFs) ARF6- GDP ARF6- GTP active Inactive ARF6: Small GTPase protein of the Ras superfamily

11. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 The diverse roles of ARF6 on cellular function and behavior Grossmann et al., Small GTPases, 2016

12. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Onken et al. Ophthalmology, 2012 Gene expression profile (GEP) Harbour JW, Methods Mol Biol., 2014

13. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 The Small GTPase ARF6 Stimulates β-Catenin Transcriptional Activity During WNT5A-Mediated Melanoma Invasion and Metastasis Grossmann et al., Sci. Signal., 2013

14. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 • Mutations in Gαq genes GNAQ or GNA11 in ~90% of cases. • The loss of ROBO1 expression is among 12 expression markers that predict progression to uveal melanoma metastasis Rationale for study ARF6 in UM

15. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 ARF6 protein levels are increased in human UM Yoo et al., Cancer Cell, 2016

16. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 What is the role of ARF6 in UM? Can we target ARF6 in UM? http://www.srimalplantation.com/complete-cure-for-cancer-with-ayurveda/

17. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 ARF6 is activated by oncogenic GNAQ Yoo et al., Cancer Cell, 2016 (Reducing) (normal cell) (Uveal melanoma cells)

18. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 ARF6 is required for uveal melanoma cell proliferation Yoo et al., Cancer Cell, 2016 (Reducing) 2D cell culture 3D cell culture (Reducing)

19. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 ARF6 is an actionable node that orchestrates oncogenic GNAQ signaling in uveal melanoma Yoo et al., Cancer Cell, 2016 PLC-PKC MAPK YAP

20. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 ARF6 controls GNAQ trafficking between the plasma membrane and cytosol/cytosolic vesicles Yoo et al., Cancer Cell, 2016 GNAQ (Green) Nucleus (Blue) GNAQ (Green) Nucleus (Blue)

21. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Silencing ARF6 reduces uveal melanoma tumorigenesis Yoo et al., Cancer Cell, 2016 cornea lens retina iris cornea lens retina iris (tumor establishment) (tumor growth)

22. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 What is the role of ARF6 in UM? Can we target ARF6 in UM? http://www.srimalplantation.com/complete-cure-for-cancer-with-ayurveda/

23. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 NAV-2729 is a specific ARF6 inhibitor Yoo et al., Cancer Cell, 2016

24. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 NAV-2729 is a specific ARF6 inhibitor Yoo et al., Cancer Cell, 2016

25. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 NAV-2729 is a specific ARF6 inhibitor Yoo et al., Cancer Cell, 2016 (tumor establishment) (tumor growth)

26. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 ARF6 is an actionable node that orchestrates oncogenic GNAQ signaling in uveal melanoma Yoo et al., Cancer Cell, 2016

27. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 https://www.cytoskeleton.com/about/arf The function of ARF6 on migration and invasion of cancer cell

29. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Does ARF6 control UM cell invasion and metastasis? Silencing of ARF6 inhibits the invasion of uveal melanoma cells Unpublished data (Reducing)

30. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Xenograft model of uveal melanoma metastasis 0 week 5 weeks Injection with UM cells and /or NAV-2729 (Daily injection for NAV-2729) Harvesting samples No metastasis https://www.clodrosome.com/animal-injection/

31. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 Xenograft model of uveal melanoma metastasis 0 week 8 weeks Injection with UM cells Harvesting samples Metastasis Retro-orbital injection Yardeni et al., Lab Anim (NY), 2011 3 week Start to inject with NAV-2729 daily

32. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 1. Oncogenic GNAQ/ARF6 is required for the proliferation of tumor cells. 2. ARF6 is required for UM cell invasion. 3. Oncogenic GNAQ/ARF6 orchestrates multiple downstream pathways. 4. Reducing ARF6 level or Inhibiting ARF6 with the drug reduces tumor establishment and growth. Summary

33. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 ACKNOWLEDGMENTS Dean Li Shannon Odelberg Allie Grossmann Weiquan (Wendy) Zhu Max Shin Coulson Rich Lehi Acosta Aaron Rogers Lise Sorensen Jackson Richards Other members Collaborators University of Miami Bill Harbour M. D. Anderson Cancer Center Scott Woodman University of Notre Dame Crislyn D’Souza-Schorey Navigen Pharmaceuticals Alan Muller Daniel Wettstein Zongzhong Tong Lab family Biological family Wife, JY and AS Funding CURE OM Junior Fellowship Award NIH NCI R01 We want to be Jedi to fight cancer

34. © U N I V E R S I T Y O F U T A H H E A L T H , 2 0 1 8 A Potential Molecular Target for the Treatment of Uveal Melanoma

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