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© 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
© 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
© 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)
© 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
© 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
© 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
© 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
© 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
© 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
© 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
© 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
© 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
© 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
© 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
© 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
© 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/
© 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)
© 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)
© 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
© 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)
© 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)
© 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/
© 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
© 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
© 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)
© 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
© 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
© 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
Steps in
metastasis
McGee et al., EMBO Rep., 2006
© 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)
© 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/
© 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
© 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
© 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
© 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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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
  • 28. © 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 Steps in metastasis McGee et al., EMBO Rep., 2006
  • 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