Technology Snapshot for Whiteboard2Boardroom on August, 28, 2018. Anti-Cancer Therapeutics: Novel Targets in the Cholesterol Biosynthesis Pathway

1. Anti-cancer Therapeutics:
Novel Targets in the
Cholesterol Biosynthetic
Pathway
August 28, 2018
Presentation by:
Brian Buntaine, M.S.,
M.B.A.
Sr. Licensing Associate
Office of Tech. Mgmt &
Industry Relations
Research by:
Salman Hyder, Ph.D.,
Xiaoqin Zou, Ph.D., Carl
Freter, Ph.D., Indira
Benakanakere, Ph.D., et al

2. What is the problem?
• Cancer is a leading cause of death globally
– Second only to cardiovascular disease
• Current treatments are insufficient
– 5-year survival rates for metastatic breast cancer and prostate
cancer patients are 25% - 30%; lung, colon, kidney, and pancreatic
are 5% - 10%*
– New classes of chemotherapeutics are needed
• Every cancer is unique, so every new chemotherapeutic we can add
to the toolbox helps
* https://www.cancercenter.com/ctca-results/
We need new treatments for cancer

3. What is the problem?
Data overview
• Identifying a novel druggable target
• Validating RO 48-8071 in breast cancer
– Efficacy in breast cancer models
• In vitro
• In vivo
– Mechanism(s) of action
• Extending applications to other cancer types
– Prostate cancer
• In vitro
– Mechanism(s) of action
• Other inhibitors of cholesterol biosynthesis
– Lovostatin, TAK-475, YM-53601, and BIBB-515
• Applications in chronic lymphocytic leukemia

4. How does product/service solve problem?
Identifying a novel druggable target

5. How does product/service solve problem?
Oxidosqualene cyclase (OSC) was identified as a cancer drug target
through computational modeling of PRIMA-1 binding
• PRIMA-1 was known to restore mutant p53’s
tumor suppressor activity
• Using MU’s docking software Mdock,
Oxidosqualene Cyclase (OSC) was identified as a
likely target of PRIMA-1.
• RO 48-8071 (previously investigated for
cardiovascular indications) was identified as an
alternate and validated potent inhibitor of OSC
Grinter et al. (2011)
Structure and binding of
PRIMA-1 to OSC
Structure of RO 48-8071

6. How does product/service solve problem?
OSC inhibitor RO 48-8071 matches
PRIMA-1 and targets cancer cells via
increased p53 binding
• RO 48-8071 increases p53 binding similar
to PRIMA-1 (right)
• RO 48-8071 adversely affects viability of
breast cancer cells BT-474 and T47D, but
not normal mammary cells AG11132A
(bottom)
Grinter et al. (2011)

7. How does product/service solve problem?
Validating a RO 48-8071 in breast cancer

8. How does product/service solve problem?
In vivo mouse xenograft
• RO 48-8071 halted tumor progression (a)
• RO 48-8071 had no effect on animal weight (b)
Liang et al. (2014)

9. How does product/service solve problem?
In vivo mouse xenograft
• 48-8071 drastically downregulated the breast cancer marker ERα
• RO 48-8071 marginally upregulated the anti-proliferative ERβ
Grinter et al. (2011)

10. How does product/service solve problem?
In vitro cell culture
• Western blot for ERα and ERβ show significant downregulation of ERα and
and significant upregulation of ERβ in RO 48-7081 treated cells
Liang et al. (2014)

11. How does product/service solve problem?
In vitro cell culture
• RO-48-8071 effects on [ERα] and [ERβ] are achieved transcriptionally
Mafuvadze et al. (2014)
ERα ERβ

12. How does product/service solve problem?
In vitro cell culture
• RO-48-8071 downregulates Androgen Receptor (AR) transcriptionally
Mafuvadze et al. (2014)
AR

13. How does product/service solve problem?
In vitro cell culture
• RO-48-8071 decreases MPA-induced CD44 [protein]
Liang et al. (2017)
T47-D
BT-474

14. How does product/service solve problem?
In vitro cell culture
• RO-48-8071 decreases [PR] post-translationally
Liang et al. (2017)
RT-PCR for PRWestern Blot for PR

15. How does product/service solve problem?
In vitro cell culture
• RO-48-8071-mediated [PR] reduction occurs via the proteasome
degradation pathway
Liang et al. (2017)

16. How does product/service solve problem?
In vitro cell culture
• RO 48-8071 abolishes MPA-induced mammosphere formation, suggesting it
reduces cancer stem cells (an important precursor of metastasis)
Liang et al. (2017)

17. How does product/service solve problem?
Extending Application to Other Cancer Types

18. How does product/service solve problem?
Applications in prostate cancer therapy
• RO-48-8071 selectively reduces prostate cancer cell viability
Liang et al. (2016)
LNCaP
Hormone-dependent
PC3 and DU145
Castration-resistant
RWPE-1
Normal Prostate Cells

19. How does product/service solve problem?
Applications in prostate cancer therapy
• RO-48-8071 selectively induces apoptosis in prostate cancer cells
Liang et al. (2016)
LNCaP
Hormone-
dependent
C4-2
Castration-
resistant
PC-3 and DU145
Castration-resistant

20. How does product/service solve problem?
Applications in prostate cancer therapy
• RO-48-8071 reduces AR and increases Erβ expression
Liang et al. (2016)
LNCaP
AR-positive
Hormone-dependent
PC-3
Castration-resistant
LNCaP
AR-positive
Hormone-dependent

21. How does product/service solve problem?
Other Inhibitors of Cholesterol Biosynthesis

22. How does product/service solve problem?
Other cholesterol biosynthesis inhibitors and their applications
• Statins enhance chemoimmuno-sensitivity in vitro
Benakanakere et al. (2014)

23. How does product/service solve problem?
Other cholesterol biosynthesis inhibitors and their applications
• SS- and OSC-inhibitors YM-53601 and BIBB-515 enhance chemoimmuno-
sensitivity in vitro
Benakanakere et al. (2014)

24. How does product/service solve problem?
Other cholesterol biosynthesis inhibitors and their applications
• SS- and OSC-inhibitors TAK-475 and BIBB-515 enhance chemoimmuno-
sensitivity in CLL patient peripheral blood mononuclear cells (PBMCs)
Benakanakere et al. (2014)

25. How does product/service solve problem?
Data Summary

26. How does product/service solve problem?
Data demonstrate a variety of cholesterol biosynthesis inhibitors
with broad application in cancer therapy
• RO 48-7081 (OSC inhib.):
– Breast cancer:
• Targets p53 in breast cancer cells and targets cancer in a dose-dependent
manner in cells and mouse xenografts with no toxicity
• Exerts its effect through transcriptional regulation of ERα, Erβ, and AR
• Reduces PR and inhibits MPA-induced mammosphere formation
- Prostate cancer:
- Selectively induces apoptosis via post-translational regulation of ERβ and AR
• Other chol. biosynth. Inhibitors (lovastatin, YM-53601, TAK-475, BIBB-515)
– Chronic Lymphocytic Leukemia
• Induce chemoimmuno-sensitivity in CLL patients

27. What is the market use?
Treat various cancers
– Demonstrated efficacy in:
• Breast cancer – in vitro and in vivo data
• Prostate cancer – in vitro data
• Chronic lymphocytic leukemia – in vitro and ex vivo data
– Resensitization to chemo-immunotherapy resistant cancers

28. What competition exists?
Current alternative treatments include
• Biological therapies / Immunotherapy
• Inhibitors of DNA synthesis & intercalators
• Anti-Hormones
• Alkylating agents
• Anti-metabolites
• Inhibitors of Cell Cycle arrest
• Plant alkaloids and terpenoids
• Topoisomerase Inhibitors
• Cytotoxic Antibiotics
• Radiotherapy
• PRIMA-1 (in PII trials)
• Others
0
10
20
30
40
50
60
70
80
90
0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
PatientSurvivalrate(%)
Years after initial diagnosis
Representative Breast/Prostate
Cancer Survival Rate (2000 – 2013)*
https://www.cancercenter.com/breast-
cancer/statistics/tab/breast-cancer-survival-statistics/

29. What is the status of the intellectual property?
Type Reference Territory Status
Patent 2011352378 Australia Issued
Patent Application 13/796,635 United States Allowed
Patent Application EP11853116.9 Europe Pending
Patent Application 2,822,207 Canada Pending
Patent 201180063224.1 China Issued
Patent 2013-546416 Japan Issued
Patent Application 14/352,950 United States Pending
Patent Application 12841499.2 Europe Pending
Patent Application 14/410,887 United States Pending
Patent Application 13810751.1 Europe Pending
Patent Application 2,876,241 Canada Pending
* RO 48-8071, BIBB-515, and YM-53601 compositions are off patent; TAK-475 has short patent
life remaining

30. What is the stage of development?
• Next Steps:
– Licensing to established company or startup
– Clinical trials

31. Contact
For more information please contact Jim Baxendale, Director of
Whiteboard2Boardroom:baxendalej@umkc.edu.

32. - Grinter et al., (2011). An inverse docking approach to identifying new anti-
cancer targets. J. Mol. Graphics and Modeling 6: 795-9.
- Liang et al. (2014). Cholesterol biosynthesis inhibitors as potent novel anti-
cancer agents: suppression of hormone-dependent breast cancer by the
oxidosqualene cyclase inhibitor RO 48-8071. Breast Cancer Res Treat 146:
51-62
- Mafuvadze et al. (2014). Cholesterol synthesis inhibitor RO 48-8071
suppresses transcriptional activity of human estrogen and androgen
receptor. Oncology Reports 32 1727-1733.
- Benakanakere et al. (2014). Targeting cholesterol synthesis increases
chemoimmuno-sensitivity in chronic lymphocytic leukemia cells.
Experimental Hematology & Oncology 3:24.
- Liang et al. (2016). Cholesterol biosynthesis inhibitor RO 48-8071
suppresses growth of hormone-dependent and castration-resistant prostate
cancer cells. OncoTargets and Therapy 9 3223-3232.
- Liang et al. (2017). Cholesterol biosynthesis inhibitor RO 48-8071 reduces
progesterone receptor expression and inhibits progestin-dependent stem
cell-like cell growth in hormone-dependent human breast cancer cells.
Breast Cancer – Targets and Therapy 9 487-494.
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