1. A novel chemosensitizing approach in myeloma
Tetrac, a small molecule integrin ligand cooperates with bortezomib and enhances cellular response in myeloma cells:
A novel chemosensitizing approach in myeloma
Osnat Ashur-Fabian1 ,Keren Cohen1 ,Aleck Hercbergs2 ,Martin Ellis1
1Translational Hemato-Oncology, The Hematology Institute,
Meir Medical Center & Sackler Faculty of Medicine, Tel-Aviv University, ISRAEL
2 Department of Radiation Oncology,
The Cleveland Clinic, Cleveland, Ohio, USA

2. Multiple Myeloma (MM) First described in 1844 * Sarah Newbury
* Dr. Samuel Solly
Plasma cell (PC)
* Bone Marrow

3. Multiple Myeloma (MM) Plasma cells * Antibodies (Ab) producing cells
Plasma cell neoplasm
* Abnormal plasma cells proliferation
* Excess Ab production
* Bone damage, Kidney

4. Multiple Myeloma (MM) 10% of hematological malignancies Treatments
* Steroids/Chemotherapy
* Bone-marrow transplantation
Incurable
* Median survival 3-5 years
* Most patients refractory/relapse
Novel “targeted” therapies

5. Multiple Myeloma timeline (MM)

6. Bortezomib (Velcade) Proteasome inhibitor The concept
* 80% of proteins are destroyed by proteasome system
* Balanced degradation (cell cycle/anticancer proteins, p53)
* Dysregulated proteasome activity in cancer
* Proteasome inhibition
* Promotes apoptosis
Bortezomib
* The first FDA approved proteasome inhibitor
* Increased proteasome activity in multiple myeloma,

7. Bortezomib in multuple myeloma
Preclinical and clinical trials in myeloma bortezomib
* Inhibited proliferation
* Enhanced apoptosis
* Synergism with chemotherapies
Improved outcome
The problem
* Side effects
* Resistance
Demand for discovery of new drugs/combination

8. Thyroid function and cancer
Dr. Aleck Hercbergs
Hypothyroidism and tumor regression.
N Engl J Med. 319(20):
Cancer patients with hypothyroidism
* Increase sensitivity to chemotherapy
* Increased sensitivity to radiation therapy
* Prolonged survival

9. Clinical supportive data
Hypothyroidism reduces cancer incidence and improves survival

10. Clinical supportive data
Hyperthyroidism increases cancer risk

11. Thyroid function and cancer
The biological process?
Metabolic rate?
Oxygen consumption
ATP formation
IGF-1/EGF
“Classical” function
RGD
T3/T4
Plasma membrane
aVb3
TRb1
Nucleus
Proliferation
PKC, MAPK
Angiogenesis
VEGF

12. Thyroid function and cancer
Mimicking selective hypothyroidism
T3/T4
Tetrac
Plasma membrane
aVb3
TRb1
Nucleus
Sensitizes
Chemo/radiation therapy
Angiogenesis
Proliferation

13. Thyroid function and cancer
The biological process

14. Clinical supportive data
Chemically induced subclinical hypothyroidism
prolongs cancer patients survival
PTU
Methimazole

15. Official consensus statement- Cleveland Clinic, USA
* Evidence for T3/4 involvement in cancer
* No thyroid hormones supplements in subclinical hypothyroidism
(Supported by “The American Thyroid Association”)
* Advocate conservatism in replacement therapy in
hypothyroid patients who harbor a diagnosis of solid cancer
* Signed by hospital oncologist/endocrinologist

16. Thyroid function and multiple myeloma (MM)
Importance of avb3 in MM and cancer

17. Thyroid function and multiple myeloma (MM)
Effect of thyroid hormones in MM?
T3/T4
Plasma membrane
aVb3
Nucleus

18. T3/T4 increases myeloma cells proliferation* * * * * * *
S phase
G2M

19. Thyroid function and multiple myeloma (MM)
Effect of thyroid hormones in MM
Will blocking thyroid hormones binding to avb3 induce
* cell proliferation?
* cell death?
T3/T4
Tetrac
Plasma membrane
aVb3
Nucleus

20. Tetrac reduces myeloma cell proliferation/survival* * * *
Cell survival
Cell proliferation

21. Tetrac induces myeloma cell death* * *
Apoptosis
Necrosis

22. RGD but not RGE blocks tetrac activity in MM cells
T3/T4
Tetrac *
Plasma membrane
aVb3
Nucleus

23. Thyroid function and multiple myeloma (MM)
Effect of thyroid hormones in MM
Will blocking thyroid hormones binding to avb3 induce
* cell proliferation?
* cell death?
Will blocking thyroid hormones sensitize bortezomib action?

24. cell proliferation cell survival
Tetrac sensitizes bortezomib action
Supra additive
cell proliferation cell survival * * * *
Drug “sparing effect”

25. Supra additive/additive
Tetrac sensitizes bortezomib action
Supra additive/additive
Apoptosis Necrosis * m

26. Combined tetrac-bortezomib and cell cycle
Control
Bortezomib
Bortezomib
+ tetrac

27. Thyroid function and multiple myeloma (MM)
Current/future work
* Biological pathways activated by t3/t4 in MM
* MAPK
* VEGF
* avb3 role in myeloma
* Level
* SiRNA
* Tetrac prior to bortezomib
* Tetrac effect on Ab production
* Co-culture with stroma cells
* Tetrac Nanoparticle

28. Thyroid function and multiple myeloma (MM)
Summary
Thyroid hormones induce proliferation in myeloma cells
Tetrac, mimics selective hypothyroidism
* Reduce proliferation
* Induce death
* Sensitized bortezomib action
*Supra-additive
* Drug sparing effect
Novel adjunct therapy in myeloma and cancer in general
* Low risk
* Bench to bed-side
* Low cost
* Combined with any chemotherapy

29. ד"ר מרטין אליס The Cleveland Clinic מרכז רפואי מאיר
Cleveland, Ohio, USA
Department of Radiation Oncology
Dr. Aleck Hercbergs
מרכז רפואי מאיר
ד"ר אשר אלחיאני
המעבדה האונקוגנטית
פרופ' מיקי לישנר
ד"ר ליאת דרוקר
ד"ר שלי מטלון
בקרוב ד"ר ויקי זיסמנוב...
צוות הפקס
חווה שפירא
רחל שיקלר
קרן כהן
Ordway Research Institute
Albany, NY, USA
Signal Transduction Laboratory
Prof. Paul J. Davis
ד"ר מרטין אליס