Osnat Ashur-Fabian 1 ,Keren Cohen 1 ,Aleck Hercbergs 2 ,Martin Ellis 1

1. Tetrac, a small molecule integrin ligand cooperates with bortezomib and enhances cellular response in myeloma cells: A novel chemosensitizing approach in myeloma OsnatAshur-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 proteasomeactivity 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):1351-2. 1988 • 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. RGD T3/T4 Angiogenesis VEGF Proliferation PKC, MAPK Thyroid function and cancer The biological process? Metabolic rate? Oxygen consumption ATP formation IGF-1/EGF “Classical” function Plasma membrane aVb3 TRb1 Nucleus

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

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

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

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

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

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

22. RGD Tetrac * * RGD but not RGE blocks tetrac activity in MM cells T3/T4 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. Supra additive Tetrac sensitizes bortezomib action cell proliferation cell survival * * * * Drug “sparing effect”

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

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. The Cleveland Clinic Cleveland, Ohio, USA • 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 • Department of Radiation Oncology • Dr. Aleck Hercbergs Ordway Research Institute Albany, NY, USA • Signal Transduction Laboratory • Prof. Paul J. Davis • ד"ר מרטין אליס