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Osnat Ashur-Fabian 1,Keren Cohen 1,Aleck Hercbergs 2,Martin Ellis 1 1 Translational Hemato-Oncology, The Hematology Institute, Meir Medical Center & Sackler.

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Presentation on theme: "Osnat Ashur-Fabian 1,Keren Cohen 1,Aleck Hercbergs 2,Martin Ellis 1 1 Translational Hemato-Oncology, The Hematology Institute, Meir Medical Center & Sackler."— Presentation transcript:

1 Osnat Ashur-Fabian 1,Keren Cohen 1,Aleck Hercbergs 2,Martin Ellis 1 1 Translational 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 Tetrac, a small molecule integrin ligand cooperates with bortezomib and enhances cellular response in myeloma cells: A novel chemosensitizing approach in myeloma

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 Incurable * Median survival 3-5 years * Most patients refractory/relapse Novel targeted therapies Treatments * Steroids/Chemotherapy * Bone-marrow transplantation

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) * Proteasome inhibition * Promotes apoptosis * Increased proteasome activity in multiple myeloma, Bortezomib * The first FDA approved proteasome inhibitor * Dysregulated proteasome activity in cancer

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

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? V 3 Plasma membrane Nucleus RGD Proliferation PKC, MAPK Angiogenesis VEGF T3/T4 Metabolic rate? Oxygen consumption ATP formation IGF-1/EGF TR 1 Classical function

12 Thyroid function and cancer Mimicking selective hypothyroidism V 3 Plasma membrane Nucleus T3/T4 Proliferation Angiogenesis Tetrac Sensitizes Chemo/radiation therapy TR 1

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 Importance of v 3 in MM and cancer Thyroid function and multiple myeloma (MM)

17 Effect of thyroid hormones in MM? Thyroid function and multiple myeloma (MM) V 3 Plasma membrane Nucleus T3/T4

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

19 Effect of thyroid hormones in MM Will blocking thyroid hormones binding to v 3 induce * cell proliferation? * cell death? Thyroid function and multiple myeloma (MM) V 3 Plasma membrane Nucleus T3/T4 Tetrac

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

21 * * * Apoptosis Necrosis Tetrac induces myeloma cell death

22 RGD but not RGE blocks tetrac activity in MM cells V 3 Plasma membrane Nucleus T3/T4 RGD Tetrac * *

23 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? Thyroid function and multiple myeloma (MM)

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

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

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

27 Current/future work * Biological pathways activated by t3/t4 in MM * MAPK * VEGF * v 3 role in myeloma * Level * SiRNA * Tetrac prior to bortezomib * Tetrac effect on Ab production * Co-culture with stroma cells * Tetrac Nanoparticle Thyroid function and multiple myeloma (MM)

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

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


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