1 / 24

NOVEL ASSOCIATION BETWEEN THYROID HORMONES and MYELOMA CELL PROLIFERATION

NOVEL ASSOCIATION BETWEEN THYROID HORMONES and MYELOMA CELL PROLIFERATION. A Unique Chemo-Sensitizing Approach in Cancer. Keren Cohen Translational Hemato-Oncology, Meir Medical Center, Israel. Multiple Myeloma (MM). First described in 1844 > Sarah Newbury > Dr. Samuel Solly.

nysa
Download Presentation

NOVEL ASSOCIATION BETWEEN THYROID HORMONES and MYELOMA CELL PROLIFERATION

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. NOVEL ASSOCIATION BETWEEN THYROID HORMONES and MYELOMA CELL PROLIFERATION A Unique Chemo-Sensitizing Approach in Cancer Keren Cohen Translational Hemato-Oncology, Meir Medical Center, Israel

  2. Multiple Myeloma (MM) • First described in 1844 >Sarah Newbury > Dr. Samuel Solly • Plasma cells >Bone Marrow > Antibodies producing cells

  3. Multiple Myeloma (MM) • Second most common hematological malignancy >2009 estimated new cases in the US: 20,580 • Treatments >Steroids/Chemotherapy >Bone-marrow transplantation • Incurable > Median survival 3-5 years >Most patients refractory/relapse • Urgent need for Novel “targeted” therapies

  4. Thyroid-Cancer AssociationSupportive Data- summary Hyperthyroidism Increases cancer risk More aggressive Hypothyroidism Increases survival Less aggressive 1 Kumar et al, Cancer Res, 1979 2. Sellitti et al, Cancer Rest, 1981 3. Ko et al. Cancer Causes Con, 2007 1 Cristofanilli et al, Cancer, 2005 2. Hercebrgs et al, abstract, ATA, 2009 3. Nelson et al. Arch Otolaryngol Head Neck Surg, 2006 4. Theodossiou et al. Am J Med Sci, 2000 4. Hellevic et al. Cancer Epidemiol Biomarkers Prev. 2009

  5. “Classical” T3 functions Oxygen consumption ATP formation IGF-1/EGF transcription T3/T4 Metabolism Angiogenesis VEGF, bFGF, Hif1a Proliferation MAPK Thyroid-Cancer association Physiological levels Plasma membrane aVb3 Tumor cells TRb1 Nucleus Cancer models: Brain, Breast, Lung, Prostate, Osteosarcoma, Renal, Neuroblastoma, Hepatocarcinoma, Myeloma, Colon, Pituitary, Pancreatic, Ovarian cancer

  6. Integrins

  7. aVb3 Integrin • Key points >Central player in cancer >Over-expressed during tumor progression >In correlation with tumor stage

  8. avb3 Imaging Next generation tumor imaging approach

  9. T3/T4 aVb3 Nucleus • Thyroid diseases and MM risk 4 Proliferation MAPK 4 Dalamga et al. Leuk. & Lymph., 49(8):1545-52, 2008 aVb3 is engaged in MM pathogenesis • aVb3 modulates MM cell: >Adhesion1 >Proliferation1 >Proteasesecretion1 >Invasiveness2 >Osteoclastactivity3 1 Vacca et al. Experimental Hematology, 29:993-1003, 2001 2 Ria et al. Haematologica, 87:836-845, 2002 3 Tucci et al. Cancer Research, 69(16):6738-46, 2009

  10. Physiological levels Western T3 T4 T3/T4 increases MM cell proliferation Cell number * * * * *

  11. Western 1nM T3 100nM T4 Control MAPK inhibitor 1nM T3 100nM T4 Control T3/T4 induce MM cells proliferation: MAPK dependent activity

  12. Physiological levels T3/T4 induce MM cells proliferation: MAPK dependent activity Immunofloresnce Physiological

  13. protein YYSRGDPP T3/T4 Proliferation Blocking T3/T4 binding to avb3 Receptor Plasma membrane aVb3 TRb1 Nucleus MAPK

  14. Blocking T3/T4 binding to avb3 Receptor RGD inhibits T4 but not T3 action Western

  15. T4 RGD Integrin Hormone Receptor Domain T4 T3 Not inhibited by RGD Inhibited by RGD plasma membrane ERK1/2 nuclear membrane Cell Proliferation Am J Physiol, 2009

  16. From bench to bedside Blocking T3/T4 actions initiated at avb3 integrin

  17. T3/T4 Tetrac Proliferation Direct blocking T3/T4 binding to avb3 Receptor Novel targeted therapy • Tetrac: >Deaminated T4 analog > No agonist activity >Nano-Tetrac (patented) aVb3 TRb1 Nucleus MAPK

  18. Tetrac blocks T3/T4 induced MAPK and aVb3 in MM Western

  19. Tetrac blocks T3/T4 induced MAPK and aVb3 in MM Immunofloresnce

  20. Tetrac Angiogenesis Proliferation Blocking T3/T4 avb3 Receptor Tetrac inhibits thyroid hormones action T3/T4 aVb3 TRb1 Nucleus MAPK Sensitizes Chemo/radiation therapy

  21. Annexin-PI • Synergistic/Additive • “Drug sparing” Blocking T3/T4 avb3 Receptor Tetrac- chemosensitizing effect * *

  22. Non-genomic thyroid hormones actionsModel of the aVb3 integrin site actions

  23. Thyroid function and multiple myeloma (MM) “Take home message” • Thyroid hormones > Growth factors in MM • Blocking T3/T4 non genomic effects > Hypothyroidism induction > Tetrac/Nano-tetrac • Novel adjunct therapy in MM and cancer > Combined with any chemotherapy

  24. Ordway Research Institute Albany, NY, USA • Signal Transduction Laboratory • Prof. Paul J. Davis Thanks The Cleveland Clinic Cleveland, Ohio, USA • Meir Medical Center • Translational Hemato-Oncology • Dr. Martin Ellis • Dr. Osnat Ashur-Fabian • Department of Radiation-Oncology • Dr. Aleck Hercbergs

More Related