Presented By: Melissa Sukernick Kristin Waterman

1. Bortezomib (Velcade): First Proteasome Inhibitor Resulting in Death of Multiple Myeloma Cancer Cells Presented By: Melissa Sukernick Kristin Waterman

2. Multiple Myeloma • Accounts for over 10,800 deaths annually • 2nd most common blood cancer after non-Hodgkin’s lymphoma • Cancer of the plasma cell in the bone marrow which plays an important role in the immune system • The bone marrow makes antibodies to help defend the body from infection and disease and is also responsible for making red blood cells and platelets

3. History • 1993: Myogenics (ProScript): • Main Goal: use inhibitors to block proteasome • 1994-1995: Bortezomib • July 1999 ProScript bankrupt bought by LeukoSite for 2.7 million • 3 months later bought by Millennium Pharmaceuticals for 635 million • Main Interest CamPath, no interest in bortezomib

4. History • Bortezomib research kept alive by the founders of the project • August 2000, clinical trial: 47 year old woman with advanced stages of multiple myeloma had all signs of cancer erased by using bortezomib • Millennium made bortezomib most funded project

5. Bortezomib • Dipeptide boronic acid • C19H25BN4O4 • Molecular weight: 384. 24 g/mol • Half life = 9-15 hrs. • Inhibitor of the 26S proteasome

6. SUMMIT (Study of Uncontrolled Multiple Myeloma Managed with Proteasome Therapy) 202 heavily pretreated patients with relapsed and refractory myeloma Median Survival of all 202: 16 months Overall Response Rate: 35% Encouraged 1st line treatment in patients with myeloma Phase II Trial

7. FDA Approval After Phase II • FDA approved Velcade on May 13, 2003 for patients who have had two prior treatments and demonstrated resistance to their last treatment • Quickly approved under the accelerated approval program: makes promising drugs for serious or life threatening diseases available earlier

8. Phase III Trial • APEX ( Assessment of Proteasome Inhibition for Extending Remissions) • 669 patients enrolled: randomly received either dexamethasone or bortezomib • Bortezomib showed significantly increased survival rates among patients (80%) after 1 year, dexamethasone (66%) • 38% response rate for bortezomib • 18% response rate for dexamethasone

9. FDA Approval • March 25, 2005 FDA fully approved bortezomib for treatment of patients with multiple myeloma who have received a minimum of one treatment • Fully approved: • Clinical benefits: increased survival • June 2008 FDA approved bortezomib for initial treatment for patients with multiple myeloma

10. Bortezomib as a Model Drug • First proteasome inhibitor • Inhibits 26S proteasome: principle regulator of intracellular protein degradation • The proteasome normally degrades IKB which activates NFKB which then promotes cell survival, stimulates growth, makes cells resistant to apoptosis and importantly induces drug resistance in myeloma cells • Bortezomib prevents all from happening by inhibiting the proteasome

11. Proteasome Inhibition with bortezomib Downregulation of gp130 Mitochondrial cytochrome c release Activates c-Jun NH2-terminal kinase, which activates capase-8 and capase-3 • Prevents activation of • NFKB, leading to: • Inhibited cell growth • alterations in adhesion • molecule expression • Inability to activate • pathways of • chemoresistance Induces p53 and MDM2 protein expression APOPTOSIS

12. How Bortezomib is Administered • Comes as a solution (liquid) to inject into the vein • Receive 1.3 mg per square meter of body-surface area • Given on a rotating schedule that alternates 2 weeks when bortezomib is given twice a week with 10 days rest

13. Fatigue, tiredness, weakness Nausea Diarrhea Decreased appetite Constipation Decreased blood counts Peripheral neuropathy Fever Vomiting Anemia Dizziness Common Side Effects of Bortezomib

14. Mantle Cell Lymphoma • Cancerous cells growing out of control in the lymph nodes • Accounts for only 6% of the non-Hodgkin’s lymphomas • December 6, 2006 FDA approved bortezomib for treatment of patients with mantle cell lymphoma who have received at least one prior therapy • Overall response rate 31% • Complete responses 8% • Median response duration 15.4 months

15. Combination Therapies • Bortezomib combined with NPI-0052 triggers synergistic apoptosis in multiple myeloma cells in vitro and in vivo (mouse model) • Combined allows for safer doses and broader range of proteasome inhibition • In combination with chemotherapy helps prevent resistance to the treatment

16. The Future for Bortezomib • Currently on-going trials: • Prostate cancer • Non-Hodgkin’s lymphoma • In cell cultures it has been shown to induce apoptosis in ovarian cancer cells and pancreatic cancer cells

17. References • Adams, J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell 2004, 5, 417-421. • American Society of Health-System Pharmacists, Consumer Medication Information, Bortezomib, Accessed March 2009; http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=meds&part=a607007 • Canfield, S.E.; Zhu, K.; Williams, S.A.; McConkey, D.J. Brotezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells. Molecular Cancer Therapeutics2006, 5, 8, 2043-2050. • Chauhan, D.; Singh, A.; Brahmandam, M.; Podar, K.; Hideshima, T., Richardson, P.; Munshi, N.; Palladino, M.A.; Anderson, K.C. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood2008, 111, 3, 1654-1664. • Goy, A.; Younes, A.; McLaughlin, P.; Pro, B.; Romaguera, J.E.; Hagemeister, F.; Fayad, L.; Dang, N.H.; Samaniego, F.; Wang, M.; Broglio, K.; Samuels. B.; Gilles, F.; Sarris, A.H., Hart, S.; Trehu, E.; Schenkein, D.; Cabanillas, F., Rodriguez, A.M. Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma. Journal of Clinical Oncology, 2005, 23, 4, 667-675. • Hattori, N.; Adachi, D.; Nakashima, H.; Saito, B.; Nakamaki, T.; Tomoyasu, S. Drug-induced hypersensitivity syndrome after bortezomib treatment for refractory multiple myeloma. Leukemia Research2009, 33, 4, 574-577. • Li, J.; Wang, L.; Shen, W.; Lu, S.; Chen, L.; Lu, H. Bortezomib in combination with dexamethasone for a young multiple myeloma with (8; 14). Leukemia Research2009, 33, 4, 584-586. • Mangiacavalli, S.; Varettoni, M.; Zappasodi, P.; Pica, G.; Lazzarino, M.; Corso, A. A striking response to bortezomib in a patient with pleural localization of multiple myeloma. Leukemia Research2009, 33, 4, 577-578. • Myeloma Therapy; Researchers from St. Bartholomew’s Hospital, Department Haematology detail findings in myeloma therapy. Clinical Trials Week. 2009,30.

18. References • National Cancer Institute, Drug Dictionary, Bortezomib, Accessed March 2009; http://www.cancer.gov/templates/drugdictionary.aspx?searchTxt=bortezomib&ctl00.x=0&ctl00.y=0&sgroup=Starts+with • Richardson, P.G.; Mitsiades, C.; Hideshima, T.; Anderson, K.C. Bortezomib: Proteasome Inhibition As An Effective Anticancer Therapy. Annual Review of Medicine 2006, 57, 33-47. • Richardson, P.G.; Barlogie, B.; Berenson, J.; Singhal, S.; Jagannath, S.; Irwin, D.; Rajkumar, S.V.; Srkalovic, G.; Alsina, M.; Alexanian, R.; Siegel, D.; Orlowski, R.Z., Kuter, D.; Limentani, S.A.; Lee, S.; Hideshima, T.; Esseltine, D.; Kauffman, M.; Adams, J.; Schenkein, D.P.; Anderson, K.C. A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma. The New England Journal of Medicine2003, 348, 26, 2609-2617. • Richardson, P.G.; Sonneveld, P.; Schuster, M.W.; Irwin, D.; Stadtmauer, E.A.; Facon, T.; Harousseau, J.; Ben-Yehuda, D.; Lonial, S.; Goldschmidt, H.; Reece, D.; San-Miguel, J.F.,; Blade, J.; Boccadoro, M.; Cavenagh, J.; Dalton, W.S.; Boral, A.L.; Esseltine, D.L.; Porter, J.B.; Schenkein, D.; Anderson, K.C. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma. The New England Journal of Medicine2005, 352, 24, 2487-2497. • Sanchez-Serrano, I. Success in translational research: lessons from the development of bortezomib. Perspectives 2006, 5, 107-114. • U.S. Food and Drug Administration, Velcade (bortezomib) Information, Accessed March 2009; http://www.fda.gov/CDER/drug/infopage/velcade/default.htm • Wikipedia, Bortezomib, Accessed February 2009. http://en.wikipedia.org/wiki/Bortezomib • Yanamandra, N.; Colaco, N.M.; Parquet, N.A.; Buzzeo, R.W.; Boulware, D.; Wright, G.; Perez, L.E.; Dalton, W.S.; Beaupre, D.M. Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion- Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia. Cancer Therapy: Preclinical2006, 12, 2, 591- 599.