Knowledge is Power: Updates in Oncology

1. Knowledge is Power:Updates in Oncology Barbara Bowers, M.D. Medical Director Fairview Southdale Medical Oncology Clinic

2. Topics Vitamin D Bisphosphonates Targeted Cancer Therapies Other Novel Approaches

3. Vitamin D

4. Vitamin D

8. What does Vitamin D do? • Regulates cell growth and differentiation • Some studies show low levels of Vitamin D: • More aggressive tumors • Increased BMI • Increased insulin levels • More research needed…

9. Natural Medicines for Breast Cancer

10. Bisphosphonates

11. Bisphosphonates • Zometa draws calcium from surrounding tissues and places it back into the bones to stimulate regrowth • Reverses osteopenia • Used to strengthen bones in patients with bone metastases Ca++ absorbed by intestinal tract Tissue Ca++ Ca++ in bone Serum Ca++ Kidney filters out Ca++

12. Biphosphonates • Recent studies for breast cancer show: • Some anti-tumor effects • Some anti-metastases effects • These are results from initial clinical studies, and further study and testing is still required

13. Targeted Cancer Therapies

14. Targeted Cancer Therapies • Tamoxifen • Arimidex • Aromasin • Faslodex • Fareston • Femara • Megace (endometrial)

15. Complex HER Receptor Signaling Pathway LPA thrombin ET, etc TGFα (1) EGF (1) Epi- regulin (1,4) β-cellulin (1) HB-EGF (1,4) Amphi- Regulin (1) NRG1 (3,4) αβ NRG2 (4) αβ NRG3 (4) NRG4 (4) Cytokines Ligands 4 2 1 4 3 2 4 4 Receptor Dimers 1 1 2 2 3 4 1 2 3 3 1 3 X X X X X Jak Src Crk Adapters & Enzymes Cbl Ras-GCP Shc PLCy Vav Grb7 P(1)3K Shp2 GAP Grb2 Ras-GTP Sos Nck Rao Akt RAF PKC PAK Abl NEK Cascades Bad S6 K JNKK MAPK JNK Jun nucleus Fos Myc Sp1 Elk Egr1 Stat Transcription Factors Source: Y. Yardin, “Untangling the ErbB Signaling Network” Nature Reviews Molecular Cell Biology 2(2): 127-137, 2001

16. E E Nucleus E E R R x E E Tumor cell Tamoxifen Blocks estrogen from entering into the cell, blocking estrogen-dependent growth Estrogen biosynthesis Estrogen biosynthesis from muscle & fat x x x Aromatase Inhibitors Aramatase DeVita, et al. Cancer Principles and Practice of Oncology. 6th ed 2001

17. The next generation of hormone therapy Works by blocking Aromatase enzyme from converting other hormones to estrogen Aromatase Inhibitors Androstenedione Testosterone attack! attack! Aromatase Aromatase Inhibitor Aromatase Estrone Estradiol

18. P P P P P P P P P P P P P P P P Targeting the VEGF Pathway Anti-VEGF Antibody VEGF Small-Molecule Inhibitors Split Kinase Domain VEGFR-1 Source: L. Harris “Novel Biologic and Small-Molecule Inhibitors of VEGF in Cancer Research” Translation Therapies in Breast Cancer Symposium 2006 VEGFR-2

19. Ras Raf MEK1/2 MAPK Proliferation ErbB Signaling Pathway ErbB1 ErbB2 Sos Grb2 Lapatinib Shc Sos Grb2 HKI-272 PI3K BIBW-2992 Akt mTOR PTEN GSK3 BAD FKHR p27 Survival Cyclin D1, E Source: J. O’Shaughnessy, “Inhibition of the ErbB Signaling Pathway by Targeted Therapy” Translation Therapies in Breast Cancer Symposium 2006 Cell-cycle progression

20. ErbB and VEGFR Receptor Crosstalk ErbB Receptor P13K Ras Akt MEK3/4/6 Raf MEK MAPK p53 S6 kinase ERK HIF-1α VEGF Source: Hope Rugo “Targeting VEGF Receptors in Breast Cancer Using Novel Small-Molecule Inhibitors Translation Therapies in Breast Cancer Symposium 2006 Tumoral hypoxia Loss of tumor suppressors (VHL)

21. VEGF VEGF TGFα VEGF VEGF Raf ERK mTOR P P P P P P P P P P Sorafenib: Mechanism of Action and Phase II Study Tumor blood vessel endothelial cell membrane Tumor cell membrane Pericyte VEGFR PDGFR VEGFR PDGFR EGFR Ras P13K Sorafenib Sorafenib Akt MEK nucleus Cell proliferation Cell adhesion Apoptosis Cell Survival Cell differentiation Angiogenesis Transcription Factors Source: Hope Rugo “Targeting VEGF Receptors in Breast Cancer Using Novel Small-Molecule Inhibitors Translation Therapies in Breast Cancer Symposium 2006

22. Types of Targeted Therapies • Monoclonal Antibodies • Small molecules • Angiogenesis inhibitors • Vaccines • Apoptosis inducers

23. Monoclonals currently used in treating cancer Drug (brand name) rituximab (Rituxan) tositumomab-1131 (Bexxar) ibritumomab-Y90 (Zevalin) alemtuzumab (Campath) cetuximab (Erbitux) panitumumab (Vectibix) trastuzumab (Herceptin) bevacizumab (Avastin) edrecolomab (Panorex) Cancer(s) treated non-Hodgkins lymphoma non-Hodgkins lymphoma non-Hodgkins lymphoma chronic lymph. leukemia colorectal, head & neck colorectal breast colorectal, NSC lung, breast colorectal

24. Tyrosine Kinase Inhibitors Drug (brand name) tretinoin (Vesanoid) dasatinib (Sprycell) nilotinib (Tasigna) imatinib (Gleevec) erlotinib (Tarceva) gefitinib (Iressa) lapatinib (Tykerb) temsirolimus (Torisel) Everolimus (Afinator) Cancer(s) treated acute promyelo. leukemia chronic myelo. leukemia chronic myelo. leukemia Chronic myelo,leukemia GI stromal tumor glioblastoma, NSC lung NSC lung breast renal

25. Anti-angiogenesis Drugs Drug (brand name) celecoxib (Celebrex) dalteparin (Fragmin) lenalidomide (Revlamid) sorafenib (Nexavar) sunitinib (Sutent) thalidomide (Thalomid) vandetanib (Zactima) Cancer(s) treated colorectal ovarian, pancreatic mult. myeloma, myelodysplastic syndromes hepatocellular, melanoma, NSC lung, renal renal mult. myeloma, hepatocellular, small/NSC lung, fallopian tube, peritoneal NSC lung

26. Trastuzumab & Pertuzumab • Pertuzumab • Activates antibody-dependent cellular cytotoxicity • Prevents receptor dimerization • Potent inhibitor of HER-mediated signaling pathways • Trastuzumab • Activates antibody-dependent cellular cytotoxicity • Enhances HER2 internalization • Inhibits shedding and formation of p95 • Inhibits angiogensis

28. Triple Negative Breast Cancer • Triple Negative Breast Cancer • Estrogen Receptor (ER) Negative • Progesterone Receptor (PR) Negative • HER2 Receptor Negative • Considered to have a poorer prognosis than many other types of breast cancer • Many existing targeted therapies do not have a place in TN Breast Cancer therapy (e.g. Herceptin, Tamoxifen)

29. Origins of Triple (-) Basal-like Breast Cancers • Triple Negative tumors have a also commonly been found to be BRCA-deficient. • BRCA-deficient tumors are often at least ER (-) • BRCA-deficiency can be hereditary or can be caused by a cell mutation. • These tumor cells often over express myoepithelial-cell-like cytokeratins. • Myoepithelial cells are found in the outer basal layer of cells in a normal breast duct. • Therefore, these tumors are defined as basal-like.

30. BRCA Deficiency or Mutation • BRCA1 is a gene that play a part in a large number of cellular processes: • DNA repair • Transcriptional Regulation • Chromatin Remodeling • Cell that lack BRCA1 cannot repair DNA double-strand breaks by the conservation mechanism or homologous recombination

31. “BRCAness” – BRCA1 mutation • BRCA1 deficiency inevitably leads to repair of DNA lesions by non-conservative mechanisms that can be potentially mutagenic. • If cancerous cells form from these mutagenic DNA repairs, they often develop along a basal-like pathway.

32. Why don’t the cells just die? • Unrepaired damage in normal cells usually triggers programmed cell death • It has been found that BRCA1 tumors generally have a higher frequency of Tumor Suppressor p53 mutations. • This increase in p53 mutations shut down programmed cell death leading to cancerous cell growth

33. A target for chemotherapy • Since a DNA-repair defect occurs in BRCA-deficient cancers, this can be exploitedas a target for chemotherapy • Tumors with BRCA1 mutations may have increased sensitivity to DNA-crosslinking agents that cause DNA double-strand breaks (e.g. carboplatin)

34. Are PARP-inhibitors an option? • Poly(ADP-ribose) Polymerase (PARP) • An enzyme involved in base excision repair and is key in the repair pathway of DNA single-strand breaks • Since DNA repair is already limited in BRCA deficient tumors, it is hypothesized that the addition of a PARP-inhibitor may futher decrease DNA repair leading to increased apoptosis of tumor cells

35. PARP-Inhibitors • PARP inhibitors are designed to target a weakness rather than a strength • Utilizing the fact that BRCA-deficient tumor cells cannot effectively repair double-stranded DNA breaks, PARP inhibitors may be able to push the cells over the edge by also inhibiting their ability to fix single-strand breaks

36. Model of Tumor-Cell killing by PARP inhibitors • BRCA-deficient tumors have diminished ability to repair double-stranded DNA breaks, yet the tumor cells continue to survive • Adding the inability to repair single-strand breaks via a PARP-Inhibitor provides enough instability in the mouse model and the cells dies. • If the model holds true, this may provide a good target for BRCA-deficient breast or ovarian tumors in humans.

37. Other Novel Approaches

38. Vaccines • Need specific targets that are unique to the cancer cell (but not to normal cells) • All current vaccine studies are targeting Her2Neu • In the future, other targets that are identified can be used • Animal data: Marked decrease in ability for transplanted tumors to grow in animals treated with the vaccine

39. Human Data • Walter Reed & MD Anderson 171 patients 90 LN + 81 LN – 90 qualified for E75 45 LN + 45 LN – 9 patients not able to evaluated LN = Lymph Node

40. Human Data • Results at 24 months: • Vaccinated patients had 5.6% reoccurrence • Non-vaccinated patients had 14.8% reoccurrence • Several centers have started vaccine studies this year, including U of M UPDATE – University’s vaccine study is now open!

41. Gene Therapy • Several possible uses: • Stimulate suppressor genes to inhibit tumor growth • Introduce “suicide genes” into cancer cells that cause them to self destruct

42. Apoptosis Therapy • Two important discoveries: • bc1-2 gene • Almost all tumors have impaired apoptosis

43. Digital Film

44. Questions?