Knowledge is Power Updates in Oncology Barbara Bowers

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

Topics Vitamin D Bisphonates Targeted Cancer Therapies Other Novel Approaches

Vitamin D

Vitamin D

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

Natural Medicines for Breast Cancer SAFETY EFFECT Likely Safe Possibly Safe Insufficient Evidence Effective Possibly Effective Beta Carotene fish oil green tea Melatonin Olive soy Vitamin A Insufficient Evidence Coenzyme Q-10 Flaxseed Shiitake mushroom Likely Ineffective Vitamin E Beta glucans Chrysin European mistletoe Indole-3 -carbinol Maitake mushroom red clover Calcium D-glucarate Genistein combined poly-saccharide Essiac Flor-Essence Possibly Unsafe

Bisphonates

Bisphonates Ca++ absorbed by intestinal tract Tissue Ca++ Serum Ca++ Kidney filters out Ca++ in bone • 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

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

Targeted Cancer Therapies

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

Complex HER Receptor Signaling Pathway LPA thrombin ET, etc TGFα (1) EGF (1) Epiregulin (1, 4) β-cellulin HB-EGF Amphi. Regulin (1) (1, 4) (1) 1 3 1 2 1 1 2 2 NRG 1 (3, 4) αβ NRG 2 (4) αβ NRG 3 (4) NRG 4 Cytokines Ligands (4) 4 2 1 4 3 2 4 4 3 3 X X X Receptor Dimers X X Jak Src Cbl Ras-GCP PLCy P(1)3 K Shp 2 GAP Bad eu l c nu Ras-GTP Akt PKC S 6 K RAF NEK MAPK s Source: Y. Yardin, “Untangling the Erb. B Signaling Network” Nature Reviews Molecular Cell Biology 2(2): 127 -137, 2001 Shc Grb 2 Sos Nck Crk Vav Grb 7 Adapters & Enzymes Rao PAK Abl JNKK Cascades JNK Jun Sp 1 Myc Fos Elk Egr 1 Stat Transcription Factors

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

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

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

Erb. B Signaling Pathway Erb. B 1 Erb. B 2 Grb 2 Sos Ras Shc Grb 2 Sos Lapatinib PI 3 K HKI-272 BIBW-2992 Raf Akt MEK 1/2 m. TOR PTEN p 27 FKHR GSK 3 BAD MAPK Survival Cyclin D 1, E Source: J. O’Shaughnessy, “Inhibition of the Erb. B Signaling Pathway by Targeted Therapy” Translation Therapies in Breast Cancer Symposium 2006 Cell-cycle progression Proliferation

Erb. B and VEGFR Receptor Crosstalk Erb. B Receptor p 53 P 13 K Ras Akt Raf MEK 3/4/6 MEK MAPK S 6 kinase ERK HIF-1α Source: Hope Rugo “Targeting VEGF Receptors in Breast Cancer Using Novel Small-Molecule Inhibitors Translation Therapies in Breast Cancer Symposium 2006 Tumoral hypoxia VEGF Loss of tumor suppressors (VHL)

Sorafenib: Mechanism of Action and Phase II Study VEGF TGFα VEGF Tumor cell membrane Tumor blood vessel endothelial cell membrane Pericyte P P VEGFR P P PDGFR EGFR Sorafenib Ras Akt Raf ERK us le nuc Source: Hope Rugo “Targeting VEGF Receptors in Breast Cancer Using Novel Small-Molecule Inhibitors Translation Therapies in Breast Cancer Symposium 2006 Transcription Factors P VEGFR PDGFR P 13 K m. TOR P P Sorafenib MEK Cell proliferation Cell adhesion Apoptosis Cell Survival Cell differentiation Angiogenesis

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

Monoclonals currently used in treating cancer Drug (brand name) rituximab (Rituxan) tositumomab-1131 (Bexxar) ibritumomab-Y 90 (Zevalin) alemtuzumab (Campath) cetuximab (Erbitux) panitumumab (Vectibix) trastuzumab (Herceptin) bevacizumab (Avastin) edrecolomab (Panorex) Cancer(s) treated non-Hodgkins lymphoma chronic lymph. leukemia colorectal, head & neck colorectal breast colorectal, NSC lung, breast colorectal

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 GI stromal tumor glioblastoma, NSC lung breast renal

Anti-angiogenesis 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 mult. myeloma, hepatocellular, small/NSC lung, fallopian tube, peritoneal NSC lung

Trastuzumab & Pertuzumab • Trastuzumab – Activates antibodydependent cellular cytotoxicity – Enhances HER 2 internalization – Inhibits shedding and formation of p 95 – Inhibits angiogensis • Pertuzumab – Activates antibodydependent cellular cytotoxicity – Prevents receptor dimerization – Potent inhibitor of HERmediated signaling pathways

Triple Negative Breast Cancer • Triple Negative Breast Cancer – Estrogen Receptor (ER) Negative – Progesterone Receptor (PR) Negative – HER 2 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)

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-celllike 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.

BRCA Deficiency or Mutation • BRCA 1 is a gene that play a part in a large number of cellular processes: – DNA repair – Transcriptional Regulation – Chromatin Remodeling • Cell that lack BRCA 1 cannot repair DNA double-strand breaks by the conservation mechanism or homologous recombination

“BRCAness” – BRCA 1 mutation • BRCA 1 deficiency inevitably leads to repair of DNA lesions by nonconservative mechanisms that can be potentially mutagenic. • If cancerous cells form from these mutagenic DNA repairs, they often develop along a basal-like pathway.

Why don’t the cells just die? • Unrepaired damage in normal cells usually triggers programmed cell death • It has been found that BRCA 1 tumors generally have a higher frequency of Tumor Suppressor p 53 mutations. • This increase in p 53 mutations shut down programmed cell death leading to cancerous cell growth

A target for chemotherapy • Since a DNA-repair defect occurs in BRCA-deficient cancers, this can be exploitedas a target for chemotherapy • Tumors with BRCA 1 mutations may have increased sensitivity to DNAcrosslinking agents that cause DNA double-strand breaks (e. g. carboplatin)

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

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

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.

Other Novel Approaches

Vaccines • Need specific targets that are unique to the cancer cell (but not to normal cells) • All current vaccine studies are targeting Her 2 Neu • 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

Human Data • Walter Reed & MD Anderson 171 patients 90 LN + 81 LN – 90 qualified for E 75 45 LN + 45 LN – 9 patients not able to evaluated LN = Lymph Node

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!

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

Apoptosis Therapy • Two important discoveries: – bc 1 -2 gene – Almost all tumors have impaired apoptosis

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