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Patricia S. Steeg, Ph.D. Director, Molecular Therapeutics Program Chief, Women’s Cancers Section, Laboratory of Patholog

New Molecular Targets for Metastatic Breast Cancer. Patricia S. Steeg, Ph.D. Director, Molecular Therapeutics Program Chief, Women’s Cancers Section, Laboratory of Pathology National Cancer Institute Bethesda, MD. We tend to focus on ER and Her-2. There is “more” !.

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Patricia S. Steeg, Ph.D. Director, Molecular Therapeutics Program Chief, Women’s Cancers Section, Laboratory of Patholog

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  1. New Molecular Targets for Metastatic Breast Cancer Patricia S. Steeg, Ph.D. Director, Molecular Therapeutics Program Chief, Women’s Cancers Section, Laboratory of Pathology National Cancer Institute Bethesda, MD

  2. We tend to focus on ER and Her-2. There is “more” ! Many new therapeutics are entering clinical trial in other types of cancer and should be tested in breast cancer

  3. Examples of New Molecular Targets for Metastatic Breast Cancer BRCA / PARP Inhibitors AG-014699 Bone Metastases Denosumab ZD4054, Atrasentan hPTH (1-34) Lung Metastases MPA Brain Metastases Her-2 directed agents HDAC Inhibitors Patupilone Sunitinib

  4. Examples of New Molecular Targets for Metastatic Breast Cancer BRCA / PARP Inhibitors AG-014699 Bone Metastases Denosumab ZD4054, Atrasentan hPTH (1-34) Lung Metastases MPA Brain Metastases Her-2 directed agents HDAC Inhibitors Patupilone Sunitinib

  5. Accumulation of proteins at DNA break Proteins halt cell proliferation Proteins also repair the break ATM ATR BRCA2 DNA Double Strand Breaks in Normal Cells Normal DNA Double strand break in the DNA BRCA1 Repaired DNA, the cell survives

  6. Loss of BRCA proteins (deletion, mutation) results in a difference in the ability to repair damaged DNA between normal and cancerous tissues. Loss of BRCA protein, combined with loss of a DNA repair protein called Poly (ADP-ribose) polymerase (PARP), combine to make the DNA damage last longer and to kill the tumor cell. Inhibitors of the DNA repair enzyme Poly (ADP-ribose) polymerase (PARP) have activity in mice: Normal cells, vehicle Normal cells, PARP Inhibitor BRCA- cells, vehicle Tumor formation after injection of ES cells into mice BRCA- cells, PARP Inhibitor Nature 434:917, 2005

  7. PARP Inhibitors will be tested clinically in BRCA-linked breast cancer. Possible combinations include radiation, temozolomide and platinum based chemotherapy.

  8. First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors R. Plummer, M. Middleton, R. Wilson, C. Jones, J. Evans, L. Robson, H. Steinfeldt, R. Kaufman, S. Reich and A. H. Calvert Northern Ctr for Cancer Treatment, Newcastle upon Tyne, United Kingdom; Oncology Unit, Churchill Hosp, Oxford, United Kingdom; Dept of Oncology; Queens Univ - Belfast, Belfast, United Kingdom; Dept of Medcl Oncology, Beatson Oncology Ctr, Glasgow, United Kingdom; Cancer Research - UK, London, United Kingdom; Pfizer Global Research & Development, La Jolla, CA 3065 Background: AG-014699 inhibits poly(ADP-ribose) polymerase (PARP) is a key enzyme in DNA repair. AG-014699 sensitizes cancer cells to DNA damaging drugs such as TMZ. AG-014699 is the first PARP inhibitor to be evaluated in cancer patients. Methods: In part 1 of the study, pts with solid tumors received AG-014699 + TMZ daily x 5 every 28 days. TMZ dose was half of standard (100 mg/m2 po) and AG-014699 (30 min infusion) was escalated up to the PARP-inhibitory dose (PID) as determined by PARP activity in peripheral blood lymphocytes (PBLs). We defined PID as maximal (at least >50%) reduction in PARP activity 24 hr after AG-014699. In part 2, AG-014699 dose was fixed at PID and TMZ was escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma pts. Endpoints included safety, efficacy, PK and tumor PARP activity (obligatory in part 2). Overall objective based on xenograft data was to achieve > 40% PARP inhibition in tumor. Results: 27 pts enrolled, safety data available on first 18. In part 1, AG-014699 dose levels in 18 pts were 1, 2, 4, 8 and 12 mg/m2. No dose-limiting toxicity (DLT) was observed. All related events were grade (gr) 1/2, except 1 case each of gr 3 infection, fatigue, low phosphate and lymphopenia. PID was 12 mg/m2 based on 74 -97% inhibition of PBL PARP activity. PK evaluation for AG-014699 alone after 2 - 12 mg/m2 shows mean terminal T = 7.4 - 11.7 hr, clearance = 25 L/hr, and linear dose proportionality for AUC and Cmax. AG-014699 did not affect TMZ PK compared to historical data. Two durable partial responses (15+, 9+ mo) occurred (GIST, melanoma). In part 2, no DLT was seen in 9 pts up to 200 mg/m2 TMZ. Median tumor PARP inhibition at 5 hours was 90% (range 50 - 98%). Conclusions: Doses up to 12 mg/m2 AG-014699 and 200 mg/m2 TMZ are safe and significantly inhibit PBL and tumor PARP. One further dose level (AG-014699 18 mg/m2, TMZ 200 mg/m2) will be tested to maximize tumor PARP inhibition. J. CLIN. ONCOL. 23 (16): 208S-208S Part 1 Suppl. S, JUN 1 2005

  9. Examples of New Molecular Targets for Metastatic Breast Cancer BRCA / PARP Inhibitors AG-014699 Bone Metastases Denosumab ZD4054, Atrasentan hPTH (1-34) Lung Metastases MPA Brain Metastases Her-2 directed agents HDAC Inhibitors Patupilone Sunitinib

  10. Types of Bone Metastases Osteoclastic Osteoblastic

  11. The Osteoclastic “Vicious Cycle” Has Become Complex Nature Medicine 12:895, 2006

  12. Rank-L activates osteoclasts, which cause bone destruction. Denosumab is a monoclonal antibody To Rank-L (Amgen) A Phase I clinical trial has been conducted to determine if Denosumab reduces bone turnover in breast cancer patients with bone mets. Eur. J. Cancer Suppl. 4: 63, 2004 EORTC-NCI-AACR Symposium on Molecular Targets And Cancer Therapeutics Poster

  13. Bone Resorption Pamidronate Denosumab mAb to RANK-L Clin. Cancer Res. 12:1221, 2006

  14. Denosumab Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) in a Phase 1 Study of Japanese Women With Breast Cancer-Related Bone MetastasisHironobu Minami, MD;1 Kouichi Kitagawa,1 MD; Kan Yonemori, MD;2 Yasuhiro Fujiwara, MD, PhD;2 Hirofumi Fujii, MD, PhD;3 Tatsuhiro Arai, MD;3 Masayuki Ohkura;4 Graham Jang, PhD;5 Tomoko Ohtsu, MD, PhD41National Cancer Center Hospital East, Kashiwa, Japan; 2National Cancer Center Hospital, Tokyo, Japan; 3Tochigi Cancer Center, Utsunomiya, Japan; 4Amgen Ltd., Tokyo Japan; 5Amgen Inc., Thousand Oaks, CA USA Eur. J. Cancer Suppl. 4: 63, 2004 EORTC-NCI-AACR Symposium on Molecular Targets And Cancer Therapeutics Poster

  15. Eur. J. Cancer Suppl. 4: 63, 2004 EORTC-NCI-AACR Symposium on Molecular Targets And Cancer Therapeutics Poster

  16. Decreases in Bone Turnover Markers: Urine N-telopeptide (corrected for creatinine) Serum C-telopeptide Eur. J. Cancer Suppl. 4: 63, 2004 EORTC-NCI-AACR Symposium on Molecular Targets And Cancer Therapeutics Poster

  17. Conclusions from Poster Well tolerated Adverse event profile similar to that seen in patients with advanced cancer Rapid (within 24h), substantial (>60%) and sustained (12 w) suppression of bone turnover markers Phase 3 trials for the prevention and treatment of skeletal related events are in progress. Eur. J. Cancer Suppl. 4: 63, 2004 EORTC-NCI-AACR Symposium on Molecular Targets And Cancer Therapeutics Poster

  18. Preclinical and Clinical Leads to Osteoblast Activation Tumors secrete Endothelin-1 (ET-1) which activates osteoblasts. It binds to a receptor on osteoblasts called endothelin-A (ET-A). ZD4054 is an ET-1 antagonist. ET-1 Atrasentan is a ET-A antagonist ET-A hPTH1-34 is a PTHrP antagonist that has been in a Phase I trial for osteoporosis E.D. Williams et al. Poster from Abstract 36 Eur. J. Cancer Suppl. 4:15, 2006 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics Osteoporosis Int. 17:1532, 2006

  19. Examples of New Molecular Targets for Metastatic Breast Cancer BRCA / PARP Inhibitors AG-014699 Bone Metastases Denosumab ZD4054, Atrasentan hPTH (1-34) Lung Metastases MPA Brain Metastases Her-2 directed agents HDAC Inhibitors Patupilone Sunitinib

  20. Nm23 Metastasis Suppressor Gene Tumor Cell Line Metastasis Suppressor Gene Control In tissue culture: Less motility Less invasion Less colonization Differentiation Equal proliferation

  21. Can Nm23 Expression be Restored to Micrometastatic Breast Cancer Cells in the Lungs? Medroxyprogesterone acetate (MPA) is traditionally a progestin; However, it also interacts with the Glucocorticoid receptor (GR) and can therefore have effects in PR-negative cancer cells. We have found that high dose MPA elevates the Nm23 metastasis Suppressor gene expression of PR-negative, metastatic breast Cancer cells through the GR. CSS FCS -Nm23-H1 -Nm23-H2 -Alpha- Tubulin 0 0.001 0.01 0.1 1 10 100 0 0.001 0.01 0.1 1 10 Clin. Cancer Res. 8:3763, 2003

  22. O CH3 O C CH3 CH3 C=O O MPA Clinical History Used previously at high doses as a progesterone receptor (PR) agonist for treatment of advanced breast and endometrial cancers. Used in low doses as slow-release contraceptive, with estrogen in HRT. Some responses observed, but optimal dose and schedule never identified. Conflicting reports on correlation of responses and PR expression. Both stimulatory and inhibitory effects in mouse models

  23. Experimental Design: Will MPA Inhibit Metastatic Colonization? MDA-MB-231T Cells: ER-, PR-, GR+ Week 4 - Micrometastases detectable in the lung parenchyma J. Nat’l. Cancer Inst. 97:632, 2005

  24. Effects of MPA on Pulmonary Metastasis of MDA-MB-231 cells Experiment: 1 2 Control 2 mg 4mg Control 0.5 mg 1 mg 2 mg Treatment: Mean Metastases per mouse: 32.3 21.7 15.6 33.4 22.2 12.6 14.5 Percent reduction: 33% 52% 34% 62% 57% Mean Metastases > 3mm: 3.2 0.6 0.9 2.0 0.8 0.5 0.5 Reduction from Control: 5x 3x 2x 4x 4x • Other effects: • Weight gain • No abnormalities in mammary fat pad histology • No change in bone density • Increased Nm23 expression in pulmonary metastases J. Nat’l. Cancer Inst. 97:632, 2005

  25. Day 10-14 trough [MPA] > 50 ng/ml CR, PR, SD Cohort 1 REGISTER MPA 1000 mg/d MPA 1000 mg/d Continue Day 10-14 trough [MPA] < 50 ng/ml PD Off study MPA 1500 mg/d Day 10-14 trough [MPA] > 50 ng/ml Cohort 2 MPA 1000 mg/d + ldoCM MPA 1000 mg/d + ldoCM CR, PR, SD Continue Day 10-14 trough [MPA] < 50 ng/ml MPA 1500 mg/d + ldoCM Off study PD MPA Revisited: A Phase II Study of Anti-Metastatic, Anti-Angiogenic Therapy in Postmenopausal Patients with Hormone Receptor Negative Breast Cancer Principal Investigator: Kathy D. Miller, M.D. Indiana University Medical Center 535 Barnhill Drive, RT-473 Indianapolis, IN 46202

  26. Examples of New Molecular Targets for Metastatic Breast Cancer BRCA / PARP Inhibitors AG-014699 Bone Metastases Denosumab ZD4054, Atrasentan hPTH (1-34) Lung Metastases MPA Brain Metastases Her-2 directed agents HDAC Inhibitors Patupilone Sunitinib

  27. Brain metastases develop in 15% of metastatic breast cancer patients. Brain metastases appear to be increasing as a sanctuary site as systemic control improves, particularly for patients with Her-2 amplified tumors. Many patients develop brain metastases when they are responding to treatment The median survival time is dismal. One year survival is estimated at 20%. Current treatments include gamma knife, whole brain radiation therapy, chemotherapy, steroids and surgery

  28. A Unique Microenvironment The blood:brain barrier (BBB) and brain microenvironment are hypothesized to provide distinct molecular pathways underlying metastasis. The brain microenvironment also contains neurons, astrocytes, microglia. Role for edema? Once tumor cells penetrate the BBB, a blood:tumor barrier (BTB) is formed. Almost nothing is known about the patency of the BTB to metastases. Am. J. Pathol. 167:913, 2005

  29. Blood-Brain Barrier Permeability of Ten Common Chemotherapeutic Drugs -In relation to drug lipid solubility as measured by the octanol/water partition coefficient.  The line and solid squares illustrate the permeability relation for solutes that cross the blood-brain barrier by simple passive diffusion. Compounds with a Log Permeability value less than -3 would be classified as having POOR blood-brain barrier permeability Courtesy of Drs. Paul Lockman and Quentin Smith

  30. Why Her-2 Status ? Of 122 women receiving trastuzumab +/- chemotherapy, symptomatic CNS metastases were identified in 34%. Fifty percent of the patients were responding to therapy, or had stable disease when they developed CNS metastases. Cancer 97: 2972, 2003 Of 93 metastatic patients receiving trastuzumab, brain metastases occurred in 25% over a median followup time of 10.8 months. 78% of patients with brain metastases had stable disease at other sites. The CNS was the first site of symptomatic progression in 82% of patients, and the only site of disease progression at that time in 69% of patients. Br. J. Cancer 91:639, 2004

  31. Why are breast cancer patients with Her-2+ tumors developing brain metastases? • Living longer • Trastuzumab poorly penetrates the BBB (BTB) • Her-2 promotes brain metastasis

  32. MDA-MB-231 Brain Seeking: Low Her-2 High Her-2 Vector Total Her-2 Tubulin A Perfect Storm: Her-2 Overexpression Promotes Brain Mets Clone: Mean Large Brain Mets (95%CI) P: Vector 1 5.1 (3.7 - 6.6) Vector 2 2.9 (2.0 – 3.8) Low Her-2 1 11.3 (8.3 – 14.4) Low Her-2 2 16.6 (15.1 – 18.1) 0.0001 High Her-2 1 10.9 (8.9 – 12.9) High Her-2 2 14.0 (11.6 – 16.4) 0.0001 Palmieri et al. Cancer Res. Under revision.

  33. Transfection of Her-2 elevated the number of “large” metastases three fold. The data indicate a functional contribution of Her-2 overexpression to the development of large (i.e., clinically detectable) brain metastases. The data confirm the need to develop Her-2 inhibitors with brain permeability. This may require a new paradigm for lead compound selection. Palmieri et al. Cancer Res. Under revision.

  34. Therapeutic Approaches to Her-2+ Brain Metastases Trastuzumab (Herceptin, Genentech) Humanized recombinant monoclonal antibody to Her-2 Efficacy in combination with chemotherapy in metastatic and adjuvant settings Relapses in the brain CSF concentrations are 300 fold lower than blood levels Lapatinib (Tykerb, GSK) Small molecule EGFR-Her-2 heterodimerization inhibitor Efficacy in Herceptin-resistant metastatic breast cancer Fewer relapses in the brain Limited efficacy in Phase I trial against established brain mets JNJ26483327 (J&J) Small molecule inhibitor of EGFR, Her-2 and Src Phase I trial open Brain permeability claimed

  35. Perera et al. Eur. J. Cancer Suppl. 4: 178, 2004 EORTC-NCI-AACR Symposium on Molecular Targets And Cancer Therapeutics Poster

  36. Other Drugs with Potential Brain Permeability HDAC Inhibitors Histone deactylase inhibitors Restores expression of “suppressor genes” Clinical trial and approved Patupilone Microtubule active Sunitinib (SU11248) VEGFR, PDGFR, KIT, RET, CSF-1R, FLT3.

  37. Sunitinib concentrations in the brain in mice and monkeys Patyna et al. Eur. J. Cancer Suppl. 4: 21, 2004 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics Poster

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