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Patricia S. Steeg, Ph.D. Director, Molecular Therapeutics Program Chief, Women’s Cancers Section, Laboratory of Pathology National Cancer Institute Bethesda,

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Presentation on theme: "Patricia S. Steeg, Ph.D. Director, Molecular Therapeutics Program Chief, Women’s Cancers Section, Laboratory of Pathology National Cancer Institute Bethesda,"— Presentation transcript:

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

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

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

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

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 BRCA- cells, PARP Inhibitor Nature 434:917, 2005 Tumor formation after injection of ES cells into mice

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 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 inhibits poly(ADP-ribose) polymerase (PARP) is a key enzyme in DNA repair. AG sensitizes cancer cells to DNA damaging drugs such as TMZ. AG is the first PARP inhibitor to be evaluated in cancer patients. Methods: In part 1 of the study, pts with solid tumors received AG TMZ daily x 5 every 28 days. TMZ dose was half of standard (100 mg/m2 po) and AG (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 In part 2, AG 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 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 % inhibition of PBL PARP activity. PK evaluation for AG alone after mg/m2 shows mean terminal T = hr, clearance = 25 L/hr, and linear dose proportionality for AUC and Cmax. AG 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 %). Conclusions: Doses up to 12 mg/m2 AG and 200 mg/m2 TMZ are safe and significantly inhibit PBL and tumor PARP. One further dose level (AG 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

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

10 Osteoclastic Osteoblastic Types of Bone Metastases

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

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

14 Eur. J. Cancer Suppl. 4: 63, 2004 EORTC-NCI-AACR Symposium on Molecular Targets And Cancer Therapeutics Poster Denosumab Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) in a Phase 1 Study of Japanese Women With Breast Cancer-Related Bone Metastasis Hironobu 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, PhD 4 1 National Cancer Center Hospital East, Kashiwa, Japan; 2 National Cancer Center Hospital, Tokyo, Japan; 3 Tochigi Cancer Center, Utsunomiya, Japan; 4 Amgen Ltd., Tokyo Japan; 5 Amgen Inc., Thousand Oaks, CA USA

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. E.D. Williams et al. Poster from Abstract 36 Eur. J. Cancer Suppl. 4:15, th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics ET-A ET-1 Atrasentan is a ET-A antagonist hPTH1-34 is a PTHrP antagonist that has been in a Phase I trial for osteoporosis Osteoporosis Int. 17:1532, 2006

19 Examples of New Molecular Targets for Metastatic Breast Cancer BRCA / PARP Inhibitors AG 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 Control Metastasis Suppressor Gene In tissue culture: Less motility Less invasion Less colonization Differentiation Equal proliferation

21 CSSFCS -Nm23-H1 -Nm23-H2 -Alpha- Tubulin Clin. Cancer Res. 8:3763, 2003 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. Can Nm23 Expression be Restored to Micrometastatic Breast Cancer Cells in the Lungs?

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

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

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

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

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

27 Current treatments include gamma knife, whole brain radiation therapy, chemotherapy, steroids and surgery 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%.

28 Am. J. Pathol. 167:913, 2005 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. A Unique Microenvironment

29 Blood-Brain Barrier Permeability of Ten Common Chemotherapeutic Drugs Compounds with a Log Permeability value less than -3 would be classified as having POOR blood-brain barrier permeability -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. Courtesy of Drs. Paul Lockman and Quentin Smith

30 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 Why Her-2 Status ? 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 Tubulin Vector Low Her-2 High Her-2 Total Her-2 MDA-MB-231 Brain Seeking: Palmieri et al. Cancer Res. Under revision. Clone: Mean Large Brain Mets (95%CI) P: Vector ( ) Vector (2.0 – 3.8) Low Her (8.3 – 14.4) Low Her (15.1 – 18.1) High Her (8.9 – 12.9) High Her (11.6 – 16.4) A Perfect Storm: Her-2 Overexpression Promotes Brain Mets

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


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