1. 1 University of Minnesota Life Science Presents: Ultra Sensitive Technology: Monitoring Bone Health Susanta K Hui, PhD, DABR Assistant Professor, Therapeutic Radiology

2. 2 Why Study Bone Health ? Osteoporosis is a bone disease in which bones become fragile. Osteoporotic fractures are a significant public health problem: 1 in 2 women and 1 in 8 men over the age of 50 will have an osteoporosis related fracture. Larger sectors of the population live with osteopenic and osteoporosis disease without knowing it. The increased levels of morbidity and disability reduce quality of life. This situation is worsening as the population ages. Advances in cancer diagnosis and treatment strategies have improved cure rates and survival times of patients. However, bone loss caused by cancer treatments is an increasingly pressing concern.

3. 3 BMD Loss Caused by Cancer Treatment © American Society for Bone and Mineral Research Contributed by Katherine Weilbaecher Normal men Early menopausal women Late menopausal women Aromatase inhibitor (AI) therapy Androgen deprivation therapy AI therapy plus gonadotropin- releasing hormone agonist Ovarian failure secondary to chemotherapy Bone marrow transplant Bone Mineral Density (BMD) Loss Caused by Cancer Therapies Hirbe A, Morgan E et al. ASBMR primer, 2006, 6, : 390-395.

4. 4 Era of Hope – Individualized Clinical Oncology Clinical Oncology brings individualized patient care through : Genetic information, Targeted therapy, and Biomarker development Reasons – DXA scan incapable of detecting rapid change in bone turnover. Biomarkers (NTx, P1NP) has large seasonal variation (~30- 70%) and day to day variation (10-30%). Specific Goals - developing and implement an ultra sensitive AMS 41 Ca based assay technique that: 1. Identifies patients at risk for bone disease 2. Allows early diagnosis 3. Allows Selection of best treatment 4. Monitors treatment response (short & long term)

5. 5 Some opportunities for industry Bone loss prevention drugs represent a large market: 70 million people have osteoporosis worldwide 1 ; By 2025, fractures and costs are projected to grow by over 48% (incurring $25.3 billion for 3 million fractures); Estimated 1.4 million cancer cases in 2006 with 600,000 cancer survivors. Clinical study of bone-loss prevention drugs comparing existing drugs to potential new ones in development. Studies could help companies quickly prioritize from among several clinical candidates Opportunities exist to develop compact, portable, affordable bone- health detection devices that can be implemented in every clinic 1 World Health Organization 2003 Report of a WHO Scientific Group. World Health Organization, Geneva, Switzerland.

6. 6 Initial 41 Ca Human Assay 1 Hui SK et al. Nuclear Instruments and Methods in Physics Research Section B In Press, With AMS it is possible to monitor bone health using 41 Ca levels frequently for whole life; a major advantage for studying dynamic variations in bone health 1 Non-invasive Urine 41 Ca Levels Indicating Steady State Bone Health over 7 years

7. 7 41 Ca based bone health assay Accelerator Mass Spectrometry (AMS) Mass AnalysisMolecular dissociationFragment analysis Particle detector Atom counting: long-lived radioisotopes 14 C, 3 H, 129 I, 36 Cl, 41 Ca High sensitivity [attomole (10 -18 )] Milligram-sized samples Microdose 1 Biomedical research that can benefit pharmaceutical and biotechnology industries and other life sciences. Needs to be optimized for clinical use 1 Big physics, small doses: the use of AMS and PET in human microdosing of development drugs. Nat Rev Drug Discov. 2003;2:233-40. Review

8. 8 AMS and Accelerated Drug Discovery Drug development Long and expensive process: on average up to a billion dollars for one drug. 50% of total cost goes to time to pass through phase 0 study: (a) FDA clearance of radiotracer, (b) animal study, and (c) time Opportunity for Accelerated Drug discovery Because of very low risk to human health, microdose (~10 -100 nCi) Adsorption, Distribution, Metabolism and Excretion ( ADME) studies do not need to request specific regulatory approval required for ARSAC (UK) / FDA (USA). This saves valuable development time (1-2 years) and resources, Bypass phase 0 trials and begin study with phase I human studies Eliminates disposal issues Much greater sensitivity (1000 to 1000,000 times higher sensitivity) Recent studies and industry participation: Drug test – Early human ADME/PK 1 study, (Xceleron Ltd. UK); 1 Lappin G, Garner RC. Expert Opin Drug Metab Toxicol. 2005 Jun;1(1):23-31. Review.

9. 9 Contact Name:Susanta K Hui, PhD, DABR Department:Therapeutic Radiology Phone:612 626 4484 Email:huixx019@umn.edu Website: www.med.umn.edu/trad/faculty/medicalphysicists/hui/home.htmlwww.med.umn.edu/trad/faculty/medicalphysicists/hui/home.html Acknowledgements Collaborators: University of Minnesota -Doug Yee, MD, Chair, Breast Cancer Research Center; Jerry Froelich, MD, Professor of Nuclear Medicine; Chung Lee, MD, Professor of Radiation Oncology, Yan Zhang, MS, Biostatistics Core, Stephen S. Hecht, PhD, Professor, Dept. of Laboratory Medicine and Pathology; Anne Minenko, MD, Rheumatology; Hebrew University, Israel – Michael Paul, PhD, Professor of Physics; Lawrence Livermore National Laboratory – Darren J. Hillegonds, PhD, CAMS; Pennsylvania State University – Demers L M, Ph.D., Professor, Pathology and Medicine. Presentation support: Michael G. Klug, Ph.D., Technology Transfer Liaison, Academic Health Center Grant support: Breast Cancer Translational Research Grant & Academic Health Center Grant