OPG-Fc inhibits ovariectomy-induced growth of disseminated breast cancer cells in bone.

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1 Title of the poster Authors Sheffield Cancer Research Centre University of Sheffield OPG-Fc inhibits ovariectomy-induced growth of disseminated breast cancer cells in bone. Dr Penelope Ottewell

2 Background ~7% patients with late stage breast cancer develop bone metastasis. This condition is considered incurable with patients surviving 2-3 years after initial diagnosis of bone involvement. Current treatments are palliative; patients receive chemotherapy to treat their tumours and anti-resoptive agents to control their bone disease. We have focused on optomising the use of anti-resorptive agents (zoledronic acid (ZOL) and OPG-Fc) to increase their anti-tumour properties.

3 Breast cancer bone metastasis Tumour cells arrive in bone Tumour cells are triggered to wake up Tumour cells grow quickly. and cause bone destruction Zoledronic acid/opg-fc Doxorubicin Bone derived tumour growth factors dormant Bone Osteoblastic factors Osteolytic factors

4 Effects of adding zoledronic acid to doxorubicin on breast cancer bone metastases 6 week female BALB/c nude mice n=1/group Experimental time line Day Day 7 Day 28 Inject dox, ZOL or (or control) dox and ZOL 1x per week Inoculate MDA-231 luc2 cells into the tail artery Inject 2mg/kg Dox and 1ug/kg ZOL Cull Experimental time line Day Day 7 Day 8 Day 28 Inject dox (or control) followed 24h later by zol (or control) 1x per week Inoculate MDA-231 luc2 cells into the tail artery Inject 2mg/kg dox Inject 1ug/kg ZOL Cull Ottewell et al Clin Can Res 28

5 Effects of doxorubicin and zoledronic acid on breast cancer growth in bone Figure 1 Zol Dox A. B. C. Histology uct µct X-ray Osteolytic lesion area (mm 2 ) * Zol Dox Dox & Zol * * Dox then Zol D. Dox and zol E. Tumour area (mm 2 ) * Dox then zol Zol Dox Dox & Zol Dox then Zol Sequential administration with Dox followed by ZOL significantly reduced MDA-MB-231 breast cancer cell growth in bone. Ottewell et al Clin Can Res 28

6 Clinical study design; AZURE Standard therapy 3,36 Breast Cancer Patients Stage II/III Countries Centres Patients UK Eire Australia Spain 8 17 Portugal 1 32 Thailand 2 25 Taiwan 2 13 R Standard therapy + Zoledronic acid 4 mg 6 doses 8 doses 5 doses Q3-4 weeks Q 3 months Q 6 months Months Zoledronic acid treatment duration 5 years Coleman et al. N Engl J Med 211; 365:

7 Analysis of relapse in bone; AZURE Bone metastasis as first recurrence Bone metastasis at any time Zoledronic acid Zoledronic acid Adjusted HR.78 95% CI: , P=.2 Adjusted HR.81 95% CI: , P=.22 Adding zoledronic acid to standard of care delayed bone metastases Coleman et al Lancet Oncology 214; 15(9):997-16

8 Disease free survival and menopausal status; AZURE ITT analysis - DFS >5 years post-menopausal No. at risk ZOL Adjusted HR.94 95% CI: , P=.298 Zoledronic acid N = events No. at risk Zoledronic acid provided significantly greater therapeutic benefit to post menopausal women, ZOL Zoledronic acid Adjusted HR.77 95% CI: N = events Coleman et al Lancet Oncology 214; 15(9):997-16

9 Emerging hypotheses from adjuvant trials Bisphosphonates predominantly reduce distant metastases rather than either local recurrence or contralateral disease Effects likely to be largest on bone recurrence Bisphosphonates only improve disease outcome in women who have low levels of reproductive hormones Established natural menopause Induced menopause at start of treatment Why do bisphosphonates specifically benefit patients with established menopause? Coleman RE SABCS 213 Abs S4-7 and Lancet in press

10 Modeling the pre-and post-menopausal bone environment in the laboratory 12 week female BALB/c nude mice n=5/group Experimental time line Day Day 7 Day 14 Day 21 Day 28 Day 35 Day 57 Ovariectomy/ ovariectomy N=35/group Cull N=5/group Cull N=5/group Cull N=5/group Cull N=5/group Cull N=5/group Cull N=5/group How does alter the bone environment over time: - Bone volume - Osteoclast activity (TRAP ELISA) - Osteoblast activity (P1NP ELISA) Ottewell et al Clin Can Res 214

11 Bone microenvironment different under preand post-menopausal conditions Baseline 8 weeks Ovariectomy reduces bone volume by increasing osteoclast induced bone resorption * Ottewell et al Clin Can Res 214

12 Effects of ovariectomy on tumour cell proliferation in bone 12-week old female BALB/c nude mice n=9/group Experimental time line Day Day 7 Day 56 Inoculate MDA-231 luc2 cells i.c. Ovariectomy/ ovariectomy Cull Ovariectomy Number of tumours per mouse In bone Outside bone * Overiectomy stimulates proliferation of MDA-MB-231 cells disseminated in bone Ottewell et al Clin Can Res 214

13 Summary/research question Mimicking the menopause with ovariectomy alters bone turnover. Ovariectomy stimulates proliferation of dormant breast cancer cells in bone. Can anti-resorptive agents prevent ovariectomy induced proliferation of breast cancer cells in bone? Do anti-resorptive agents have different anti-tumour effects in pre- and post- menopausal bone environments?

14 Effects of ZOL on normal bone Zol % bone in contact with osteoclasts *** Zol BV/TV% 6 *** 4 2 Zol Number of osteoblasts per mm bone Zol ZOL inhibits bone turnover by reducing osteoclastic resorption of bone Ottewell et al JNCI 28

15 Effects of ZOL on ovariectomy induced tumour growth and bone resorption 12-week old female BALB/c nude mice n=1/group (X2) Experimental time line Day Day 4 Day 7 Day 35 Inject zol/saline 1x per week Mice with tumours in bone (%) control Inoculate MDA-231 luc2 cells i.c. zol Ovariectomy/ ovariectomy control zol ZOL inhibits stimulated growth of disseminated breast cancer cells in bone but had no effect of spontaneous tumour development from these cells. * BV/TV (%) control con Cull zol ** control * zol zol con zol Ottewell et al Clin Can Res 214 **

16 Do other anti-resorptive agents prevent induced bone metastases? Denosumab in the clinic: Human specific monoclonal antibody that binds RANKL with high affinity blocking RANK/RANKL interactions essential for osteoclatogenesis. Superior to zoledronic acid for prevention of skeletal complecations in patients with breast cancer bone metastasis. OPG-Fc in the laboratory: Potent inhibitor of osteoclatioenesis that acts by preventing RANK/RANKL binding. We investigated the effects of inhibiting -induced bone resorption through targeting RANK/RANKL interactions in our in vivo model of disseminated breast cancer cells in bone.

17 BV/TV (%) Effects of OPG-Fc on bone Morphology TRAP Goldners Safranin O osteoclasts osteoblasts OPG-Fc OPG-Fc 25 *** TRAP (U/L) 1 5 * * OPG-Fc P1NP * OPG-Fc OPG-Fc OPG-Fc inhibits osteoclastic bone resorption and osteoblastic bone formation Ottewell et al Int J Can 215

18 Effects of OPG-Fc on growth of disseminated breast cancer cells in bone 12-week old female BALB/c nude mice n=7/group (X2) Day Day 4 Day 7 Day 35 Inject OPG-Fc/saline 1x per week Inoculate MDA-231 luc2 cells i.c. Ovariectomy/ ovariectomy Cull Saline Saline OPG-Fc OPG-Fc Mice with tumours (%) BIL / tumour (p/s) *** Bone Non-bone saline saline OPG-Fc OPG-Fc Bone Non-bone *** *** saline saline OPG-Fc OPG-Fc OPG-Fc inhibits ovariectomy induced proliferation of disseminated MDA- MB-231 breast cancer cells in bone. Ottewell et al Int J Can 215

19 Effects of OPG-Fc on tibiae of mice following tumour cell inoculation saline saline OPG-Fc OPG-Fc 4 3 ^^^ ^^^ BV/TV% 2 1 ** saline saline OPG-Fc OPG-Fc 15 ^ 4 TRAP (U/L) 1 5 *** *** Saline Saline OPG-Fc OPG-Fc P1NP ng/ml *** *** Saline Saline OPG-Fc OPG-Fc OPG-Fc inhibits ovariectomy induced bone resorption leading to a net increase in bone volume and decrease in bone cell activity. Ottewell et al Int J Can 215

20 Summary Bone derived growth factors Tumour cells arrive in bone Ovariectomy stimulates bone turnover Tumour cells are triggered to wake up Tumour cells grow quickly. and cause bone destruction Zoledronic Acid/OPGFc Bone derived tumour growth factors dormant Bone Osteoblastic factors Osteolytic factors

21 Conclusions Cellular mechanisms responsible for driving tumour growth are different in pre- (sham) and post menopausal () bone metastasis models. Osteoclast mediated mechanisms drive progression of disseminated tumour cells only in the post-menopausal model. Inhibition of osteoclast activity with ZOL or disruption of RANK/RANKL interactions following administration of OPG-Fc inhibits induced stimulation of dormant tumour cells in bone Our data support early intervention with anti-resorptive therapy in a low oestrogen environment to prevent development of bone metastases.

22 Acknowledgements University of Sheffield Prof. Ingunn Holen Dr. Ning Wang Mrs. Anne Fowles Dr. Colby Eaton Dr. Hannah Brown Ms. Orla Gallagher Garvan Institute of medical research Prof Peter Croucher

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