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The Emerging Role of Bisphosphonates in the Early Treatment of Prostate Cancer

The Emerging Role of Bisphosphonates in the Early Treatment of Prostate Cancer. Carlos Rabaça IPOFG Coimbra FMUC XIV WORKSHOP DE UROLOGIA ONCOLÓGICA Carvoeiro , 22-23 de Outubro de 2010. Prostate Cancer Epidemiology. • Most common cancer in men

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The Emerging Role of Bisphosphonates in the Early Treatment of Prostate Cancer

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  1. The Emerging Role of Bisphosphonates in the Early Treatment of Prostate Cancer Carlos Rabaça IPOFG Coimbra FMUC XIV WORKSHOP DE UROLOGIA ONCOLÓGICA Carvoeiro, 22-23 de Outubro de 2010

  2. Prostate Cancer Epidemiology • Most common cancer in men • High rate of diagnosis in industrialized nations because of testing for prostate-specific antigen (PSA) • PC often diagnosed in early stages, allowing for early treatment • Prognosis is worse for other regions and for some ethnic groups PC, prostate cancer.American Cancer Society. 2007.

  3. Early Stage Active surveillance Brachytherapy Surgery Radiation LHRH analogue Combination Treatment Recommendations for Patients With Prostate Cancer Recurrent/Metastatic • HSPC • Salvage radiotherapy • LHRH analogue • Orchiectomy • Combined androgen blockade • CRPC • Chemotherapy • Zoledronic acid • Radiation • Radio-pharmaceuticals • New agents T1a T4 HSPC, hormone-sensitive prostate cancer; CRPC, castration-resistant prostate cancer; LHRH, leutinizing hormone releasing hormone. Note: palliative therapies are not included in this list. Heidenreich A, et al. Eur Urol. 2008;53(1):68-80.

  4. Would CRPC Therapies Be Beneficial in Earlier PC Settings? Phase III trials of docetaxel in adjuvant/neoadjuvant PC CRPC, castration-resistant prostate cancer; PC, prostate cancer; XRT, external-beam radiotherapy; RP, radical prostatectomy.Fizazi K, personal communication; Mazhar D, et al. Nat Clin Pract Urol. 2008;5(9):486-493.

  5. Effects on Tumours Outside of Bone Can BPs also affect tumour growth outside bone? How? Bisphosphonates Effects in Bone Bisphosphonates reduce tumour burden in bone in a range of different cancer types. A result of direct and indirect effects - targeting both tumour and the bone microenvironment.

  6. Inhibits angiogenesis Stimulates immune surveillance Induces tumor cell apoptosis Decreases adhesion to bone Decreases matrix invasion Direct antitumor effect Bisphosphonates Can Inhibit SeveralKey Steps of the Metastatic Cascade Primary tumor Angiogenesis Intravasation Inhibits bone resorption ? Metastases Adhesion & extravasation Arrest in distant capillary Indirect antitumor effect Micrometastases Adapted from Mundy GR, et al. Nat Rev Cancer. 2002;2(8):584-593.

  7. How Can Tumour Growth in Bone be Reduced by BPs? Induce apoptosis of tumour cells Tumour/bonemicroenvironment: Macrophages Immune cells Fibroblasts Stromal cells Endothelial cells Bone marrow precursors Adipocytes BP BP Potentially exerts anticancer effects on a range of additional cell types involved in tumour development BP Induce apoptosis of osteoclasts Reduce release of bone-derived tumour growth factors Tumour cells Osteoblasts ??? Osteoclast Osteocyte

  8. Cancer stem cell niche Can Bisphosphonates Inhibit Several Key Steps or Cellular Components of the Cancer Niche? • Disseminated tumor cells (DTCs) • Osteoclast and macrophages • Osteoblasts • Bone Marrow Stromal cells • CEP and CEC • Gamma/delta () and alfa/beta T cells • MSC (Mesenchimal Stem Cells) • HSC VEGFR1 or 2 pos • Cancer Stem Cells

  9. Cancer stem cell niche Disseminated Tumor Cells 77%Reduced BM micromets at 1 year Zoledronic acid 4 mg/month × 1 year Lin et al ASCO 2008 N = 45 with BM micromets after adjuvant chemotherapy N= 31 13% Persistent BM micromets at 39 months Zoledronic acid 8 mg, then 4 mg/month × 6 months Rack et al 2008 N= 141 27% Persistent BM micromets at 39 months No zoledronic acid N = 172 with BM micromets after adjuvant chemotherapy

  10. Antitumour Effect of Amino Bisphosphonates- Potential Mechanism Reduced release of VEGF from the extracelluar matrix VEGF levels too low to signal mobilisation of hematopoietic stem cells from the bone marrow Treated tumour Control tumour Reduced tumour angiogenesis and growth Coscia M, et al. J Cell Mol Med. 2009 Oct 10. [Epub ahead of print]. Melani C, et al. Cancer Res. 2007;67(23):11438-11446. Giraudo E, et al. J Clin Invest. 2004;114:623-633. Reprinted from Ottewell PD, et al. J Nat Cancer Inst. 2008;100(16):1167-1178. Reduced release of proteolytic enzymes (MMP-9) from tumour macrophages

  11. Induction of Dendritic Cell Functions of Macrophages and Adoptive Immune Response Increase in alfa/beta T cells activities (Adoptive responses) Increase in gamma/delta T cells activieties (Innate responses) GAPDH 347- Fiore F, et al. Blood. 2007;110(3):921-927.

  12. Apoptosis Bisphosphonate Triangle via Ras protein inhibitions Leukemia1 RCC2Lung cancer3 Osteosarcoma4 Bladder cancer5 BP gd T cell Osteoclast RCC, renal cell carcinoma; BP, bisphosphonate; , gamma-delta. 1. Kuroda J, et al. Blood. 2003;102(6):2229-2235; 2. Yuasa T, et al. Clin Cancer Res. 2005;11(2 Pt 1):853-859; 3. Matsumoto S, et al. Lung Cancer. 2005;47(1):31-39; 4. Horie N, et al. Br J Cancer. 2007;96(2):255-261; 5. Sato K, et al. Br J Cancer. 2006;95(10):1354-1361.

  13. Gamma-delta (V9/v2) T cells: • ~1-5% of PBMC in healthy human adults • First line defense against pathogens(non-peptidic compounds like phosphoantigens) • Spontaneous antitumor activity in vitro(MM and NHL cell lines) • Involved in immunosurveillance in vivo(2M-/-; PF-/- mice) • Enhancers of adaptive immune responses(DC, antibody production) • Activated and expanded by nBPs(Kunzman et al,N Engl J Med. 1999;340(9):737-738)

  14. Increased IPP in cells may become tumor antigen. Zoledronic acid gd T cell Squalene Cholesterol Farnesylation Farnesyl-PP Geranylgeranyl-PP (panRas,Rheb etc.) Cancer cells Geranylgeranylation (K-Ras, N-Ras, RhoA, etc.) Does Zoledronic Acid Induce a Tumor Antigen? HMG-CoA Mevalonate Geranyl-PP Isopentenyl-PP FPP synthase Reprinted from Sato K, et al. Int J cancer. 2005;116(1):94-99.

  15. Zoledronic Acid Increases Activity of  T Cells and Other Immune Pathways 2. IPP stimulates , T cells to proliferate and secrete cytokines 1. ZOL inhibits FPPS in PBMCs, causing accumulation of IPP ZOL ZOLXFPPS IPP IPP ZOL IPP ZOL TNF- IFN- IL-4 IL-10 5. TNF-, IFN- stimulate antigen-presenting cells and T-helper cells 3. Activated , T cells are directly cytotoxic to tumor cells 4. IL-4, IL-10 stimulate B cell humoral response to tumor cells Santini D, et al. Cancer Immuno Immunother. 2009 Jan;58(1):31-38.

  16. gd T Cells Attack Myeloma Cells

  17. gd T cell = 4.6% IL-2 86% PB (Pre) IL-2 + ZOL T Cell After 2 Weeks of Ex Vivo Expansion 9.4% IL, interleukin; PB, peripheral blood; PRE, pretreatment; ZOL, zoledronic acid. Reprinted from Sato K, et al. Int J Cancer. 2005;116(1):94-99.

  18. Cancer stem cell niche Osteoblasts Low doses of ZOL increased OPG protein secretion and reduced transmembrane RANKL protein expression in osteoblast-like cells • Osteoclast activity • Bone turnover Pan B, et al. J Bone Miner Res. 2004 Jan;19(1):147-54.

  19. Cancer stem cell niche Bone Marrow Stromal Cells (BMSCs) Tumor cells localize within the BM through the interaction of adhesion receptors with their ligands on BM stromal cells (BMSCs) BMSCc from MM patient ZOL 50 microg Increase in apoptosis • Decrease of adhesion molecules, CD106, CD54, CD49d, and CD40 • Decrease in proliferation Corso A, et al. Cancer. 104(1):118-125.

  20. Cancer stem cell niche Circulating Endothelial Cells (CEC)Circulating endothelial Progenitors (CEP) CEC and CEP from human PBMC • Inhibition of endothelial progenitor cell differentiation at low doses (1-10 mM) • Induction of endothelial progenitor cell apoptosis at higher doses (> 10 mM) Yamada J, et al. J Surg Res. 2009;151(1):115-120.

  21. Cancer stem cell niche Mesenchimal Staminal Cells (MSCs) Bone marrow MSCs increase breast cancer motility and invasion by secreting RANTES Zoledronic acid inhibits RANTES secretion by MSCsa Zoledronic acid inhibits migration of MSCsa a Images not available. Normanno N, et al. Presented at ECCO 2009. Abstract 35LBA.

  22. Cancer stem cell niche P#2 100 P#4 P#6 P#8 P#9 HD#1 50 Cytotoxicity (%) HD#2 HD#3 0 Zol Zol Zol Zol Zol Zol Zol Zol Zol Nil Nil Nil Nil Nil Nil Nil Nil Nil CSC#1 CSC#2 CSC#3 CSC#4 CSC#5 CSC#6 CSC#7 CSC#8 CSC#9 Cancer Staminal Cells (CSCs) Colon cancer comprises a small population of cancer stem cells (CSC) that is responsible for tumor maintenance and resistant to cancer therapies Zoledronic acid sensitizes colon CSCs to T cell-mediated killing Todaro M, et al. J Immunology. 2009;182:7287-7296.

  23. Cancer stem cell niche Conclusions Prevention of metastases Reduction of DTCs, inhibition of bone turnover, inhibition of angiogenesis, inhibition of growth factors, stimulation of antitumoral innate and adoptive immunity, inhibition of MSC,inhibition of CSCs 1. Lin A, et al. ASCO. 2008; Abstract 559; 2. Dunford Je, et al. J Pharmacol Exp Ther, 2001; 3. Tsagozis P et al. Cancer Immunology and Immunotherapy, 2008; 4. Pan B. et al. J Bone Miner Res, 2004; 5. Corso A. et al. Cancer 2005; 6. Yamada J et al. J Surg Res, 2009; 7. Kunzmann V et al. Blood 2000; 8. Fiore F et al. Blood 2007: 9. Normanno N. et al ECCO-ESMO, 2009; 10. Dieli F. et al. Journal of Immunology, 2009

  24. Combination Therapy in Vivo Effect Tumour type BP Cytotoxic drug Breast cancer (MDA-MB-231 IT) Risedronate Docetaxel  Tumour size 150ug/kg/5x/week 4mg/kg/2x/week (van Beek 2009) Prostate cancer Zoledronic acid IM (1mg/d)  Lymph node mets 1ug/kg/day Pac (0.16mg/week)  Tumour incidence (Kim, 2005) Ewing Sarcoma Zoledronic acid Paclitaxel (12mg/week)  Tumour incidence 4ug/2x/week (Zhou, 2005) Prostate cancer (PC3) Zoledronic acid SC-236 (0.24mg 5x/w)  Tumour growth 8ug/2x/week Gefitinib (3mg 5x/w) (Melisi ,2005) Osteosarcoma Zoledronic acid IFO 0.3mg 3x  Tumour recurrence 4ug/week (Heymann, 2005) Leukemia (BV173) Zoledronic acid IM (2.4m/d)  Overall survival 1.6ug/kg/3x/week (Kuroda, 2003) In all cases - combination therapy superior to single agents Reprinted from Brown HK and Holen I. Curr Cancer Drug Targets. 2009;9(7):807-823.

  25. Ongoing Studies

  26. ZEUS: Zoledronic Acid for the Preventionof Bone Metastases in Prostate Cancer Key endpoints:Time to bone metastases,overall survival, PSA doubling time, substudies on bone markers, adverse events • 1,433patients • Prostate cancer, M0 • +/- previous local curative treatment, +/- ADT • High-risk PCa with at least 1 of the following criteria • Gleason Score 8 - 10 • pN+ • PSA  20 at diagnosis R Zoledronic acid 4 mg q 3 months No zoledronic acid Treatment duration 4 years Accrual complete ADT, androgen deprivation therapy; PC, prostate cancer; PSA, prostate-specific antigen.

  27. RADAR: Zoledronic Acid for the Prevention of Bone Metastases and Effects on Overall Survival in PC • Key endpoints:PSA relapse-free survival, overall survival, local failure, QOL, bone metastases-free survival, bone mineral density Short-term AD (STAD) – LHRH analogue for 5 mo before and during first mo of radiation treatment (total 6 mo) • 1,071 patients • Prostate Cancer • T2a (Gleason score >/= 7 and • PSA >/= 10), T2b-4, N0, M0 • Stratification • T2a/T2b/T3,4 • <60 yr/60 - 70 yr/>70 yr • Gleason primary pattern 1 - 3/4, 5 • PSA <10/10 - 20/>20 • Treatment center R Short-term AD (STAD) – LHRH analogue for 5 mo before and during first mo of radiation treatment (total 6 mo) + ZOL 4 mg q 3 mo / 18 mo Intermediate term AD – LHRH analogue as for STAD arm, but continued for further 12 mo (total 18 mo) Intermediate term AD – LHRH analogue as for STAD arm, but continued for 12 mo (total 18 mo) + ZOL 4 mg q 3 mo / 18 mo ZOL treatment 18 mo total follow-up 5 years + Participating Countries: Australia, New Zealand ClinicalTrials.gov identifier: NCT00193856

  28. STAMPEDE: Zoledronic Acid for the Effects on Failure-Free Survival in Prostate Cancer • Key endpoints:Failure-free survival (PSA failure, new lesions or increase of baseline lesions, death), QOL, cost-effectiveness, toxicity, SREs, overall survival Pilot Confirm Safety in 210 patients on trial for min 18 weeks R Efficacy stages I - IV Reject arms not improving Failure- Free Survival at each stage 1,264 patientsa Prostate Cancer High-risk newly diagnosed or relapsed after prostatectomy or radiotherapy who start ADT therapy (patients with or without bone metastases) Androgen suppression (AD) AD + Taxotere (T) AD + zoledronic acid (Z) AD + celecoxib AD + celecoxib + Z AD + T + Z 24 months ZOL • Follow-up until death • Participating Countries: United Kingdom a Enrollment current as of October 2009. Planned enrollment is between 2,800 and 3,600 patients.

  29. Conclusions • Substantial evidence from a range of models show that BPs reduce tumour growth in bone • Increasing evidence that BPs may also affect tumours outside the skeleton (but the dosing/ scheduling often intensive) • BPs may have a substantial anti-tumour effect when used in combination with other anti-cancer agents

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