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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 1 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 (2007 data) New cases, n Demographics - Location Developed countries Underdeveloped countries a Prostate cancer incidence General prognosis 782,600 — ~75% of diagnoses ~25% of diagnoses Favorablea Poor Survival may be relatively low in countries with conservative versus active management practices. PC, prostate cancer. American Cancer Society. 2007. Treatment Recommendations for Patients With Prostate Cancer Early Stage T1a • Active surveillance • Brachytherapy • Surgery • Radiation • LHRH analogue • Combination • • • • Recurrent/Metastatic HSPC CRPC Salvage radiotherapy • Chemotherapy LHRH analogue • Zoledronic acid Orchiectomy • Radiation Combined androgen • Radio-pharmaceuticals blockade • New agents 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. Would CRPC Therapies Be Beneficial in Earlier PC Settings? Phase III trials of docetaxel in adjuvant/neoadjuvant PC Principal investigator Local treatment No. patients (enrolled/planned) Status GETUG 12 K. Fizazi (France) XRT 413 / 400 Accrual completed RTOG 0521 H. Sandler (USA) XRT 260 / 600 Ongoing M. Eisenberger (USA) RP 228 / 1,700 Early enrollment termination AdPro Ahlgren (Sweden) RP 154 / 396 Ongoing DOCET-L-02357 A. D’Amico (USA) XRT 100 / 350 Ongoing VA # 553 CAP Montgomery (USA) RP 65 / 636 Ongoing CALGB 90203 Eastham (USA) RP 14 / 750 Ongoing Kellokumpu-Lehtinen (Fin) XRT 9 / 924 Ongoing Study name TAX 3501 AdRad 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. 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. Effects on Tumours Outside of Bone Can BPs also affect tumour growth outside bone? How? Bisphosphonates Can Inhibit Several Key Steps of the Metastatic Cascade Primary tumor Angiogenesis Intravasation Inhibits angiogenesis Stimulates immune surveillance Induces tumor cell apoptosis Inhibits bone resorption Metastases Decreases adhesion to bone ? Decreases matrix invasion Adhesion & extravasation Arrest in distant capillary Indirect antitumor effect Direct antitumor effect Micrometastases Adapted from Mundy GR, et al. Nat Rev Cancer. 2002;2(8):584-593. 6 How Can Tumour Growth in Bone be Reduced by BPs? Induce apoptosis of tumour cells BP Tumour cells Tumour/bone microenvironment: Macrophages Immune cells Fibroblasts Stromal cells Endothelial cells Bone marrow precursors Adipocytes Osteoblasts BP Osteocyte Reduce release of bone-derived tumour growth factors Potentially exerts anticancer effects on a range of additional cell types involved in tumour development ??? Osteoclast Induce apoptosis of osteoclasts BP 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 Cancer stem cell niche Gamma/delta () and alfa/beta T cells MSC (Mesenchimal Stem Cells) HSC VEGFR1 or 2 pos Cancer Stem Cells 8 Disseminated Tumor Cells Cancer stem cell niche Lin et al ASCO 2008 Zoledronic acid 4 mg/month × 1 year 77% Reduced BM micromets at 1 year N = 45 with BM micromets after adjuvant chemotherapy N= 31 Zoledronic acid 8 mg, then 4 mg/month × 6 months Rack et al 2008 N = 172 with BM micromets after adjuvant chemotherapy N= 141 No zoledronic acid 13% Persistent BM micromets at 39 months 27% Persistent BM micromets at 39 months 9 Antitumour Effect of Amino Bisphosphonates - Potential Mechanism Reduced release of proteolytic enzymes (MMP-9) from tumour macrophages 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. 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. 11 Bisphosphonate Triangle via Ras protein inhibitions Apoptosis Leukemia1 RCC2 Lung cancer3 Osteosarcoma4 Bladder cancer5 BP 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. Gamma-delta (V9/v2) 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) 13 Does Zoledronic Acid Induce a Tumor Antigen? HMG-CoA Mevalonate Increased IPP in cells may become tumor antigen. Isopentenyl-PP Geranyl-PP Zoledronic acid Squalene Cholesterol T cell FPP synthase Farnesyl-PP Farnesylation (panRas,Rheb etc.) Geranylgeranyl-PP Geranylgeranylation Reprinted from Sato K, et al. Int J cancer. 2005;116(1):94-99. Cancer cells (K-Ras, N-Ras, RhoA, etc.) 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 ZOL ZOL X FPPS IPP IPP IPP ZOL IL-4 IL-10 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. TNF- IFN- 5. TNF-, IFN- stimulate antigen-presenting cells and T-helper cells 15 T Cells Attack Myeloma Cells T Cell After 2 Weeks of Ex Vivo Expansion 9.4% T cell = 4.6% IL-2 86% PB (Pre) IL-2 + ZOL IL, interleukin; PB, peripheral blood; PRE, pretreatment; ZOL, zoledronic acid. Reprinted from Sato K, et al. Int J Cancer. 2005;116(1):94-99. Osteoblasts Cancer stem cell niche 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. 18 Bone Marrow Stromal Cells (BMSCs) Cancer stem cell niche 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. 19 Circulating Endothelial Cells (CEC) Circulating endothelial Progenitors (CEP) Cancer stem cell niche 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. 20 Mesenchimal Staminal Cells (MSCs) Cancer stem cell niche 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. 21 Cancer Staminal Cells (CSCs) Cancer stem cell niche 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 P#2 P#4 P#6 P#8 P#9 HD#1 HD#2 HD#3 Cytotoxicity (%) 100 50 CSC#1 CSC#2 CSC#3 CSC#4 Todaro M, et al. J Immunology. 2009;182:7287-7296. CSC#5 CSC#6 CSC#7 CSC#8 Zol Nil Zol Nil Zol Nil Zol Nil Zol Nil Zol Zol Nil Nil Zol Nil Zol Nil 0 CSC#9 22 Conclusions Cancer stem cell niche Disseminated tumor cells (DTCs)1 yes (apoptosis) Osteoclast2 and macrophages3 yes (apoptosis, APC functions) Osteoblasts4 yes (decrease RANKL, increase OPG) Bone Marrow Stromal cells5 yes (< prolif; > apoptosis) (apoptosis, inhibit. differentiation) Prevention ofyes metastases CEP and CEC6 Gamma/delta7 and alfa/beta T8 yes (immunomodulation) MSC (Mesenchimal Stem Cells)9 yes (inhibition of migration and cytokine secretion) Cancer Stem Cells10 yes (sensitizes colon CSCs to g/d T cell cytotoxicity) • HSC VEGFR1 or 2 pos ? 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 23 Combination Therapy in Vivo Tumour type BP Effect Cytotoxic drug Breast cancer (MDA-MB-231 IT) Prostate cancer Risedronate 150ug/kg/5x/week Docetaxel 4mg/kg/2x/week Tumour size Zoledronic acid 1ug/kg/day IM (1mg/d) Pac (0.16mg/week) Lymph node mets Tumour incidence (van Beek 2009) (Kim, 2005) Ewing Sarcoma Prostate cancer (PC3) Osteosarcoma Leukemia (BV173) Tumour incidence Zoledronic acid 4ug/2x/week Paclitaxel (12mg/week) Zoledronic acid 8ug/2x/week SC-236 (0.24mg 5x/w) Gefitinib (3mg 5x/w) Tumour growth Zoledronic acid 4ug/week IFO 0.3mg 3x Tumour recurrence Zoledronic acid 1.6ug/kg/3x/week IM (2.4m/d) (Zhou, 2005) (Melisi ,2005) (Heymann, 2005) Overall survival (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. 24 Ongoing Studies 25 ZEUS: Zoledronic Acid for the Prevention of Bone Metastases in Prostate Cancer Key endpoints: Time to bone metastases, overall survival, PSA doubling time, substudies on bone markers, adverse events 1,433 patients 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 Zoledronic acid 4 mg q 3 months R No zoledronic acid Treatment duration 4 years Accrual complete ADT, androgen deprivation therapy; PC, prostate cancer; PSA, prostate-specific antigen. 26 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 Participating Countries: Australia, New Zealand ClinicalTrials.gov identifier: NCT00193856 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 + 27 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 Androgen suppression (AD) patientsa 1,264 Prostate Cancer High-risk newly diagnosed or relapsed after prostatectomy or radiotherapy who start ADT therapy (patients with or without bone metastases) AD + Taxotere (T) R AD + zoledronic acid (Z) AD + celecoxib AD + celecoxib + Z Pilot Confir m Safety in 210 patient s on trial for min 18 weeks AD + T + Z 24 months ZOL • Efficacy stages I IV Reject arms not improving FailureFree Survival at each stage 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. 28 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 29