Mechanism of Bone Metastases

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Mechanism of Bone Metastases

• Priya Gopalan
• 10/10/08

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Outline

• Background
• Predictors of metastasis to bone
• Tumor cell homing to bone
• Tumor cell interaction with bone
• Therapeutic interventions

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Tsai and Kalluri, J Cell Biochem 2007
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Bone Metastases
Coleman, Cancer 2000
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Bone Metastases
(Total 368 pts)
Bone pain
In U.S., in 1990, hospital costs were 2000 per
month per patient, with skeletal complications
accounting for 63 of total cost
Coleman, Cancer 2000
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Types of bone metastases

• Dysregulation of normal bone remodeling
• Osteoblastic (e.g. prostate CA)
• Production of bone with poorly organized
  microstructure
• Osteolytic (e.g. breast CA)
• Mixed (majority)
• e.g. with osteolytic metastases, secondary
  formation of bone occurs in response to bone
  destruction

Roodman NEJM 2004
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Diagnosis

• Bone scan - best for osteoblastic lesions
• MRI
• CT scan with bone windows
• PET-CT
• Plain films

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Diagnosis

• Markers of bone turnover
• Bone-specific alkaline phosphatase (serum)
• C-telopeptide (serum)
• N-telopeptide (NTX) (urine)
• For
• Progression Costa et al. -97 patients with
  solid tumor bone mets imaged q3 months - change
  in NTX was 152 with progression (PPV 71 for dx
  of bone disease progression)
• Prognosis
• Response to treatment

Coleman JCO 2005 Costa et al., JCO 2002
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Prognosis

• 1824 patients treated with bisphosphonates -
  baseline levels of NTX
• Low lt 50 nmol/mmol Cr
• Moderate 50-99 nmol/mmol Cr
• High - 100 nmol/mmol Cr

Coleman JCO 2005
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Relative risk ratios during zoledronic acid
therapy
(skeletal-related events)
Coleman et al. JCO 2005
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Prognosis

• 2 phase III trials with zoledronate prostate
  cancer (n203), and NSCLC and other solid tumors
  (n238)
• Looked at patients on placebo arm
• Measured NTX every 3 months
• Low NTX lt 100nmol/mmol Cr
• High NTX 100nmol/mmol Cr

Brown et al., JNCI 2005
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Prognosis
High vs. low NTX levels
Prostate CA
NSCLC and solid tumors
Brown et al., JNCI 2005
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Reasons for preferential metastasis to bone

• Highly vascular organ (sluggish blood flow)
• Pagets seed-and-soil hypothesis
• Bone marrow niche provides
• Chemotactic signal to home (e.g. SDF-1)
• Adhesion receptors to extravasate
• Growth factors to proliferate (e.g. TGF-b,
  IGF-1)

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Predictors of metastasis to bone (Breast Cancer)

• Kang et al. - 122-gene expression signature of
  bone metastases by comparing breast cancer cell
  lines highly metastatic to specific sites
  (e.g.MDA-MB-231)
• Enhanced bone metastasis when overexpressed
  IL-11, MMP-1, CXCR4, connective tissue-derived
  growth factor

Kang et al., Cancer Cell 2003
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Predictors of metastasis to bone (Breast Cancer)

• Smid et al. - 31-gene signature predictive of
  bone metastases
• 107 women who developed metastases to bone or
  other sites
• Training set n72, test set n35
• TFF-1 and TFF-3 correlated best with bone
  metastases

Smid et al., JCO 2006
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Tumor cell homing

• Organs that are primary sites of breast cancer
  metastasis produce high levels of SDF-1
• Blocking CXCR4 in vitro inhibited prostate cancer
  migration through bone marrow endothelial cells
• Blocking CXCR4 in vivo reduces bone metastases in
  breast and prostate cancers

Muller et al., Nature 2001 Liang et al., Cancer
Res 2004 Sun et al., J Bone Min Res 2005
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Tumor cell homing

• CXCR4/ SDF-1 axis also important in
• NSCLC
• NSCLC cell lines undergo chemotaxis in response
  to SDF-1
• SDF-1 expressed in high levels in metastatic
  sites
• Neutralizing antibodies to SDF-1 inhibit
  metastasis in vivo
• RCC
• Patients with known metastatic RCC have
  significant expression of CXCR4 in circulating
  tumor cells
• Neutralization of SDF-1 inhibits metastasis to
  target organs with high SDF-1 expression in vivo

Phillips et al., Resp Crit Care Med 2003 Pan et
al., Molec Cancer 2006
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Tumor cell homing

• Integrins may also direct organ-specific mets
• When avb3 is overexpressed on breast cancer
  cells, bone metastases are enhanced
• CXCR4 binding to SDF-1 activates avb3 and
  mediates its binding to endothelial cells
• avb3 antagonist inhibits bone colonization by
  avb3-expressing tumor cells
• a2b1 on prostate cancer cells supports bone
  colonization

Zhao Y et al., Cancer Res 2007 Sun et al.,
Prostate 2007 Hall et al., Cancer Res 2006
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(No Transcript)
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Tumor cell homing

• Other chemokines produced by OBs
• Osteopontin
• Bone sialoprotein

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Normal bone remodeling
PTH Vit. D PGE2 IL-1
M-CSF, RANKL
Osteoprotegerin
Clezarin et al., Clin Exp Metastasis 2007
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Osteoblasts/osteoclasts interaction with tumor
cells
PDGF
(BMPs)
IGFs
Clezardin and Teti, Clin Exp Metastasis 2007
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Osteomimicry by tumor cells

• Tumor cells adopt OB phenotype, expressing
  factors associated with bone remodeling
• Minn et al. - Molecular profiling of breast CA
  cell line with high bone metastatic potential
  (MDA-MB231) - several genes in its signature are
  typical of OB phenotype
• Breast and prostate tumors express high levels of
  bone matrix proteins (osteopontin, osteocalcin,
  osteonectin, bone sialoprotein), bone
  morphogenetic proteins (BMPs), TGFb,
  osteoprotegerin (OPG), RANK, Runx2, Msx2 and
  Cathepsin K
• Osteomimetic properties of malignant cells
  facilitate the development of secondary lesions
  in the bone

Minn et al., J Clin Invest 2005
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SDF-1/CXCR4 - other roles

• AMD 3100 - small molecule inhibitor of CXCR4
• Systemic administration inhibits growth of
  intracranial glioblastoma and medulloblastomas
  xenografts
• Increase apoptosis and decrease proliferation of
  tumor cells
• CXCR4 neutralizing Ab
• Growth of PC3 (prostate CA cell lines) directly
  injected into tibia was inhibited after treatment

Rubin et al., PNAS 2003 Sun et al. J Cell Biochem
2003
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Therapeutic targets
Tu and Lin, Cancer J, 2008
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Therapeutic targets

• Osteoblastic lesions
• Endothelin-1 (anti-receptor antibody)
• Osteolytic lesions
• Bisphosphonates
• RANKL (anti-RANKL antibody)
• PTHrP
• Osteoprotegerin (Fc-OPG)

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Therapeutic targets

• Endothelin A receptor inhibitor, Atrasentan
• M00-211 trial - Double-blinded, randomized,
  multi-institutional placebo-controlled Phase III
  trial with 809 patients with hormone-resistant
  metastatic prostate cancer
• Endpoint - TTP
• Results
• TTP HR 0.89 (CI 0.76,1.04, p0.136)
• Median time to bone alk phos progression 505 vs
  254 days (plt0.01)

Carducci et al., Cancer 2007
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Bisphosphonates

• Long-term treatment of osteolytic metastases
• Preferentially bind areas of high bone turnover
• Aminobisphosphonates
• e.g. zoledronate, aledronate, risedronate
• Block prenylation of osteoclast proteins (small
  GTP-binding proteins, e.g. ras and rho), leading
  to apoptosis
• Non-aminobisphosphonates
• e.g. clodronate, etidronate
• Inhibit ATP-dependent enzymes, leading to
  apoptosis
• Also may inhibit tumor adherence to bone, inhibit
  angiogenesis, reduce IL-6 production

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Bisphosphonates-clodronate

• Clodronate approved in Europe but not US
• Double-blind, placebo-controlled, multicenter
  trial with 1,069 patients with operable breast
  cancer randomized to clodronate or placebo
• 1 endpoint - relapse in bone
• 2 endpoints - relapse in other sites, mortality,
  toxicity
• Significant reduction in bone metastases during
  medication period (HR 0.44, CI 0.22-0.86,
  p0.016), but not in total follow-up period
• Reduced mortality (98 in clodronate arm, 129 in
  placebo arm, p0.047)

Powles et al., JCO 2002
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Bisphosphonates-pamidronate

• 754 pts with metastatic breast cancer (with
  osteolytic bone metastases) randomized to
  pamidronate or placebo
• 1 objective - skeletal events per year and time
  to 1st skeletal-related event (SRE)
• Only 115 of 367 (31.3) on pamindronate arm and
  100 of 384 (26.0) on placebo arm completed the
  study
• Pamidronate arm - 2.4 skeletal events/yr
  placebo arm - 3.7 events/yr (plt0.001) also
  observed longer time to 1st SRE in pamidronate
  arm (12.7 vs 7 months, plt0.001)
• Limited by significant number of pts who did not
  complete study

Lipton et al., Cancer 2000
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Bisphosphonate - zoledronate

• 1803 premenopausal women with Stage I and II
  breast cancer randomized to tamoxifen/anastrozole
  zoledronic acid
• 1 endpoint DFS 2 RFS, OS explor bone
  met-free survival
• DFS (HR 0.643 CI 0.46-0.91, p0.011)
• RFS (HR 0.653 CI 0.46-0.92, p0.014)
• No change in OS
• See effects outside bone

Gnant et al., ASCO 2008
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Bisphosphonates - zoledronate (prostate cancer)

• Zometa 039 trial 643 men with
  hormone-refractory metastatic prostate cancer
  received zoledronate 4 mg, 8mg then 4mg, or
  placebo for 18 months
• Zometa decreased SREs and pain, but no difference
  in disease progression or performance status
• Trials with pamidronate and clodronate in
  metastatic prostate cancer showed no significant
  benefits

Saad JNCI 2002
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Bisphosphonates - zoledronate (other tumors)

• Randomized, placebo-controlled Phase III trial,
  with 773 pts with lung, RCC, etc. metastatic to
  bone randomized to zoledronate vs placebo q3
  months for 21 months
• 1 endpoint - patients with 1 SRE
• Zolendronate delayed the onset and reduced risk
  of skeletal-related events compared to placebo in
  pts with bone metastases due to lung cancer or
  other solid tumors.
• Reduced time to 1st SRE with treatment (236 vx
  155 days, p0.009), decreased number of
  events/year (1.74 vs. 2.71, p0.012), HR
  developing skeletal event reduced in zoledronate
  arm (HR 0.693, p0.003)

Rosen LS Cancer 2004
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Bisphosphonates

• Osteonecrosis of the jaw
• Presence of exposed bone in the maxilloracial
  region that did not heal within 8 weeks after
  identification by a health care provider
• Estimated to be 1-10100 patient-treatment years
  in patients with cancer (i.v. bisphosphonates)
• Risks
• 94 received zoledronate or pamidronate (not
  clodronate)
• Time and dose-dependent (median 22-39 months)
• Trauma, dental surgery, dental infection (60 had
  dental surgery)
• Management
• Remove all sites of potential infection before
  beginning bisphosphonates
• Treat with pain meds, antibiotics, local
  debridement (no wide excision), discontinuation(?)

Khosla et al., JBMR 2007 Woo et al., Ann Int Med
2006
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Other therapies

• Denosumab (AMG 162)- RANKL antibody - Phase II
  study in patients with bone metastases due to
  breast cancer, other solid tumors and multiple
  myeloma
• Interim analysis - reduced bone resorption marker
  N-telopeptide

Dansey et al., Cancer Treat Rev 2006
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Other therapies

• Radiopharmaceuticals
• Strontium-89 - calcium analog - delays new bone
  mets (randomized PhIII) increased OS (randomized
  PhII of doxorubicin Sr-89) PhIII in combo with
  chemo in progress
• Samarium-153 - concentrates in areas of high bone
  turnover in association with hydroxyapatite
• shorter half-life, so can be given in larger
  doses over shorter time
• Both also alleviate pain (Quilty et al. Radiother
  Oncol 1994 Serafini et al. Cancer 2000)

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Other therapeutic targets

• Calcitriol (vitamin D active metabolite) -
  Powerful agonist of vitamin D receptor
• CXCR4 inhibitor - MSX-122 in Phase I prostate
  cancer trial

Dansey et al., Cancer Treat Rev 2006