Mechanism of Bone Metastases

Mechanism of Bone Metastases
by: Dr.Priya Gopalan

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

Bone Metastases
Types of bone metastases
Diagnosis
* Bone scan - best for osteoblastic lesions
* MRI
* CT scan with bone windows
* PET-CT
* Plain films
* Markers of bone turnover

Prognosis
Relative risk ratios during zoledronic acid therapy
(skeletal-related events)
NSCLC and solid tumors
High vs. low NTX levels
Reasons for preferential metastasis to bone
* Highly vascular organ (sluggish blood flow)
* Paget’s “seed-and-soil” hypothesis
o 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)
Predictors of metastasis to bone (Breast Cancer)
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
* CXCR4/ SDF-1 axis also important in
o NSCLC:
o RCC:
* Integrins may also direct organ-specific mets
o When avb3 is overexpressed on breast cancer cells, bone metastases are enhanced
o CXCR4 binding to SDF-1 activates avb3 and mediates its binding to endothelial cells
o avb3 antagonist inhibits bone colonization by avb3-expressing tumor cells
o a2b1 on prostate cancer cells supports bone colonization
* Other chemokines produced by OBs
o Osteopontin
o Bone sialoprotein

Normal bone remodeling
Osteoprotegerin
Osteoblasts/osteoclasts interaction with tumor cells
Osteomimicry by tumor cells
Therapeutic targets
* Osteoblastic lesions
o Endothelin-1 (anti-receptor antibody)
* Osteolytic lesions
o Bisphosphonates
o RANKL (anti-RANKL antibody)
o PTHrP
o Osteoprotegerin (Fc-OPG)
* Endothelin A receptor inhibitor, Atrasentan
o 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, p=0.136)
# Median time to bone alk phos progression 505 vs 254 days (p<0.01)

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

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
o 1° endpoint - relapse in bone
o 2° endpoints - relapse in other sites, mortality, toxicity
o Significant reduction in bone metastases during medication period (HR 0.44, CI 0.22-0.86, p=0.016), but not in total follow-up period
o Reduced mortality (98 in clodronate arm, 129 in placebo arm, p=0.047)

Bisphosphonates-pamidronate
* 754 pts with metastatic breast cancer (with osteolytic bone metastases) randomized to pamidronate or placebo
o 1° objective - skeletal events per year and time to 1st skeletal-related event (SRE)
o Only 115 of 367 (31.3%) on pamindronate arm and 100 of 384 (26.0%) on placebo arm completed the study
o Pamidronate arm - 2.4 skeletal events/yr; placebo arm - 3.7 events/yr (p<0.001); also observed longer time to 1st SRE in pamidronate arm (12.7 vs 7 months, p<0.001)
o Limited by significant number of pts who did not complete study
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], p=0.011)
* RFS (HR 0.653 [CI 0.46-0.92], p=0.014)
* No change in OS
* See effects outside bone

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
o 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
* 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.
o Reduced time to 1st SRE with treatment (236 vx 155 days, p=0.009), decreased number of events/year (1.74 vs. 2.71, p=0.012), HR developing skeletal event reduced in zoledronate arm (HR 0.693, p=0.003)

Bisphosphonates
* Osteonecrosis of the jaw

Other therapies

Mechanism of Bone Metastases.ppt