Bone-targeted Therapy Research Articles

Should the Denosumab Metastasis Prevention Trial Change Practice for Men with Nonmetastatic Prostate Cancer?

Presentation of the case. A 68-year-old man presents for management of prostate-specific antigen (PSA)-recurrent prostate cancer. His PSA level had become undetectable after prostatectomy for a high-risk localized tumor but began to rise 8 months later. This later led to the initiation of androgen deprivation therapy (ADT), which he has received for the last 3.5 years. After initially falling in response to ADT, his PSA level again trended steadily upward and is now 13.2. Restaging with an abdominal and pelvic computed tomography scan and a bone scan reveals no evidence of metastases. Is this man likely to benefit from denosumab? Bone is the most common site of metastasis for advanced prostate cancer. Bone metastases can cause considerable morbidity in the form of pain, pathologic fractures, and even spinal cord compression. Two bone-targeted therapies (zoledronic acid and denosumab) have been shown to reduce the risk for skeletal events (SREs) among men with bone metastases and a rising PSA level despite a testosterone level <50 ng/dL (castration-resistant prostate cancer [CRPC]). Until recently, no therapy had been shown to reduce the risk for developing bone metastases for the first time. Denosumab 147 was a randomized, placebo-controlled, phase III trial that enrolled 1,432 men with CRPC, no bone metastases, and at least one feature consistent with a high risk for the development of bone metastases (PSA ≥8 ng/mL or PSA doubling time ≤10 months). Participants were treated every 4 weeks with s.c. denosumab (120 mg) or placebo. The trial was positive because denosumab led to a 4.2-month significantly longer bone-metastasis-free survival time relative to placebo (median, 29.5 months versus 25.2 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73-0.98; p = .028) [1]. The time to first bone metastasis and risk for symptomatic bone metastasis were also significantly better with denosumab treatment. Dror Michaelson and Philip Saylor discuss the potential implications of this trial.

Castration-resistant prostate cancer: mechanisms, targets, and treatment.

Patients with castration-resistant prostate cancer (CRPC), who progress after docetaxel therapy, had until very recently, only a few therapeutic options. Recent advances in this field brought about new perspectives in the treatment of this disease. Molecular, basic, and translational research has given us a better understanding on the mechanisms of CRPC. This great investment has turned into a more rational approach to the development of new drugs. Some of the new treatments are already available to our patients outside clinical trials and may include inhibitors of androgen biosynthesis; new chemotherapy agents; bone-targeted therapy; and immunotherapy. This paper aims to review the mechanisms of prostate cancer resistance, possible therapeutic targets, as well as new options to treat CRPC.

Die ossäre Metastasierung des Prostatakarzinoms

Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients. In addition to established bone-targeted therapies, new drugs such as endothelin A receptor antagonists, MET and VEGFR-2 antagonists or radiopharmaceuticals are in the focus of development. The standard care in prostate cancer patients with bone metastases to prevent skeletal-related events (SRE) are bisphosphonates. Denosumab, a human monoclonal antibody against RANKL, appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases-free survival. In contrast to zoledronic acid, denosumab clearance is not dependent on kidney function and can be administered subcutaneously. Similar rates of toxicity were observed for both substances; however, long-term data for denosumab are limited.

P4-16-07: Breast Cancer Bone Metastasis Prevalence and Survival Outcomes: A Quantitative Review of the Literature.

Abstract Background Bone metastases are common in breast cancer patients and an important cause of morbidity and mortality. This review provides the first systematic and quantitative summary of the proportion of breast cancer patients with bone metastasis and their survival, presented by stage at diagnosis and length of follow-up. Materials and methods: A literature review was conducted using PubMed to identify full-text studies published in English 1999–2009. Studies were included if they had ≥100 adult patients with Stage I-IV breast cancer and were generalizable to the overall breast cancer population. The design and intent of included studies varied, including clinical trials of bone-targeted therapies and observational studies of cancer patients evaluating staging techniques, biomarkers, and other factors. To improve homogeneity, studies were grouped by stage at diagnosis, whether follow-up for bone metastases occurred, and the clinical point at which the proportion of patients with bone metastasis was estimated (e.g., at initial staging). Studies reporting survival were only included in quantitative summaries if survival was measured from the date of bone metastasis diagnosis. With regard to clinical trials of bisphosphonates, only proportion and survival data from the placebo group were utilized since the goal was to describe bone metastasis among patients untreated with bone-targeted therapy. Meta-analytic techniques were applied to (1) proportion data using random effects models to calculate weighted averages, and (2) survival data using an average of reported median survivals. Various sensitivity analyses were also conducted. Results: Nineteen studies were included in our quantitative summary of proportion data. At initial staging of breast cancer, 7% (N=2; 95% confidence interval [CI]=5-9%) of all patients had bone metastases and 69% (N=2; 95% CI=47-85%) of Stage IV patients had bone metastases. Among breast cancer patients followed from the diagnosis of Stage I-III breast cancer, 10% (N=6; 95% CI=6-15%) had bone metastases after a median follow-up &amp;lt;10 years, compared to 24% (N=3; 95% CI=19-31%) after a median follow-up ≥10 years. Twelve studies were included in our quantitative summary of survival data. Survival was longer among patients with metastases solely in bone (N=7; average median=30 months), compared to patients with bone metastases and metastases at other sites (N=5; 23 months) and patients with metastases only at sites other than bone (N=3; 9 months). Discussion: Significant heterogeneity across studies was observed, reflecting the variability in study populations, locations, and other factors. Despite this and other limitations (e.g., few studies in some categories), this represents the first analysis of the literature to quantify the prevalence and survival of bone metastasis in breast cancer. Our results indicated that bone is a site of metastasis among more than 50% of Stage IV patients at diagnosis of breast cancer. Median survival among breast cancer patients with metastases located solely in the bone is at least six months longer compared to those with metastases at multiple sites (including bone) and sites other than bone. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-07.

P2-01-15: RT-PCR Gene Profiling for the Prediction of Bone Metastases in Primary Breast Cancer.

Abstract Background: Patients with breast cancer frequently develop bone metastases, which are responsible for high morbidity and mortality. It is known that numerous molecules are involved in the bone metastasization process and that only cancer cells with a specific molecular profile are capable of reaching and colonizing bone tissue. The early detection of patients with a high probability of relapsing to bone could be used to select candidates for tailored therapy with bone-specific drugs such as bisphosphonates or RANK-L inhibitors. The aim of the present study was to identify a pattern of tissue markers from primary breast cancer capable of predicting bone metastatization. Material and methods: The expression of different markers was retrospectively analyzed in frozen breast cancer tissue samples from 40 patients comprising 15 cases with no evidence of disease (NEDP), 15 with bone metastases (BMP), and 10 with visceral metastases (VMP). Twelve transcripts were analyzed by Quantitative Real time PCR: trefoil factor 1(TFF1), DKK1, bone sialoprotein (IBSP), heparanase (HPSE), osteopontin (SPP1), Agr2, SPARC, CTGF, COMP, follistatin (FST), osteoprotegerin and RANK. The predictive accuracy of each marker was calculated using receiver operating characteristic (ROC) curves. Results: Analysis of marker expression in the 3 different subgroups showed twofold higher median values of COMP and HPSE in BMP with respect to either NEDP or VMP (no significant difference). Furthermore, TFF1 median value was about sevenfold higher in BMP than in the other 2 subgroups (p=0.05). The area under the curve (AUC) was 0.73 for TFF1 and 0.62 for COMP and HPSE. Considering markers as dichotomous variables, TFF1 expression in BMP reached 67% compared to 21% and 20% in NEDP and VMP, respectively. In dichotomous variable analysis, the most important result was observed for TFF1; in particular, TFF1 positivity was observed in 67% of cases in the BMP subgroup compared to only 21% and 20% in NEDP and VMP, respectively. The combination analysis of TFF1 and other markers showed that positivity to at least one of the three markers, TFF1, DKK1, or IBSP, was observed in 80% of cases for the BMP group, and in only in 21% and 20% of cases in NEDP and VMP subgroups (p=0.041). Another interesting marker was RANK: although sensitivity was fairly low (12%), specificity reached 100% in both control groups. Conclusions: Our preliminary study identified a RT-PCR gene expression pattern in primary breast cancer that could predict patients destined to bone relapse. Such patients could consequently benefit from adjuvant treatment with bone-targeted therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-15.

Bone metastases

Bone metastases result from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells. Receptor activator of NF-kB ligand (RANKL) is a key mediator in this process. Within the bone microenvironment, factors secreted by tumour cells stimulate stromal cells and osteoblasts to secrete RANKL, which binds to RANK on the surface of precursor and mature osteoclasts. Release of RANKL leads to stimulation of osteoclastic bone resorption, and provides the rationale for bone-targeted therapies as an adjunct to traditional anticancer agents. Recent studies indicate that the risk of skeletal complications is related to the rate of bone resorption.Multiple, randomised controlled trials over the past two decades have clearly demonstrated that bisphosphonates (BPs) are effective in reducing skeletal morbidity from metastatic cancer. Zoledronic acid is the most potent BP, and has shown superior efficacy to pamidronate in the prevention of skeletal complications in breast cancer, and is the only agent to show clear benefit in the management of metastatic bone disease from prostate cancer (castrate resistant), lung cancer and other solid tumours. Oral agents such as ibandronate and clodronate provide a useful alternative for some clinical situations.Denosumab is a fully humanised monoclonal antibody that inhibits RANKL. A dose of 120mg 4 weekly administered by subcutaneous injection has been defined for the treatment of advanced malignancy. Preclinical data suggest that denosumab is a more complete inhibitor of osteoclast function than the BPs. Additionally, a randomised phase II study in patients with increased bone resorption, despite ongoing BPs, has compared changing to denosumab to continuation of the BP; rapid and sustained biochemical response was seen in >80% of patients switched to denosumab compared with <30% for those continuing on BPs. In a large phase III programme comparing denosumab to zoledronic acid in metastatic bone disease from a range of solid tumours (n=>5,000), denosumab was more effective, easier to administer and had some safety advantages.The bone-targeted agents are an important component of management in advanced malignancy. Combined with systemic cancer therapy, effective symptom control and appropriate surgical and radiological interventions, modern multi-disciplinary care has transformed the care of patients with metastatic bone disease. Bone metastases result from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells. Receptor activator of NF-kB ligand (RANKL) is a key mediator in this process. Within the bone microenvironment, factors secreted by tumour cells stimulate stromal cells and osteoblasts to secrete RANKL, which binds to RANK on the surface of precursor and mature osteoclasts. Release of RANKL leads to stimulation of osteoclastic bone resorption, and provides the rationale for bone-targeted therapies as an adjunct to traditional anticancer agents. Recent studies indicate that the risk of skeletal complications is related to the rate of bone resorption. Multiple, randomised controlled trials over the past two decades have clearly demonstrated that bisphosphonates (BPs) are effective in reducing skeletal morbidity from metastatic cancer. Zoledronic acid is the most potent BP, and has shown superior efficacy to pamidronate in the prevention of skeletal complications in breast cancer, and is the only agent to show clear benefit in the management of metastatic bone disease from prostate cancer (castrate resistant), lung cancer and other solid tumours. Oral agents such as ibandronate and clodronate provide a useful alternative for some clinical situations. Denosumab is a fully humanised monoclonal antibody that inhibits RANKL. A dose of 120mg 4 weekly administered by subcutaneous injection has been defined for the treatment of advanced malignancy. Preclinical data suggest that denosumab is a more complete inhibitor of osteoclast function than the BPs. Additionally, a randomised phase II study in patients with increased bone resorption, despite ongoing BPs, has compared changing to denosumab to continuation of the BP; rapid and sustained biochemical response was seen in >80% of patients switched to denosumab compared with <30% for those continuing on BPs. In a large phase III programme comparing denosumab to zoledronic acid in metastatic bone disease from a range of solid tumours (n=>5,000), denosumab was more effective, easier to administer and had some safety advantages. The bone-targeted agents are an important component of management in advanced malignancy. Combined with systemic cancer therapy, effective symptom control and appropriate surgical and radiological interventions, modern multi-disciplinary care has transformed the care of patients with metastatic bone disease.

Pilot Trial of Bone-Targeted Therapy Combining Zoledronate With Fluvastatin or Atorvastatin for Patients With Metastatic Renal Cell Carcinoma

Background The biological rationale for this study came from the observation that bisphosphonates and statins affect bone metastasis in different ways and thus combination therapy may provide synergistic benefit. This pilot trial evaluated the efficacy and safety of combining a bisphosphonate and a statin in patients with RCC metastatic to bone. Methods Patients with RCC and bone metastasis received zoledronate and fluvastatin or atorvastatin. Patients were monitored clinically and by imaging for skeletal events. Concentrations of the bone resorption markers deoxypyridinoline (DPD) and N-telopeptide (NTX) and the bone formation marker bone-specific alkaline phosphatase (BSAP) were monitored for changes during treatment. Results Eleven patients were enrolled and followed for a median of 6 months. The median time to first skeletal-related event for all patients was 9.0 months. Seven (63%) patients experienced skeletal events with a median time to first skeletal-related event of 4.0 months (range, 3-18 months); 4 patients (36%) experiences no skeletal events for a median of 12 months of follow-up (range, 2-28 months); 4 patients (36%) demonstrated treatment responses with development of sclerosis in lytic bone lesions. Differences in the median changes in biomarker levels between patients who had skeletal events and those who did not were statistically significant for DPD and NTX ( P = .03 and .01, respectively) but not for BSAP ( P = .4). The regimen was well tolerated, with few adverse reactions related to the study drugs. Conclusion Although the use of bone-targeting therapy combining zoledronate and fluvastatin or atorvastatin affected certain bone biomarkers and provided bone response in several patients with RCC and bone metastasis, we could not demonstrate a statistically significant improvement in time to skeletal events.

Oncolytic Adenovirus Expressing Soluble TGFβ Receptor II-Fc-mediated Inhibition of Established Bone Metastases: A Safe and Effective Systemic Therapeutic Approach for Breast Cancer

In recent years, oncolytic adenoviruses have shown some promise as a novel class of antitumor agents. However, their utility in targeting bone metastases is relatively less studied. We have examined whether the systemic therapy of oncolytic adenoviruses expressing the soluble form of transforming growth factor-β (TGFβ) receptor II fused with human immunoglobulin G1 can be developed for the treatment of established breast cancer bone metastases. MDA-MB-231-luc2 human breast cancer cells were injected in the left heart ventricle of nude mice to establish bone metastasis. Mice with hind limb tumors were administered (on days 8 and 11) oncolytic adenoviruses-Ad.sTβRFc or mhTERTAd.sTβRFc. Skeletal tumor growth was monitored weekly by bioluminescence imaging (BLI) and radiography. At the termination time on day 28, hind limb bones were analyzed for tumor burden, synchrotron micro-computed tomography, and osteoclast activation. Intravenous delivery of Ad.sTβRFc and mhTERTAd.sTβRFc induced significant inhibition of tumor growth, reduction of tumor burden, osteoclast activation, and increased animals' survival. Oncolytic adenoviruses were safer than dl309, a wild-type virus. A slight elevation of liver enzyme activity was observed after Ad.sTβRFc administration; this subsided with time. Based on these studies, we believe that Ad.sTβRFc and mhTERTAd.sTβRFc can be developed as a safe and effective approach for the treatment of established bone metastasis.

Emerging therapies to prevent skeletal morbidity in men with prostate cancer.

Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly elevate the risk for fractures and other structural complications. Distinct from the problem of metastases, treatment-related osteoporosis and associated fragility fractures are potential complications of androgen-deprivation therapy. Bone-targeted therapies for prostate cancer have therefore been the focus of considerable research and drug development efforts. The osteoclast is a validated therapeutic target in the management of prostate cancer. Osteoclast inhibition with zoledronic acid (a bisphosphonate) or with denosumab (a monoclonal antibody to RANK ligand) reduces risk for skeletal events in men with castration-resistant prostate cancer metastatic to bone. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density, a surrogate for osteoporotic fracture risk. Denosumab and toremifene (a selective estrogen receptor modulator) have each been shown to reduce osteoporotic fracture risk among men receiving androgen-deprivation therapy. Beta-emitting radiopharmaceuticals reduce pain due to metastatic disease. Investigations involving alpha-emitting radium-223, endothelin-A receptor antagonists atrasentan and zibotentan, proto-oncogene tyrosine-protein kinase (SRC) inhibitor dasatinib, and tyrosine kinase inhibitor cabozantinib (XL184) are ongoing in clinical trials and are also discussed.

Targeting Bone as a Therapy for Myeloma

Myeloma bone disease (BD) not only impairs quality of life, but is also associated with impaired survival. Studies of the biology underlying BD support the notion that the increased osteoclastogenesis and suppressed osteoblastogenesis, is both a consequence and a necessity for tumour growth and clonal expansion. Survival and expansion of the myeloma clone is dependent on its interactions with bone elements, thus targeting these interactions should have antimyeloma activities. Indeed both experimental and clinical findings indicate that bone-targeted therapies not only improve BD, but also create an inhospitable environment for myeloma cell growth and survival, favouring improved clinical outcome. This review summarizes recent progress in our understandings of the biology of myeloma BD, highlighting the role of osteoclasts and osteoblasts in this process and how they can be targeted therapeutically. Unravelling the mechanisms underlying myeloma-bone interactions will facilitate the development of novel therapeutic agents to treat BD, which as a consequence are likely to improve the clinical outcome of myeloma patients.

Current status of bone-targeted therapy for cancer patients

Current status of bone-targeted therapy for cancer patients

Bisphosphonates and their impact on disseminated tumor cells in early stage breast cancer

Bone is the most common site of relapse in breast cancer. Unlike many other malignancies, breast cancer is often associated with late-onset metastases, most commonly seen in bone and soft tissue. Pre-clinical and clinical evidence suggest that micrometastases occur at a very early stage of cancer development but do not become overt metastases until a later time when the microenvironment is more suitable. Bisphosphonates (BPs), especially zoledronic acid (ZOL), decrease bone resorption by suppressing the activity of osteoclasts and are used to prevent further bone loss in patients with osteoporosis. In addition, pre-clinical and clinical evidence suggest that potent BPs have direct and/or indirect anti-tumor effects, through induction of apoptosis, inhibition of invasion and metastases as well as angiogenesis, and through alteration of the immune system. ZOL is approved for the treatment of metastatic cancer to bone, and has been shown to prevent skeletal related events and reduce associated pain, without a clear impact on survival. Several large clinical trials (ABSCG 12, ZO-FAST and AZURE) have studied the direct anti-tumor effect of BPs in early stage breast cancer. The results are controversial, suggesting that ZOL may have benefits in specific settings. Targeting patients at particularly high risk for relapse, and identifying surrogate markers of BP effect is clearly a critical component necessary to understand the anti-tumor effect of these agents. Disseminated tumor cells (DTCs) are surrogate markers that have been correlated with an increased risk of recurrence in patients with early stage breast cancer. Several studies have either used the presence of DTCs to assess risk and determine eligibility for BP treatment, or have used DTCs as a surrogate marker of BP anti-tumor effect. This review summarizes the pre-clinical data supporting anti-tumor effects of BPs as well as their impact on DTCs in clinical studies. New candidates for bone-targeted therapy are briefly discussed.

Effect of abiraterone acetate (AA) on pain control and skeletal-related events (SRE) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) post docetaxel (D): Results from the COU-AA-301 phase III study.

4520 Background: Reduction in morbidity and clinical sequelae of bone metastases is a significant unmet medical need of mCRPC pts. AA, a potent androgen biosynthesis inhibitor, increases survival in mCRPC pts (HR = 0.646). Here we assess the effect of AA on pain control and SRE. Methods: COU-AA-301 is an international, randomized, double blind study of AA (1 g QD) + P (5 mg BID) vs placebo + P in mCRPC post D. Pain was assessed at baseline and each treatment cycle until discontinuation using the BPI-SF questionnaire. Palliation/progression of pain intensity (P-INT) and pain interference (P-INF) was evaluated and pain scores analyzed for changes over time. Analyses were conducted using prospective response definitions. Results: 797 pts were randomized to AA and 398 to placebo. Median treatment duration was 8 and 4 months, respectively. Time to SRE (pathologic fracture, spinal cord compression or palliative radiation/bone surgery) was 301 d (AA) vs 150 d (placebo; P = 0.0006). Cumulative proportion of pts with a change (vs baseline) in P-INT was consistently in favor of AA. AA yielded significantly improved pain outcomes (Table), including better and faster palliation of P-INT and P-INF. Fewer AA pts had progression of P-INT and P-INF at 6 (22% vs 28%; 20% vs 31%), 12 (30% vs 38%; 28% vs 32%) and 18 months (35% vs 46%; 30% vs 35%). The pain profile of AA was superior to placebo from cycles 1 to 10. Conclusions: Therapy with AA + P offers significant clinical benefits, incl. pain relief and delay of pain recurrence while preventing SRE, in post D mCRPC. There may be potential for integrating bone targeting therapy with AA to further improve symptom free survival of mCRPC pts. AA (N = 797) Placebo (N = 398) P P-INT Palliation, n (%) 155/349 (44.4) 44/163 (27.0) 0.0002 Time to palliation [median], d (95% CI) 169 (113, 302) 312 (165, 450) 0.0010 Time to progression [25th percentile], d (95% CI) 225 (171, 315) 142 (91, 253) 0.0056 P-INF Palliation, n (%) 132/223 (59.2) 38/100 (38.0) 0.0004 Time to palliation [median], d (95%CI) 31 (28, 58) 113 (82, 135) 0.0009 Time to progression [25th percentile], d (95% CI) 282 (225, 392) 139 (85, 197) 0.0019

A randomized phase II study of bone-targeted therapy in advanced androgen-dependent prostate cancer.

4649 Background: Bone is the most common site of progression in prostate cancer and the development of bone-targeted therapy may benefit such patients The aim of this phase II randomized controlled trial was to determine the progression-free survival of hormonal ablative therapy, combined with zoledronic acid and doxorubicin, with or without strontium-89, for patients with androgen-dependent prostate cancer and bone metastases. Methods: A total of 80 patients were enrolled on this study; 79 patients were randomized: 40 to the arm without and 39 to the arm with Sr-89 treatment. Eligible patients also received after randomization LHRH agonists of choice AND doxorubicin (20 mg/m2 on days 1, 8, and 15 q 4 weeks x2 cycles) AND zoledronic acid (4 mg IV q 4 weeks x6). Kaplan-Meier methodology was used to evaluate the primary outcome, which was progression-free survival (PFS). In addition, multivariate Cox proportional hazards regression was used to evaluate the effects of strontium-89 after controlling for the n...

Emerging therapies in metastatic bone pain

Introduction: Current treatment for metastatic bone pain is mainly palliative. Recent insights into the molecular mechanisms involved in bone metastases have led to the identification of promising therapeutic targets. This review offers an update of preclinical and clinical data on new drugs for metastatic bone pain.Areas covered: Biphosphonates are the gold standard of bone-targeted therapy in bone metastases, for their anti-resorptive and analgesic effects. New drugs aim at breaking the ‘vicious cycle’ of bone metastatic disease, due to the bidirectional interaction between cancer cells and bone microenvironment. Osteoprotegerin, RANK/RANKL interaction, cathepsin K, the Wnt/beta-catenin pathway and sclerostin are emerging targets for modulation of cancer-induced bone desorption. Other promising targets are those expressed in cancer cells that metastasize to bone, including Src, nerve growth factor, endothelin A, TGF-beta and CXCR4. Interesting therapeutic options include targets on nociceptors that innervate the bone, such as TPRV1, Trk and cannabinoid receptors.Expert opinion: Emerging therapies promise, in the next 10 years, a significant expansion in the array of therapeutic options for bone metastases. Most of these drugs are still in an early phase of development. Further clinical trials are needed to support the evidence of their efficacy and tolerability profile.

Life-threatening hypophosphatasia (HPP): Results of up to two years bone-targeted Enzyme Replacement Therapy (ERT) in infants and young children

Life-threatening hypophosphatasia (HPP): Results of up to two years bone-targeted Enzyme Replacement Therapy (ERT) in infants and young children

Abstract 1597: A novel preclinical model of prostate cancer bone metastasis derived from a human primary tumor

Abstract Background: Prostate cancer is frequently associated with bone metastases which are the main cause of morbidity and mortality for this tumor. Animal models are important tools to investigate the pathogenesis and develop treatment strategies for bone metastases in humans. However there are few animal models that recapitulate spontaneous clinical bone metastases. We recently obtained the new prostate cell line IGR-CaP1 derived from primary epithelial prostate cancer that has been characterize in vitro. Methods: The IGR-CaP1 cell line was stably transduced with a luciferase expressing viral vector to monitor tumor growth by bioluminescence imaging (BLI) in male nude mice. Bone lesions were observed after direct intratibial injections of 5×105 luciferase-expressing IGR-CaP1 cells and after injection of 106 cells into the left cardiac ventricle of mice. Bone metastases were detected by bioluminescence imaging and were evaluated by both Computerized Tomography (CT) and micro Single-Photon Emission Computed Tomography (SPECT) measuring the bone fixation of 99Tc methylenediphosphonate (m99Tc-MDP). Results: In contrast with the widely used PC3 preclinical model showing only osteolytic activity after bone injection, high resolution CT scan showed both lytic lesions in the cortical bone and osteoblastic lesions in the trabecular bone in the IGR-CaP1-injected mice 5 weeks after injection. The mixed nature of the lesions and the intensive bone remodeling were confirmed by bone scintigraphy with a ∼5 fold increase in m99Tc-MDP fixation in injected tibia versus control tibia. Intracardiac injection led to bone metastasis mainly localized in the spinal column, fore and hind limbs and in the mandible. Immunohistochemistry confirmed the presence of these bone metastases and showed high expression of vimentin in metastatic tumor cells. In this model, we are currently analyzing by RT-PCR, the expression of a 25-gene signature that corresponds to genes highly expressed in human bone metastases. Conclusion: IGR-CaP1 is a unique model issued from a primary tumor able to reconstitute human prostate adenocarcinoma in animals and provide bone metastases. This model provides a novel means for identifying and understanding mechanisms that contribute to bone metastasis and allows for preclinical testing of new anticancer therapies, specifically bone-targeting therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1597. doi:10.1158/1538-7445.AM2011-1597

Emerging novel therapies in the treatment of castrate-resistant prostate cancer

The treatment options for patients with castration-resistant prostate cancer (CRPC), until very recently, only included docetaxel. In the past 10 months, newly Federal Drug Administration (FDA) approved agents in the United States have shown survival benefit for patients with CRPC. This review takes a closer look at these newer agents: sipuleucel-T (immune therapy) and cabazi-taxel (cytotoxic therapy). We also review the evidence supporting the FDA's approval of denosumab (bone-targeted therapy) as a treatment option for men with CRPC and bony metastases. Newer agents currently being investigated in phase III clinical trials for their potential role in metastatic CRPC are also reviewed. These agents include abiraterone (hormonal therapy), TAK-700 (hormonal therapy), MDV3100 (hormonal therapy), ipilimumab (immune therapy), zibotentan (endothelin-A receptor antagonist) and dasatinib (tyrosine kinase inhibitor). As ongoing studies using all the aforementioned agents continue to evolve, our understanding of how and where these agents fit into the treatment paradigm for patients with CRPC will become clearer.

Therapeutic targets for bone metastases in breast cancer

Breast cancer is prone to metastasize to bone. Once metastatic cells are in the bone marrow, they do not, on their own, destroy bone. Instead, they alter the functions of bone-resorbing (osteoclasts) and bone-forming cells (osteoblasts), resulting in skeletal complications that cause pathological fractures and pain. In this review, we describe promising molecular bone-targeted therapies that have arisen from recent advances in our understanding of the pathogenesis of breast cancer bone metastases. These therapies target osteoclasts (receptor activator of nuclear factor kB ligand, integrin αvβ3, c-Src, cathepsin K), osteoblasts (dickkopf-1, activin A, endothelin A) and the bone marrow microenvironment (transforming growth factor β, bone morphogenetic proteins, chemokine CXCL-12 and its receptor CXCR4). The clinical exploitation of these bone-targeted agents will provide oncologists with novel therapeutic strategies for the treatment of skeletal lesions in breast cancer.

Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances

Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances.