Osteoblastic Metastatic Lesions Research Articles

Primary Adenosquamous Carcinoma of the Prostate.

Prostate cancer accounts for 29% of malignant diagnoses among men in the United States and is the second leading cause of death from cancer. Effective screening methods and improved treatment have decreased the mortality rate significantly. This decreased mortality rate, however, does not apply to all histologic variants. Adenosquamous carcinoma of the prostate is an extremely aggressive neoplasm with no current known curative therapy. It is often diagnosed after chemotherapy, radiation, or androgen deprivation therapy for traditional prostatic adenocarcinomas. Primary carcinomas of the prostate with squamous features include, but are not limited to, pure squamous cell carcinoma and adenocarcinoma mixed with squamous cell carcinoma (SCC). Important distinguishable clinical features of adenosquamous carcinoma include normal prostate-specific antigen (PSA) levels, even with advanced disease and osteolytic versus osteoblastic metastatic lesions in adenocarcinoma. Additional entities to consider in the differential diagnosis are squamous metaplasia of the prostate, secondary involvement of pure SCC, and urothelial carcinoma with squamous differentiation. Here, we present a de novo case of adenosquamous carcinoma in a 48-year-old man who rapidly developed extensive metastatic disease.

Radium-223 mechanism of action: implications for use in treatment combinations.

The targeted alpha therapy radium-223 (223Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases. Preclinical studies demonstrate that 223Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. 223Ra might also modulate immune responses within the bone. The clinical utility of 223Ra has encouraged the development of other anticancer targeted alpha therapies. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of 223Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease.

MON-500 A Case of Tumor-Induced Osteomalacia Caused by Metastatic Prostate Cancer

Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia due to renal phosphate wasting. An overproduction of the phosphatonin fibroblast growth factor 23 (FGF-23) has been implicated in TIO pathogenesis. FGF-23 increases renal phosphate excretion by reducing the expression of sodium-dependent phosphate co-transporters NPT2a and NTP2c in the proximal tubules. TIO is most commonly associated with mesenchymal tumors. Epithelial tumors are estimated to account for only 5% of reported cases of TIO. Here we report a rare case of TIO associated with castration resistant metastatic prostate cancer. Clinical Case: A 59 year old male with high grade castration-resistant metastatic prostate adenocarcinoma presented with worsening fatigue and bone pain. Nine years before presentation, he was treated with prostatectomy, pelvic radiation, and taxotere followed by one year of luteinizing hormone-releasing hormone (LHRH) agonist. Bony metastases were identified 8 years later, and he was treated with a combination of LHRH agonist, RANK-ligand inhibitor denosumab, antiandrogenic therapy abiraterone and prednisone. Due to refractory disease, he received three cycles of sipuleucel-T, a cell-based cancer immunotherapy, and was enrolled in a phase 1B clinical trial involving enzalutamide. Laboratory evaluation included phosphorus 1.2 (2.5-4.5 mg/dL), urine phosphate excretion 1984 (400-1300 mg/24 hour), parathyroid hormone 110 (15-65pg/mL), calcium7.9 (8.7-10.2 mg/dL), vitamin D-25 85.3 (30-100mg/dL), inappropriately low vitamin D 1,25 40 (19.9-79.3 mg/dL) and FGF-23 387 (44-215 ref units/mL). Whole body scan showed widespread osteoblastic metastatic lesions. He was treated with high-dose calcitriol, vitamin D, calcium carbonate, and potassium phosphate with improvement in hypophosphatemia and bone pain. Clinical Lessons: Hypophosphatemic osteomalacia in the setting of advanced prostate cancer was first reported in 1975. The role of FGF-23 as a phosphatonin in such cases has since emerged, due to advancement of laboratory assays and improved understanding of the pathophysiology of TIO. Review of existing literature reveals five reported cases of prostate cancer-associated TIO with associated elevated FGF-23. This condition poses a diagnostic challenge, as TIO-related bone pain and weakness can be mistaken for that associated with bony metastases. Given the inability to resect widely metastatic disease, treatment of such cases consists of reducing tumor burden with chemotherapy and radiation and supplementation with calcitriol and phosphorus. While other FGF pathways have been implicated in prostate cancer-related angiogenesis, drug resistance, and metastases, the role FGF23 may play in an aggressive disease course warrants further investigation, particularly given it may represent a treatment target.

Selection and monitoring of patients with metastatic castration-resistant prostate cancer for treatment with radium-223.

Despite the improvement provided by androgenic suppression in the treatment of prostate cancer, most of tumors develop resistance to castration. However, new therapies have demonstrated an increase in patient survival such as radium-223 (Ra-223), an alpha emitter and calcium mimetic with the capability of targeting osteoblastic metastatic lesions. According to results of the ALSYMPCA phase III trial, Ra-223 has demonstrated its activity by improving symptoms and survival of patients with metastatic castration-resistant prostate cancer (mCRPC), symptomatic bone metastases, and no known visceral metastatic disease, without interfering with subsequent treatments. This review examines the key evidence to establish the best patient selection criteria to use Ra-223, how to assess the response to treatment, treatment-related toxicity, and follow-up, but also current research regarding imaging techniques and biomarkers to assess the efficacy of Ra-223. Finally, we briefly describe the clinical trials that are currently ongoing with Ra-223.

Contemporary use of radium-223 (Ra-223) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): Feasibility and safety.

210 Background: Ra-223 is an α-emitter that binds to the newly formed bone matrix and targets osteoblastic metastatic lesions. Treatment with Ra-223 delays symptomatic skeletal-related events (SREs) and improves overall survival (OS) in men with mCRPC. Concerns about the efficacy and safety of Ra-223 in the pre-chemotherapy space, given alone or in combination with Abiraterone Acetate (AA) or enzalutamide (ENZ), have been raised. Methods: To determine the feasibility, efficacy and safety profile of Ra-223 given alone or in combination with AA or ENZ to men with docetaxel-naïve mCRPC a retrospective study was conducted. PSA decline, rPFS and safety data for patients (pts) treated at Cleveland Clinic (CC) and Tulane University (TU) were analyzed. Results: Fifty-one (27 CC and 24 TU) chemo-naïve mCRPC pts with bone metastases were identified. The median age was 63 (46-87). Testosterone suppression was maintained during treatment. Pre-treatment alkaline phosphatase (ALP) was elevated in 16 pts (33%). In addition to bone, 24 pts (47%) had soft-tissue metastases. While 23 pts received Ra-223 alone, 22 pts (43%) received concomitant AA or ENZ therapy. To date, the median number of Ra-223 cycles received is 5 (1-6) with 39% of pts (20/51) receiving all 6 cycles. PSA declines >30% were observed in 31% of pts. All but one pt had at least some decline in ALP. ALP decline >30% was observed in 68% of pts. Reasons for treatment discontinuation included; completion of 6 cycles 39% (20/51); PD 35% (18/51); AEs 8% (4/51) and pt choice 4% (2/51). Grade (G) 3/4 AEs were observed in 4 pts; G3 anemia (n=3) and G4 thrombocytopenia (n=1). The vast majority of pts had PSA progression (81%) and 42% of pts have died. Estimated median time to PSA progression and OS are 3.9 (95% C.I. 1.84-4.82) and 11.0 months (95% C.I. 7.5-16.4), respectively. Pts with normal baseline hemoglobin levels and those who received concomitant AA tended to have better PSA progression-free and OS (p<.06). Conclusions: Treatment with Ra-223 in combination with AA or ENZ in chemo-naïve mCRPC pts is feasible with no new safety signals of concern. Further evaluation of the combination of AA or ENZ with Ra-223 in this setting is warranted.

Osteopoikilosis: A case with osteopenia

Osteopoikilosis is a benign osteosclerotic dysplasia of unknown origin, which is an inherited autosomal disorder. It is usually asymptomatic and may only be recognized on radiological examination. We report a 20-year-old man who suffers from back and shoulder pain during the routine physical examinations performed prior to the military recruitment. Numerous symmetric, small, ovoid and circular sclerotic bone lesions were found on the X-rays of the spine and shoulder. Dual energy X-ray absorptiometry (DXA) examination revealed osteopenia. In conclusion, typical radiographic examination of osteopoikilosis is usually diagnostic. However, it may sometimes be difficult to rule out the other diseases like osteoblastic metastatic lesions as it is an uncommon disease. Physicians should be aware of possible coexisiting osteopenia or osteoporosis as reported in our case.

Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions

Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here we identified the functional activities of Runx2 in facilitating tumor growth and osteolysis. Our studies demonstrate that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin), and secreted bone resorbing factors (PTHrP, IL-8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies demonstrating that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, where Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.

Intraosseous growth of human prostate cancer in implanted adult human bone: Relationship of prostate cancer cells to osteoclasts in osteoblastic metastatic lesions

More than 80% of patients with advanced prostate cancer have skeletal involvement, but the biology of bone metastasis is poorly understood. This study investigated the in vivo formation and progression of bone metastases under conditions that resembled the human bone environment as closely as possible. Adult human bone fragments were implanted subcutaneously into 120 male NOD/SCID mice. Four weeks later, 1 x 10(7) LNCaP prostate cancer cells or phosphate-buffered saline were injected intravenously into 80 or 40 mice, respectively. The implanted bone fragments were removed from 20 to 10 mice in each group at 2, 4, 6, and 8 weeks after injection. LNCaP colonized the bone marrow blood vessels within 2 weeks, and then gradually expanded into the entire medullary cavity. An osteoblastic response often occurred at the edges of metastatic foci (intertrabecular bone metaplasia). In addition, new bone formation was observed adjacent to mature lamellar bone (appositional bone formation). These two processes appeared to occur through different mechanisms, but might similarly cause osteosclerosis. Osteoclasts showed a marked increase in numbers at sites of early tumor invasion, whereas few osteoclasts were observed at sites where tumor invasion was complete. The predominance of osteoblastic change with resorption may lead to bone remodeling in metastatic lesions, and osteoclasts may play an important role in bone metastasis from prostate cancer.