Targeting Bone Metastases Research Articles

68 Ga-DOTA-Ibandronic Acid PET/CT in a Patient With Chemotherapy-Induced Salivary Gland Hypofunction.

DOTA-ibandronic acid (IBA) is a novel precursor targeting bone metastasis. It can be radiolabeled with 68 Ga for the diagnosis of bone metastases. However, extraosseous lesions can also show increased DOTA-IBA uptake. We report the 68 Ga-DOTA-IBA PET/CT findings in a case with cholangiocarcinoma with multiple bone metastases. 68 Ga-DOTA-IBA PET/CT revealed increased uptake of DOTA-IBA in bone metastases. Besides, symmetrical and diffuse increased DOTA-IBA uptake in bilateral salivary glands was observed. 99m TcO 4- salivary gland scintigraphy showed impaired salivary gland function.

Castration resistant prostate cancer: recent advances in novel therapeutic treatments

Prostate cancer is a prevalent and deadly malignancy that poses challenges in diagnosis and treatment. It is the second most common cancer in men worldwide and the fifth leading cause of cancer-related deaths. This abstract provides an overview of current treatments and recent advances in the field of prostate cancer treatment, with a focus on metastatic castration-resistant prostate cancer (mCRPC). Current treatments for mCRPC include chemotherapy, endocrine therapy, and bone-targeting therapy. Chemotherapy drugs such as docetaxel and cabazitaxel are commonly used, but their efficacy is limited. Endocrine therapy, particularly androgen-receptor signaling inhibitors like abiraterone acetate, has shown significant clinical benefits. Bone-targeting therapies such as bisphosphonates and denosumab provide symptomatic relief for bone metastases. Recent advances in novel treatments have shown promise in improving outcomes for patients with mCRPC. Trials investigating the PARP inhibitor rucaparib have demonstrated longer progression-free survival, particularly in patients with BRCA mutations. The combination of talazoparib and enzalutamide has also shown improved progression-free survival and delayed the need for chemotherapy. Another promising treatment is darolutamide, which has been shown to reduce the risk of metastasis or death and extend metastasis-free survival. Immunotherapy, particularly sipuleucel-T and PROSTVAC, has shown potential in reducing mortality risk and increasing overall survival (OS) in mCRPC patients. The combination of sipuleucel-T with abiraterone acetate or enzalutamide has been found to be effective and safe. The introduction of lutetium Lu 177 vipivotide tetraxetan, a PSMA-targeted therapy, has shown improved OS in PSMA-positive mCRPC patients. Radium-223, a radioactive drug targeting bone metastasis, has also demonstrated improved OS and delayed skeletal-related events. These recent advances in prostate cancer treatment offer hope for improved outcomes for patients with mCRPC. Further research and clinical trials are needed to validate these findings and explore additional treatment options.

Exploring the Potential of Zirconium-89 in Diagnostic Radiopharmaceutical Applications: An Analytical Investigation

This study highlights the use of 89Zr-oxalate in diagnostic applications with the help of WinAct and IDAC2.1 software. It presents the biodistribution of the drug in various organs and tissues, including bone, blood, muscle, liver, lung, spleen, kidneys, inflammations, and tumors, and analyzes the maximum amount of nuclear transformation per Bq intake for each organ. The retention time of the maximum nuclear transformation and the absorbed doses of the drug in various organs and tissues are also examined. Data from clinical and laboratory studies on radiopharmaceuticals are used to estimate the coefficients of transition. The accumulation and excretion of the radiopharmaceutical in the organs is assumed to follow an exponential law. The coefficients of transition from the organs to the blood and vice versa are estimated using a combination of statistical programs and digitized data from the literature. WinAct and IDAC 2.1 software are used to calculate the distribution of the radiopharmaceutical in the human body and to estimate the absorbed doses in organs and tissues. The results of this study can provide valuable information for the biokinetic modeling of wide-spectrum diagnostic radiopharmaceuticals. The results show that 89Zr-oxalate has a high affinity for bones and a relatively low impact on healthy organs, making it helpful in targeting bone metastases. This study provides valuable information for further research on the development of this drug for potential clinical applications.

Current and potential treatment of colorectal cancer metastasis to bone

BackgroundColorectal cancer (CRC) with subsequent bone metastasis is associated with a poor prognosis compared with patients who do not develop bone metastasis. However, metastasis in bone is rare, contrasted with more common locations such as the liver and lungs. As a result, the treatment methods targeting CRC bone lesions are limited. This review aims to compile information regarding current and potential medical and surgical treatment methods for colorectal cancer with specific regard to bone metastasis. MethodsA computer-based literature review of animal- and human-based studies was conducted using multiple database searches. Case reports were excluded. ResultsPreliminary findings demonstrate that treatments specifically targeting bone metastasis due to colorectal cancer are categorized by local vs. systemic treatment. The primary goals are the alleviation of skeletal-related events and improvement in quality of life. Current options include: chemotherapy, radiation, monoclonal antibodies, and surgery. Emerging options include intratumoral mellitin, MRgFUS, and bone microenvironment targeting. ConclusionTreatment of CRC metastasis to bone is necessary to slow down metastatic progression, alleviate symptoms, and improve quality of life. With a possible rise in bone metastasis due to increased overall CRC survival rates, more clinical trials should be performed to address this growing concern.

Abstract 81: In depth single cell profiling of a case of breast cancer bone metastases with associated organoid models reveal a precision medicine approach to treatment

Abstract Occurring in 65-80% of metastatic breast cancer (BC), bone metastasis (BoM) is the major cause of BC related mortality. Lack of understanding of BoM evolution and heterogeneity at patient specific levels and precise application of targeted therapies are major challenges of managing BoM. In this study, we described in depth histologic and molecular characterization of a case of invasive lobular breast cancer (ILC) bilateral metastasis to bone, and identified and tested potential targets for treating BoM. H&E/IHC staining, whole exome sequencing (WES), and RNAseq were performed on FFPE primary tumor and pelvis and tibia BoMs collected from our study case. Organoids were derived from the two BoMs and single cell RNA sequencing (scRNAseq) undertaken on the organoids and their originating tumors. H&E/IHC demonstrated evolution of the disease from an ER+ primary ILC to ER- BoM with mixed lobular and ductal carcinoma features. WES revealed two druggable mutations including PIK3CA (E545K) and BRCA1 (D1813H/H399P). RNAseq revealed upregulation of TGF-β, Wnt/beta-catenin and PI3K pathways, epithelial to mesenchymal transition (EMT) and angiogenesis in BoM compared to primary tumor, representing promising targets for BoM. scRNAseq revealed 5 major cell types including epithelial, fibroblasts, immune, osteoclasts and endothelial cells, and pronounced intracellular heterogeneity. Six epithelial clusters were identified, featuring high TNF-α signaling, high partial EMT signatures regulated by PRRX1/2, TWIST1/2, and FOXS1, high proliferation, and endocrine resistance signatures. In fibroblasts, 9 clusters were identified representing ECM remodeling, angiogenesis, osteoclast-like, MSC, IFN response and myofibroblasts. Immune cells majorly composed of monocytes/macrophages, CD4+, CD8+ and Treg T cells, and NK cell. WES and scRNAseq analysis demonstrated that organoids preserved mutational landscape and cellular heterogeneity of matched BoMs. Consistent with the BRCA1 and PIK3CA mutations, organoids were responsive to a PARP (Talazoparib: IC50 1.3uM) and PI3K (Alpelisib: IC50 4-9uM) inhibitors. In summary, we have identified potential therapeutic targets from understanding evolution and heterogeneity of BC BoM, and evaluated these in patient-specific organoids, thereby providing insights for the design of a precision medicine based clinical treatment strategy. Citation Format: Kai Ding, Fangyuan Chen, Nolan Priedigkeit, Daniel D. Brown, Tanya Heim, Rebecca Watters, Kurt Weiss, Peter C. Lucas, Jennifer M. Atkinson, Steffi Oesterreich, Adrian V. Lee. In depth single cell profiling of a case of breast cancer bone metastases with associated organoid models reveal a precision medicine approach to treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 81.

Image Analysis of Circulating Tumor Cells and Leukocytes Predicts Survival and Metastatic Pattern in Breast Cancer Patients.

BackgroundThe purpose of the present work was to test whether quantitative image analysis of circulating cells can provide useful clinical information targeting bone metastasis (BM) and overall survival (OS >30 months) in metastatic breast cancer (MBC).MethodsStarting from cell images of epithelial circulating tumor cells (eCTC) and leukocytes (CD45pos) obtained with DEPArray, we identified the most significant features and applied single-variable and multi-variable methods, screening all combinations of four machine-learning approaches (Naïve Bayes, Logistic regression, Decision Trees, Random Forest).ResultsBest predictive features were circularity (OS) and diameter (BM), in both eCTC and CD45pos. Median difference in OS was 15 vs. 43 (months), p = 0.03 for eCTC and 19 vs. 36, p = 0.16 for CD45pos. Prediction for BM showed low accuracy (64%, 53%) but strong positive predictive value PPV (79%, 91%) for eCTC and CD45, respectively. Best machine learning model was Naïve Bayes, showing 46 vs 11 (months), p <0.0001 for eCTC; 12.5 vs. 45, p = 0.0004 for CD45pos and 11 vs. 45, p = 0.0003 for eCTC + CD45pos. BM prediction reached 91% accuracy with eCTC, 84% with CD45pos and 91% with combined model.ConclusionsQuantitative image analysis and machine learning models were effective methods to predict survival and metastatic pattern, with both eCTC and CD45pos containing significant and complementary information.

Abstract 2070: Androgen deprivation and its impact on DNA repair in combination with ionising radiation and Radium-223 in prostate cancer

Abstract Abiraterone acetate and Enzalutamide are novel anti-androgens shown to be one of the few treatments to improve both progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. However, many questions exist regarding the optimal combination and scheduling with radiation, the degree of additivity or synergism and the underlying mechanisms governing any potential synergy. This study is attesting the biological rationale for the selection of Abiraterone or Enzalutamide as, currently, the choice of therapy is a clinical decision based on experience and side effect profiles. As well as external beam radiotherapy a key unexplored area of interest is the combination of these inhibitors with the α-emitter radium-223, which targets bone metastases, with preliminary studies, such as the ERA-223 study, highlighting the need for further studies to mechanistically determine if these combinations are effective and safe. To better understand this, we conducted a detailed analysis of the effects of Abiraterone (10µM), Enzalutamide (10µM) or DMSO (Control) alone or in combination with a dose range of X-rays and radium-223 exposure on cell cycle, DNA damage, DNA repair and cell viability across a panel of androgen-insensitive (PC3), androgen-sensitive (LNCaP) and osteoblastic bone models (SJSA-1, SAOS-2). We report significant differences in the synergy of these AR inhibitors in combination with radiation, with Abiraterone causing significant radiosensitisation regardless of AR status and radiosensitisation with Enzalutamide being dependent on AR-sensitivity. This suggests a potential alternative mechanism of action of Abiraterone, not dependent on AR status. AR suppression alone was also shown to impact cell-cycle distribution, with most notable changes being increases in sub-G1 at the expense of S phase, with observed increases in PARP-cleavage supporting this being a result of increased levels of apoptosis and potential reductions in RAD51 levels. Studies with radium-223 confirmed the highly damaging nature of α-particles, with radium-223 treatments shown to be highly cytotoxic compared to equivalent doses of X-rays. Compared to X-rays, radium-223 induced cell cycle distribution changes in the form of much larger shifts towards G2, which also took longer to recover. As well as increased levels of apoptosis through observed increases in PARP-cleavage. Combinations of radium-223 with Abiraterone or Enzalutamide led to a loss of all additive or synergistic effects previously measured with X-rays. Most likely due to the highly cytotoxic nature of α-particles due to the induction of non-reparable DNA dsb. In conclusion, these results support the use of Abiraterone and Enzalutamide in combination with X-rays and radium-223 to enhance tumor response independently of androgen receptor status. Citation Format: Timothy Wright, Victoria Dunne, Aidan Cole, Kevin Prise. Androgen deprivation and its impact on DNA repair in combination with ionising radiation and Radium-223 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2070.

Optimization of a syngeneic murine model of bone metastasis

Many cancers metastasize to the bones, particularly in cases of breast and prostate cancers. Due to the “vicious cycle” of cancer cells inducing bone resorption, which promotes further tumor growth, they are difficult to treat and may lead to extreme pain. These factors increase the urgency for emerging therapeutics that target bone metastases more specifically and effectively. Animal studies are essential to the development of any therapeutics, but also require robust animal models of human diseases. Robust animal models are often challenging to develop in the case of bone metastasis studies. Previous methods to induce bone metastasis include intracardiac, intravenous, subcutaneous via mammary fat pad, and intraosseous cancer cell injections, but these methods all have limitations. By contrast, the caudal artery route of injection offers more robust bone metastasis, while also resulting in a lower rate of vital organ metastases than that of other routes of tumor implantation. A syngeneic animal model of bone metastasis is necessary in many cancer studies, because it allows the use of immunocompetent animals, which more accurately mimic cancer development observed in immunocompetent humans. Here we present a detailed method to generate robust and easily monitored 4T1-CLL1 syngeneic bone metastases with over 95% occurrence in BALB/c mice, within two weeks. This method can potentially increase consistency between animals in bone cancer metastasis studies and reduce the number of animals needed for studying bone metastases in mice.

Potential of Targeting Bone Metastases with Immunotherapies

Potential of Targeting Bone Metastases with Immunotherapies

Abstract P6-04-01: Identification and targeting of clinically actionable genes in bone metastases

Abstract BACKGROUND: The most common site of cancer metastases from breast is to bone, which occurs in 65-80% of patients resulting in significant comorbidities caused by pathological fractures, pain, hypercalcemia, and nerve compression. The current standard of care involves surgery, radiation, and treatment with bisphosphonates to target osteoclast driven resorption. These modalities all have limitations, complications, and cannot prevent new bone metastases from developing. There is an obvious unmet need for new therapeutic targets and models to treat and study breast cancer related bone metastasis. A large portion of breast cancer research utilizes cell lines and animal models with tissues taken from early stage, primary breast cancers. Furthermore, endpoints such as tumor size reduction and growth in these studies do not always translate to tumor spread. As a result, these study endpoints are not relevant for individuals that are already living with metastatic disease. MATERIALS and METHODS: Potential therapeutic targets involved in metastasis and osteomimicry were identified by performing exome-capture RNA-sequencing (ecRNA-seq) on eleven matched primary breast tumor and bone metastases. Expression gains and losses were identified from the clinically actionable gene set obtained using the Drug Gene Interaction Database (DGBIdB 2.0). A unique organotypic bone model comprised of endothelial cells (EC), osteoblasts (OB), and mesenchymal stem cells (MSC) co-cultured with primary metastatic bone samples from breast cancer patients is being utilized to target these genes of interest. RESULTS: ecRNA-seq of metastatic bone samples revealed expression gains in genes of interest (GOI): EPH Receptor A3 (EPHA3), Protein Tyrosine Phosphatase, Receptor Type D (PTPRD), Patched 1 (PTCH1), and Platelet Derived Growth Factor Receptor Alpha (PDGFRA). The GOI were highly recurrent in patients with endocrine-resistant disease that had developed bone metastases after treatment but were absent in the de novo bone metastasis cases where patients had not yet received endocrine therapy. Analysis for expression of these GOI as well as osteomimicry genes are being assessed in our organotypic bone model. CONCLUSIONS: The GOI identified in this study have been previously associated with the growth and progression of cancer. Furthermore, these genes may be regulated by the RB1-E2F pathway, which was also found to be upregulated in these same samples, and previous studies have linked this pathway's ability to either directly or indirectly regulate our GOI expression levels. Targeting EPHA3, PTPRD, PTCH1, and PDGFRA in breast cancer recurrences may provide a novel therapeutic approach to treat bone metastases that have developed endocrine resistance in patients. Our organotypic bone scaffold provides a unique model to study the interactions of breast cancer cells with bone cells and to test inhibition of novel target genes. Future development of this model will provide a tool for high-throughput screening of drugs to target bone metastases of breast cancer. Citation Format: Watters RJ, Hersh B, Hankins M, Patel V, Martin B, Li Z, Clark KL, Pirosa A, Priedigkeit N, Weiss KR, Lee AV, Tuan RS, Alexander PG, Oesterreich S. Identification and targeting of clinically actionable genes in bone metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-04-01.

Abstract LB-260: Development and validation of propeptide therapeutics for treating bone metastatic prostate cancer

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States. Most prostate cancer related fatalities are not due to tumors at origination sites, but rather due to prostate cancer metastasis throughout the body. Although the relative 5-year survival rate for localized prostate cancer nears 100%, unfortunately, upon metastasis the 5-year survival rate drops to 29.8%. Bone metastases disrupt tissue homeostasis and weaken the skeleton, resulting in an increased risk of severe bone pain and fracture. This is due to increased formation of immature unmineralized bone by osteoblasts, and increased osteolysis by osteoclasts, which induce high levels of bone resorption. Thus, a primary therapeutic objective for malignant bone disease is to eliminate tumors while promoting bone homeostasis. Current therapies are very limited and include palliative radiotherapy, and biphosphate or anti-RANK treatments, which target osteoclasts and decrease the rate of bone resorption. However, these treatments only delay, but do not prevent, skeletal related injuries. Our laboratory has recently developed a strategy aimed at disrupting malignant cytokines signals using inhibitory peptides targeting IL-6 receptors. I here present a novel strategy to express these peptides in vivo following gene delivery as targeted and multifunctional “propeptides.” These propeptides target bone metastases via EGFR antagonist (tumor-homing peptide) and contain dual therapeutic domains consistent of IL-6Ra antagonistic peptides and a pro-osteogenesis peptide, osteostatin. The propeptides are activated by metalloproteases (MMP2/9), which are overexpressed in metastatic prostate tumors and associated bone lesions. We can detect expression of the propeptides following C2C12 muscle cell transfection via real time quantitative PCR and are currently optimizing biochemical strategies for detecting propeptide products via western blot. We hypothesize that optimized secretion and targeting of the therapeutic propeptides will be effective in eliminating prostate tumor metastases, and restoring bone homeostasis. Future studies will examine the expression of propeptide in vivo following gene delivery to muscle and efficacy of propeptides in treating bone metastatic prostate tumors in a TRAMP-C2Ras tibial implantation model. Citation Format: Janelle W. Salameh, Charles S. Umbaugh, Marxa L. Figueiredo. Development and validation of propeptide therapeutics for treating bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-260.

Radium-223 and atezolizumab in platinum refractory urothelial carcinoma with bone metastases: NCT03208712.

TPS543 Background: Immunologically, radiation increases tumor antigen release, cytotoxic CD8+ T cell infiltration while reducing myeloid derived suppressor cells (MDSCs), with distant abscopal responses occasionally reported. Radium-223 is a systemically administered bone-targeted alpha emitter that causes double-stranded DNA breaks and may induce similar immune effects. Anti-PD(L1) immune checkpoint inhibitor monotherapy with Atezolizumab demonstrates objective responses in metastatic urothelial cancer. In mouse models, radiotherapy and checkpoint immune inhibitor in combination synergistically reduce tumor growth. We hypothesized that the combination of Atezolizumab and Radium-223 in metastatic urothelial cancer pts with bone metastases would target bone metastases more effectively and yield higher response rates. Methods: Eligibility criteria for this single-site, phase 2 trial of Radium-223 in combination with Atezolizumab include diagnosis of advanced urothelial carcinoma with ≥1 bone metastasis, RECIST 1.1 measurable disease, progression of disease after/on platinum-containing chemotherapy in the metastatic or perioperative setting, ECOG PS of 0-2 and adequate organ function. Twenty-two pts will be treated with Radium-223 at a dose of 55 kBq/kg IV and Atezolizumab 1200mg IV both on day 1 of 21 day cycles. Up to 6 doses of Radium-223 will be administered. Atezolizumab will be continued until lack of clinical benefit or intolerable toxicity for up to 17 cycles. Routine response assessment will be performed every 12 weeks. Primary endpoint is best overall response per RECIST 1.1. Secondary objectives are to determine the safety and tolerability; determine the overall survival, progression free survival, clinical benefit rate, complete response rate and duration of response; and changes in quality of life as assessed by the EORTC QLQ-C30 score. Exploratory objectives are PD-L1 status by IHC, changes in bone scan per EXINI bone scan index and efficacy measures by irRC. If ≥6 pts respond, corresponding to an ORR of 27% with 80% confidence limits of 15%-43%, further study of the combination would be warranted. Blood and archival tissue will be collected for correlative studies. Clinical trial information: NCT03208712.

A randomized, phase II study of repeated rhenium-188-HEDP (rhenium) combined with docetaxel versus docetaxel alone in castration resistant prostate cancer (CRPC) metastatic to bone: The Taxium II trial.

5081Background: Docetaxel is first line chemotherapy in CRPC. Re-188 is a beta-emitting radiopharmaceutical that targets bone metastases. We investigated whether treatment with docetaxel plus Re-18...

ERA 223: A phase 3 trial of radium-223 dichloride in combination with abiraterone acetate and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients with bone-predominant metastatic castration-resistant prostate cancer.

TPS5088Background: Radium-223 dichloride (Ra-223), a first-in-class alpha-emitting radiopharmaceutical targeting bone metastases (mets), reduced risk of death and delayed time to first symptomatic ...

Targeting Bone Metastases in Metastatic Castration-Resistant Prostate Cancer.

Skeletal involvement in metastatic castrate-resistant prostate cancer (mCRPC) is common and results in significant morbidity and mortality. The interaction of prostate cancer with the bone microenvironment contributes to progression of cancer in the bone leading to skeletal-related events (SREs). Studies aimed at targeting the bone have been carried out over the recent years. Bisphosphonates are synthetic pyrophosphate analogs first investigated for their role in SRE prevention with zoledronic acid as the main bisphosphonate that is approved by the US Food and Drug Administration for retardation of skeletal events in men with metastatic prostate cancer. Denosumab is another bone-targeted agent against uncontrolled osteolysis and serves as a RANK ligand inhibitor, superior to zoledronic acid in delaying SREs. Radiopharmaceuticals have played a role in targeting the bone microenvironment mainly in pain palliation in mCRPC utilizing strontium or samarium in the remote past, but only radium-223 is the first radiopharmaceutical that has yielded improvement in overall survival. The combination and sequencing strategies of these agents is the subject of multiple ongoing trials to guide the best use of these emerging agents.

Abstract OT2-01-05: A phase 2 randomized, double-blind, placebo-controlled trial of hormone therapy ± radium-223 dichloride in human epidermal growth factor receptor 2–negative, hormone receptor–positive breast cancer patients with bone metastases

Abstract Background: Treatment options for bone-metastatic breast cancer (MBC) are limited. Multimodality therapy may improve symptom control and survival. In a phase 2a study of advanced breast cancer patients with bone-dominant and no visceral disease, radium-223 dichloride (radium-223), a first-in-class α-emitter selectively targeting bone metastases, reduced baseline bone biomarker levels with favorable safety (Coleman et al. Breast Cancer Res Treat 2014). This study (NCT02258464) evaluates efficacy and safety of radium-223 versus placebo in human epidermal growth factor receptor 2–negative (HER2-), hormone receptor–positive (HR+) bone-MBC patients receiving single-agent hormone therapy. Trial design: Patients receive (1:1) radium-223 50 kBq/kg IV or placebo q 4 wk (6 cycles) + concurrent single-agent hormone therapy + best supportive care. Stratification is by geographic region, prior lines of hormone therapy for MBC, and number of prior skeletal events. Main eligibility criteria: Eligible patients are pre- or postmenopausal with estrogen receptor–positive, HER2-, bone-dominant MBC with ≥ 2 bone metastases and ≥ 1 or 2 prior symptomatic skeletal events (external beam radiotherapy for bone pain, pathologic bone fracture, spinal cord compression, orthopedic surgery). Patients had ≥ 1 line of hormone therapy for MBC; are taking bisphosphonates or denosumab for ≥ 1 month before study; are eligible for endocrine treatment; and have evaluable disease (RECIST v1.1), asymptomatic or mildly symptomatic bone disease (Brief Pain Inventory), ECOG performance status 0-1, and adequate hematologic, renal, and liver function. Patients may not have had visceral or brain metastases or leptomeningeal disease, need for chemotherapy for metastases, and untreated spinal cord compression. Specific aims: Patients are assessed for efficacy and safety, and followed to symptomatic skeletal events, radiologic progression, death, or withdrawal. Primary endpoint is symptomatic skeletal event–free survival. Statistical methods: Assuming a 1-sided α of 0.1, power of 90%, ∼ 119 symptomatic skeletal events are required for the analysis. Time-to-event variables will be analyzed using a log-rank test, accounting for stratification. Kaplan-Meier estimates and survival curves will be given for each treatment group. Safety analyses will be descriptive. Present and target accruals: As of May 2015, 5 patients have been screened and 3 enrolled. Target enrollment is 227 patients. Citation Format: Coleman RE, Huang L, Petrenciuc O, Zaccarini P, Rugo HS. A phase 2 randomized, double-blind, placebo-controlled trial of hormone therapy ± radium-223 dichloride in human epidermal growth factor receptor 2–negative, hormone receptor–positive breast cancer patients with bone metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-05.

177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment

BackgroundMetastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [89Sr]SrCl2 and [153Sm]Sm-EDTMP. No-carrier-added (n.c.a.) 177Lu is remarkably suitable for an application in this scope.MethodsFive 1,4,7,10-tetraazacyclododecane N,N′,N′′,N′′-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. 177Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [177Lu]citrate.ResultsRadiolabelling yields for [177Lu]Lu-DOTA and [177Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All 177Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. 177Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [177Lu]Lu-DO2A(PBP)2; SUVfemur = 5.41 ± 0.46 for [177Lu]Lu-DOTA(MBP)2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [177Lu]Lu-DO2A(PBP)2; SUVblood = 1.43 ± 0.32 for [177Lu]Lu-DOTA(MBP)2).ConclusionsLu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.

Targeting Bone Metastases in Metastatic Castration-Resistant Prostate Cancer

Skeletal involvement in metastatic castrate-resistant prostate cancer (mCRPC) is common and results in significant morbidity and mortality. The interaction of prostate cancer with the bone microenvironment contributes to progression of cancer in the bone leading to skeletal-related events (SREs). Studies aimed at targeting the bone have been carried out over the recent years. Bisphosphonates are synthetic pyrophosphate analogs first investigated for their role in SRE prevention with zoledronic acid as the main bisphosphonate that is approved by the US Food and Drug Administration for retardation of skeletal events in men with metastatic prostate cancer. Denosumab is another bone-targeted agent against uncontrolled osteolysis and serves as a RANK ligand inhibitor, superior to zoledronic acid in delaying SREs. Radiopharmaceuticals have played a role in targeting the bone microenvironment mainly in pain palliation in mCRPC utilizing strontium or samarium in the remote past, but only radium-223 is the first radiopharmaceutical that has yielded improvement in overall survival. The combination and sequencing strategies of these agents is the subject of multiple ongoing trials to guide the best use of these emerging agents.

ERA 223: A phase 3 trial of radium-223 dichloride (Ra-223) in combination with abiraterone acetate (abiraterone) and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone predominant metastatic castration-resistant prostate cancer (mCRPC).

TPS5082 Background: Ra-223, a first-in-class alpha-emitting radiopharmaceutical targeting bone metastases, reduced risk of death by 30% and delayed time to first symptomatic skeletal event (SSE) ve...

Targeting bone metastases in prostate cancer: improving clinical outcome

Bone metastases develop in most patients with metastatic castration-resistant prostate cancer (mCRPC). They affect the structural integrity of bone, manifesting as pain and skeletal-related events (SREs), and are the primary cause of patient disability, reduced quality of life (QOL) and death. Understanding the pathophysiology of bone metastases resulted in the development of agents that improve clinical outcome, suggesting that managing both the systemic disease and associated bone events is important. Historically, the treatment of CRPC bone metastases with early radiopharmaceuticals and external beam radiation therapy was largely supportive; however, now, zoledronic acid and denosumab are integral to the therapeutic strategy for mCRPC. These agents substantially reduce skeletal morbidity and improve patient QOL. Radium-223 dichloride is the first bone-targeting agent to show improved survival and reduced pain and symptomatic skeletal events in patients with mCRPC without visceral disease. Five other systemic agents are currently approved for use in mCRPC based on their ability to improve survival. These include the cytotoxic drugs docetaxel and cabazitaxel, the hormone-based therapies, abiraterone and enzalutamide, and the immunotherapeutic vaccine sipuleucel-T. Abiraterone and enzalutamide are able to reduce SREs and improve survival in this setting. Novel agents targeting tumour and bone cells are under clinical development.