Background: Outcomes with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) are influenced by tumor burden, disease kinetics, and host factors. We evaluated the relative prognostic impact of metastatic pattern, laboratory markers, and prostate-specific antigen (PSA) dynamics in a real-world cohort. Methods: We retrospectively analyzed 72 patients with mCRPC treated with enzalutamide. Progression-Free Survival (PFS) and Overall Survival (OS) were estimated using the Kaplan-Meier method. Multivariate Cox proportional hazards models were utilized to identify independent predictors of survival, incorporating clinical variables (visceral metastases, bone tumor burden), kinetic parameters (Time to Castration Resistance [TTCR], Time to PSA Nadir [TTN]), and host factors (Charlson Comorbidity Index [CCI], Eastern Cooperative Oncology Group Performance Status (ECOG PS), Systemic Immune-Inflammation Index [SII], HALP score). Results: Visceral metastasis was a dominant predictor of poor outcomes, increasing the risk of death by 4.0-fold (HR: 4.05; 95% CI: 1.84-8.89; p < 0.001). A high skeletal tumor burden (≥5 bone lesions) was identified as a critical threshold, associated with a 5.5-fold increase in mortality risk (HR: 5.53; p < 0.001). Delays in initiating enzalutamide significantly compromised survival, with each 1-month delay increasing the risk of death by 7.3% (HR: 1.07; p = 0.003). While early PSA decline (≥50% at 3 months) did not independently predict OS, a prolonged TTN (>12 months) was associated with superior survival. Notably, host-related factors, including age, CCI, and ECOG PS, were not found to be significantly associated with survival outcomes in this specific dataset. Conclusions: Our preliminary findings suggest that survival in real-world mCRPC patients treated with enzalutamide may be influenced predominantly by intrinsic tumor biology-specifically anatomical extent and resistance kinetics-rather than host frailty or comorbidity burden. However, given the retrospective and single-center nature of this study, these findings should be considered hypothesis-generating and require validation in larger, multi-center cohorts. Host-related variables (including age and CCI) were evaluated but were not retained as independent predictors in the final multivariable model. Early initiation of therapy and monitoring of kinetic markers like TTN and TTCR offer superior prognostic stratification compared to static baseline characteristics.

Bone metastasis is a frequent and devastating complication in lung adenocarcinoma (LUAD), where excessive osteoclast activation drives osteolytic destruction and skeletal-related events. How tumor-derived exosomes reprogram osteoclast precursors to establish a bone-metastatic niche remains incompletely understood. Here, we identify an exosomal miR-484–platelet endothelial cell adhesion molecule-1 (PECAM1) axis that links LUAD to pathological osteoclastogenesis and osteolytic bone metastasis. Using a highly bone-tropic Lewis lung carcinoma (BM-LLC) model, we show that BM-LLC-derived exosomes are preferentially internalized by osteoclast precursors and are markedly enriched in miR-484. Exosomal transfer of miR-484 increases intracellular miR-484 in these precursor cells and directly suppresses PECAM1, a negative regulator of osteoclastogenesis. PECAM1 repression activates NFATc1 and c-Fos, up-regulates osteoclast markers (TRAP, CTSK, RANK), and promotes osteoclast differentiation and bone matrix degradation in vitro. Gain- and loss-of-function studies demonstrate that PECAM1 overexpression or miR-484 inhibition attenuates BM-LLC exosome–induced osteoclastogenesis, whereas PECAM1 knockdown phenocopies miR-484 and further amplifies osteoclast activation. In vivo, systemic administration of BM-LLC exosomes exacerbates osteolytic lesions and bone tumor burden without altering lung colonization, while therapeutic delivery of antagomiR-484 partly restores PECAM1 expression, suppresses osteoclastogenic signaling, and alleviates bone loss. Circulating exosomal miR-484 levels correlate with the severity of osteolysis, supporting its potential as a liquid biopsy biomarker. Collectively, our data define exosomal miR-484–mediated PECAM1 suppression as a critical mechanism by which LUAD cells remodel the bone microenvironment, and highlight the miR-484–PECAM1axis as a tractable target for preventing or treating osteolytic bone metastasis.

Denosumab, a bone-modifying agent, reduces the incidence of skeletal-related events (SREs), but its optimal use in real-world metastatic castration-resistant prostate cancer (mCRPC) settings remains unclear. We conducted a retrospective cohort study of 235 patients with bone mCRPC treated with denosumab between 2015 and 2024. The primary endpoint was identification of risk factors associated with symptomatic skeletal events (SSEs) after denosumab initiation. Secondary endpoints were risk factors for SREs occurring prior to denosumab. Multivariate Cox regression analyses assessed independent predictors. Over a median follow-up of 11months, 27 patients (11.5%) developed an SSE. The most common events were EBRT to bone (7.7%) and pathologic fractures (4.3%). The 2-year SSE-free survival rate was 79.4%. A prior history of SREs was independently associated with a significantly increased risk of subsequent SSEs (hazard ratio [HR]: 2.09; 95% confidence interval: 1.02-4.92; p = 0.047). In a separate analysis of SREs occurring prior to denosumab, grade 2 and ≥ 3 disease at the time of bone metastasis diagnosis were associated with higher risk (HR: 2.62 and 2.32, respectively; both p < 0.05). Denosumab was discontinued in 62.6% of patients, primarily due to clinical deterioration, death, or difficulty attending appointments. In this real-world study, approximately 10% of patients with bone mCRPC developed SSEs during denosumab therapy, mostly within the first year. A prior SRE and high baseline bone tumor burden were significant predictors of skeletal complications, underscoring the importance of early risk stratification and timely initiation of bone-targeted therapies.

PurposeEstablishing accurate methods for red marrow (RM) dosimetry is an important step toward patient-specific treatment guidance. We compared image-based dosimetry methods and investigated their role in predicting changes in blood counts following [177Lu]Lu-PSMA-617 radioligand therapy (177Lu RLT).MethodsFour image-based dosimetry methodologies were applied to patients who received 2-bed position serial 177Lu SPECT/CT after cycle 1 of RLT, with segmentation of all spongiosa within the field-of-view performed on CT using deep learning tools. Cycle 1 RM absorbed doses (ADs) were estimated with: 1) the time-integrated activity (TIA) in segmented spongiosa coupled with MIRD-based S-values (MIRD); 2) the TIA concentration in the segmented aorta (a surrogate for blood-based dosimetry) coupled with MIRD-based S values (MIRDaorta); 3) the voxel-level TIA map coupled with an in-house Monte Carlo (MC) dosimetry code that incorporated a micro-scale modeling of the spongiosa (MC); and 4) a novel method that utilizes [68Ga]Ga-PSMA-11 PET/CT and [99mTc]Tc-sulfur colloid (SC) SPECT/CT for tumor and marrow localization coupled with the above MC code, modified to allow tumor infiltration of the spongiosa (MCSC+PET). Spearman rank correlation of AD from the four methods with changes in select blood counts was evaluated.ResultsImaging data was available for 20 patients for methods 1–3, while SC images were available for 12 patients for method 4. Cycle 1 AD to the FOV RM was, on average, 1.9 Gy (range: 0.1–8.0 Gy) for MIRD, 0.08 Gy (range: 0.01–0.27 Gy) for MIRDaorta, 2.5 Gy (range: 0.1–10.3 Gy) for MC, and 1.6 Gy (range: 0.1–4.6 Gy) for MCSC+PET. The ADs from MIRDaorta were not concordant with MIRD, MC, or MCSC+PET (|CCC|< 0.01) and were generally underestimates. For 3 patients with high bone tumor burden, MCSC+PET gave lower average AD than MIRD (39%) and MC (53%), potentially due to more accurate localization of marrow and tumor. Cycle 1 RM ADs were correlated with relative change in blood counts at 6-weeks post-cycle 1 with significant correlation observed for neutrophils with MIRD, MC, and MCSC+PET with Spearman rank correlations ranging from r = − 0.61 to r = − 0.88 (P < 0.01). Correlation with white blood cells at 6-months was also significant with r = − 0.80 (P < 0.01) for these three methods. MIRDaorta did not correlate with any acute or chronic changes in blood counts.ConclusionThe RM AD estimates from the blood-based surrogate were not concordant with the other image-based calculations and did not correlate with changes in blood values. Including patient-specific tumor and marrow distribution information resulted in lower AD for patients with a high bone metastatic burden. These findings have implications for managing hematological toxicities in 177Lu RLT, especially if dosimetry-guided treatment planning is considered.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40658-025-00816-6.

Myeloma bone disease, a complication of multiple myeloma (MM), is characterized by impaired osteogenic function of bone marrow stromal cells (BMSCs) and can be an indicator of disease progression. The underlying mechanisms driving BMSC dysfunction are not yet fully understood. This work investigated MM cell interaction with BMSCs, finding that BMSC ciliogenesis is inhibited in the presence of myeloma cells. We demonstrated that direct interaction between myeloma cells and BMSCs through CD40-CD40L led to BMSC down-regulation of sentrin-specific protease 1 (SENP1), a cysteine protease that removes small ubiquitin-like modifier (SUMO) posttranslational modifications. SENP1 down-regulation led to increased SUMOylation of oral-facial-digital syndrome type 1 protein (OFD1), a centriole and centriolar satellite protein, at K931. Increased SUMOylation led to increased OFD1 protein stability and localization at centriolar satellites of primary cilia and decreased ciliogenesis. Consequently, BMSCs lacking primary cilia became desensitized to shear stress stimulation and decreased Hedgehog signaling activation. This cascade of events resulted in inhibited ciliogenesis and osteogenesis in myeloma-BMSC-interacting models, in Prx1CreCd40lf/f mice, and in clinical samples. Treatment with an anti-CD40 neutralizing antibody effectively mitigated bone disruption and tumor burden in the Vk*MYC and SCID (severe combined immunodeficient)-hu mouse models of MM. Overall, our study provides experimental insights into BMSC dysfunction in MM and suggests that targeting the CD40-SENP1-OFD1 axis could hold promise for MM treatment in clinical settings.

Breast cancer cells frequently spread to the bone, causing osteoclast-mediated bone destruction and pathological fractures. Bone anabolic agents, such as abaloparatide, are used clinically to increase bone formation in osteoporotic patients, but their effectiveness against tumor-induced bone destruction is poorly understood. In this study, we present the first evaluation of abaloparatide in preclinical models of breast cancer cells disseminated to the bone marrow and demonstrate that intermittent abaloparatide dramatically increases trabecular bone volume in mice inoculated with triple negative breast cancer cells. Abaloparatide also increases BMD in a model of estrogen receptor positive breast cancer, despite elevated baseline bone volume due to estradiol supplementation. Importantly, abaloparatide does not increase tumor burden or incidence in bone or soft tissue sites in either model. These results suggest that abaloparatide may be effectively used to increase bone mass without stimulating growth of cancer cells in the bone marrow and may be beneficial for cancer patients with low bone mass.

Abstract CDK9 is a promising target in many cancers. Development of first generation CDK9 inhibitors has been stopped due to severe adverse effects, but next generation selective CDK9 inhibitors are considered safer and more effective. OBP-004 is a highly potent selective small-molecule inhibitor of CDK9 with favorable physicochemical properties, 17-20 h in vivo half-life and high tissue biodistribution in brain, lung, spleen and kidneys. Triple-negative breast cancer (TNBC) patients have limited treatment options together with high incidence of metastatic relapse. TNBC typically forms multi-organ metastases and has a high incidence of bone metastases. In this study, we demonstrate preclinical efficacy of OBP-004 on metastatic tumor burden, and more specifically on bone metastatic TNBC. For studying efficacy on metastatic disease, NMRI nude mice were inoculated intravenously with luciferase-labelled MV4-11 human acute monocytic leukemia cells. OBP-004 was given orally at a dose of 1.0 mg/kg three times a week (3-day on, 4-day off). The mice were randomized to groups based on body weight and bioluminescence imaging (BLI) signal at day 15, and tumor growth was monitored by BLI during the study. Treatment was started after the randomization at day 15 and continued until day 32. For studying efficacy on tumor growth in bone metastatic microenvironment in more detail, BALB/c mice were inoculated intratibially with aggressive luciferase-labelled 4T1 mouse TNBC cell line. OBP-004 was given orally at a dose of 0.8 mg/kg three times a week (Mon/Wed/Fri). The mice were randomized to groups based on body weight and BLI signal at day 4. Treatment was started after the randomization at day 4 and continued until day 21. During the study, tumor growth was monitored by BLI, cancer-induced bone changes by X-ray radiography, and bone pain by mechanical allodynia using Von Frey filaments. The 1.0 mg/kg dosing (3-day on, 4-day off) of OBP-004 in the MV4-11 study resulted in slight decrease of body weight without any clinical signs. The optimized dosing with 0.8 mg/kg (Mon/Wed/Fri) in the 4T1 study was well tolerated. In the MV4-11 model, OBP-004 showed strong decrease of bone, brain, lung and lymph node metastases. In the intratibial 4T1 model, OBP-004 decreased tumor growth in bone from day 10 forward, bone pain at day 14, and cancer-induced bone loss at day 21. We conclude that the highly potent selective CDK9 inhibitor OBP-004 reduces metastatic tumor growth in bone, brain, lung and lymph nodes and decreases metastatic growth of TNBC cells in bone microenvironment, bone pain and cancer-induced bone loss in an aggressive preclinical TNBC model. Citation Format: Tiina E. Kahkonen, Gergana Galabova, Ru Yang, Jie Wen, MIchael Thormann, Jussi M. Halleen. A highly potent selective CDK9 inhibitor OBP-004 reduces metastatic tumor burden in bone, brain, lung and lymph nodes and decreases growth of triple-negative breast cancer cells in bone. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3012.

Abstract Background: CDK4/6 inhibitors (CDK4/6i) have revolutionized HR+ metastatic breast cancer treatment. Trials like PALOMA, MONALEESA, and MONARCH showed improved progression-free survival (PFS) with endocrine therapy (ET), establishing it as first-line treatment. Bone metastases are common in HR+ breast cancer, with 40% of patients having bone-only disease (BoD), which has a distinct course and better prognosis. However, CDK4/6i trials showed less significant PFS benefits in BoD subgroups. This study explores BoD survival outcomes and CDK4/6i efficacy. Methods: Patients with HR+, HER2- metastatic breast cancer from a retrospective study at Washington University School of Medicine were included. All the patients received CDK4/6i in the first- or second-line settings from June 2014 to March 2020. Outcomes were collected through June 2023. The Kaplan-Meier with log-rank test and multivariable Cox model were used for survival analysis. We used murine triple negative 4T1 and ER+ luminal B PyMT Bo1 breast tumor cell line-derived models in immunocompetent mice. Results: We included 167 female patients (131 first, 36 second line) treated with palbociclib plus ET for at least two months. Median age was 62 years (28-87), and 70 (41%) were in the BoD group. Median PFS was significantly shorter in the BoD group compared to the BV (Visceral +/- Bone) group (16.8 vs. 25 months, p=0.04). Multivariate analysis, adjusted for age and race, showed BoD had an HR of 1.65 (95% CI: 1.05-2.68) for PFS.The results of preclinical models showed that single-agent ribociclib decreased the primary mammary gland tumor burden. This effect was abolished when CD8+ T-cells were depleted. However, in the bone colonization model, ribociclib had a nonsignificant effect on bone tumor burden despite decreases in tumoral Ki-67. Arg1+ immune suppressive macrophages were significantly decreased in primary tumors but not in bone tumors after ribociclib administration, suggesting a relative treatment resistance and immune suppression in the bone tumors. Next, we analyzed baseline bone biopsies from 44 patients, categorized as responders (PFS &amp;gt;1 year) or non-responders (PFS &amp;lt;6 months). Ki67 expression was not different between groups but was decreased in 4 patients with paired pre-and post-treatment biopsies. Using Hyperion imaging mass cytometry, we profiled a patient’s bone tumor before and after Palbociclib; we found increased PD-L1, CD8+ T-cells, and CD206+ myeloid cells post-treatment. Immune profiling for all 44 patients is ongoing, with future efforts to understand different immune cell populations’ role in CDK4/6i response and identify targets to enhance their effects in bone metastases. Conclusion: Our retrospective study and preclinical data suggest CDK4/6i may be less effective in the bone microenvironment, underscoring the need for research into the role of the bone tumor immune microenvironment in treatment response. Citation Format: Mahta Mardani, Suleyman Noordeen, Katherine Clifton, Cynthia Ma, Jingyu Xiang, Jingqin Luo, Takayuki Kobayashi, Jing Xi, Nusayba Bagegni, Foluso Ademuyiwa, Rama Suresh, Ashley Frith, Andrew A. Davis, Ron Bose, Lindsay Peterson, Shana Thomas, Yu Tao, Kaylee O’Donnell, Netra Navadkar, Kristin Kwakwa, Will Mattock, Thomas Walsh, Yalin Xu, Deborah J. Veis, Xinming Su, Katherine Weilbaecher. CDK4/6 inhibitors in patients with bone-only metastatic breast cancer, the role of immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5333.

To identify key risk factors and construct a predictive model for the progression of high bone tumor burden prostate cancer (HBTB-PCa) to castration-resistant prostate cancer (CRPC). This retrospective study included 367 HBTB-PCa patients treated between January 2018 and May 2021, with 286 cases progressed to CRPC (progression group) and 81 cases did not (non-progression group). Patients were randomly divided into training (n=257) and validation (n=110) sets at a 7:3 ratio. Logistic regression was used to identify independent risk factors, and a Nomogram was built to predict progression risk. Model performance was evaluated using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Compared with the non-progression group, patients in the progression group had significantly higher rates of perineural invasion (P=0.011), Gleason score ≥8 (P=0.002), and T4 stage (P=0.012). Laboratory markers including ALP (P<0.001) and LDH (P<0.001) were also elevated in the progression group. Multivariate analysis identified perineural invasion (P=0.032), Gleason score (P=0.002), initial PSA (P=0.025), ALP (P=0.011), LDH (P<0.001), and ALB (P=0.019) as independent predictors of progression to CRPC. The Nomogram demonstrated strong discrimination power (AUC=0.845 in the training set; AUC=0.746 in external validation), with LDH being the most influential predictor. DCA indicated a net clinical benefit up to 77.82%. Perineural invasion, Gleason score ≥8, and elevated ALP and LDH are closely associated with progression from HBTB-PCa to CRPC. The constructed Nomogram (internal AUC=0.845; external AUC=0.746) offers a practical tool for individualized risk assessment and guiding treatment planning in clinical settings.

Abstract Background: CDK4/6 inhibitors (CDK 4/6i) have significantly advanced the treatment of hormone receptor-positive (HR+) metastatic breast cancer in the last decade. Several clinical trials including PALOMA, MONALEESA, and MONARCH have shown improved progression-free survival (PFS) rates when CDK4/6i were combined with endocrine therapy (ET). These results led to recommending their use in combination with ET as the first line of therapy in the metastatic settings. Bone metastasis is the most common site of disease in patients with HR+ metastatic breast cancer, about 40% of whom have bone as the only site of metastasis (bone-only disease [BoD]). While previous studies have shown that BoD can have a unique clinical course and a more favorable prognosis compared to non-BoD metastasis, most of the aforementioned CDK 4/6i clinical trials have not shown significant improvements in PFS in BoD subset of patients. Here we aimed to investigate the survival outcomes of BoD patients at a single institution center and evaluate CDK 4/6i activity in preclinical models of bone metastasis in breast cancer. Patients and methods: Patients with HR+, HER2-negative metastatic breast cancer from a retrospective CDK4/6i study at Washington University School of Medicine were included in this analysis. We selected all the patients who received CDK4/6i in the first- or second-line settings from June 2014 to March 2020. Outcomes were collected through June 10, 2023. The Kaplan-Meier method with log rank test and multivariable cox model were used for survival analysis. Results: 114 female patients (n=75 first line, n=39 second line, n=20 African American, n=94 Caucasian) were included in this study. All patients received Palbociclib as the first exposure to CDK4/6 inhibitor in combination with ET for at least two months. Median age was 60 years (range, 28-87) and forty-seven patients (41%) were in the BoD group. Survival outcomes for BoD group were compared to the rest of patients who had either bone and visceral or visceral only metastatic lesions (BV group). Our results demonstrated a significantly reduced median PFS in BoD group compared to BV group (13.1 months [95%CI:8-18.2] vs 19.6 months [95%CI:6.8-32.4], p=0.01) respectively. There was no significant difference in overall survival between BoD and BV groups (36.6 months [95%CI:32.2-41] vs 41.7 months [95%CI 36.1-47.2] p=0.74) respectively. In multivariate analysis regarding the associated risk factors with PFS, after adjusting for age and race, BoD had a HR of 1.62 (95%CI:1.04-2.54) for PFS. Among the 75 patients who received CDK4/6i as their first line of therapy, BoD (n=32 patients [42.7%]) also showed an inferior (p=0.05) median PFS (20 months [95%CI 12.9-27]) compared to BV group (n=43 patients [57.3%], median PFS=28.4 months [95%CI: 16.3-40.4]). To investigate potential treatment resistance mechanisms in bone metastases, we used the triple negative 4T1 and the ER+ luminal B PyMT Bo1 breast tumor cell line derived mammary gland models in immunocompetent mice. Single agent CDK4/6i, ribociclib, decreased primary mammary gland tumor burden. This effect was abrogated when CD8+ T-cells were depleted. In the bone colonization model using these cell lines, ribociclib had little effect on bone tumor burden. Arg1+ immune suppressive macrophages were significantly decreased in the primary mammary tumor but not in the bone tumor after ribociclib administration, suggesting a relative treatment resistance and immune suppression in the bone tumor microenvironment compared to the primary mammary gland. Conclusion: CDK4/6i play a significant role in the treatment of patients with HR+ metastatic breast cancer. Our single institution, retrospective study and preclinical data suggests that CDK4/6i may not be as effective for the treatment of tumors residing in the bone microenvironment, warranting future studies to understand the mechanisms of CDK4/6 inhibitors action in bone versus visceral metastases. Citation Format: Mahta Mardani, Suleyman Noordeen, Katherine Clifton, Cynthia Ma, Jingqin Luo, Jing Xi, Nusayba Bagegni, Foluso Ademuyiwa, Rama Suresh, Ashley Frith, Andrew Davis, Ron Bose, Lindsay Peterson, Shana Thomas, Yu Tao, Takayuki Kobayashi, Jingyu Xiang, Yalin Xu, Xinming Su, Katherine Weilbaecher. Clinical outcomes of CDK4/6 inhibitors in patients with bone only metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-05-05.

Bone metastases (BM) are a serious cancer complication, potentially causing substantial morbidity. Among the clinical issues related to BM, there is the lack of specific tools for early diagnosis and prognosis. We explored whether combining bone turnover markers (BTM) with dual-energy X-ray absorptiometry (DXA) assessment could identify early BM progression and risk of skeletal-related events (SREs) during zoledronate treatment. Before the initiation of zoledronate (T0) and after six months of treatment (T1), serum levels of five BTM were measured, and patients (N = 47) underwent DXA evaluation. Standard radiological imaging was performed to assess bone tumor response to medical anti-cancer treatment. High tumor burden in bone correlated with higher serum CTX (p = 0.007) and NTX (p = 0.005) at baseline. Low concentrations of OPG at T0 predicted BM progression with a sensitivity and specificity of 63% and 77%, respectively, when a cutoff of 5.2 pmol/l was used; such a predictive meaning was stronger in patients with lytic BM (sensitivity: 88%, specificity: 80%; p = 0.0006). As for the risk of SREs, we observed an association between low baseline OC (p = 0.04) and OPG (p = 0.08) and the onset of any-time SREs, whereas an increase in OPG over time was associated with reduced risk of on-study events (p = 0.03). Moreover, a statistically significant correlation emerged between low baseline lumbar T-score and femur BMD and on-study SREs (p < 0.001 in both instances). These findings suggest that addition of DXA to BTM dosage could help stratifying the risk of SREs at the time of BM diagnosis but does not enhance our capability of detecting bone progression, during zoledronate treatment.

Nex-T TM Cluster of Differentiation 19 (CD19) Chimeric Antigen Receptor (CAR) T-Cell Therapy BMS-986353 (CC-97540): Comparative Analysis of Baseline Patient Data from Trials in Systemic Lupus Erythematosus (SLE) and Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL) Related to Manufacturability and Potential Safety

High bone tumor burden to identify advanced non-small cell lung cancer patients with survival benefit upon bone targeted agents and immune checkpoint inhibitors

We report the case of a 68-year-old man with advanced hepatocellular carcinoma (HCC) with multiple bone metastases (BM) treated with tyrosine kinase inhibitors. Despite an insufficient disease control on BM with a progression free survival (PFS) of 6 months, sorafenib was not discontinued and multiple radiation therapy (RT) sessions with a palliative purpose were performed. Thanks to this aggressive radiotherapy approach in order to control the bone tumor burden, the patient has continued sorafenib for 34.6 months achieving an overall survival (OS) of 41.3 months. This result highlights the importance of a tailored management of patients with advanced HCC and the role of the RT for BM control, even if at lower cumulative radiation dose, for extending patient survival.

Bone metastasis is frequently common in advanced lung cancer with the major issue of a pathological fracture. Previous studies suggested that Astragalus membranaceus (Qi) and Ampelopsis japonica (Lian), which are used as folk medicine in China, have potential effects on inhibiting tumor growth and protecting bones, respectively. In this study, an experiment on the inhibitory effect of the Qilian formula (AAF) in vivo was designed to examine tumor growth in bone and osteoclast formation. The bone metastasis xenograft models were established by implanting NCI-H460-luc2 lung cancer cells into the right tibiae bones of mice. After confirming the model's viability through optical imaging 7 days post-implantation, 2 groups, namely the AAF group and the control group, were administered 0.3 mL of AAF extract (9 g/kg/day) or normal saline via intragastric delivery for a duration of 4 weeks. Throughout the study, we longitudinally assessed tumor burden, bone destruction, and weight-bearing capacity in vivo using reporter gene bioluminescence imaging (BLI), micro-CT, and dynamic weight-bearing (DWB) tests. Mechanistic insights were gained through Hematoxylin-eosin (H&E) staining, immunohistochemical (IHC) analysis, western blotting, and flow cytometry. Qilian formula produced significant inhibition to the progress of bone destruction and tumor burden in the right tibiae bone in the treatment group. It was further evidenced by molecular imaging in vivo via small animal micro-CT and BLI with parametric quantification, characterizing significantly lower uptake of BLI signal in the treated tumor lesions and improving the pathological changes in the microstructure of bone. Furthermore, DWB tests revealed that Qilian formula treatment significantly maintained the weight-bearing capacity. According to immunohistochemical analysis, the effect of the Qilian formula appeared to involve the suppression of osteoclast formation by lower expression of the tartrate-resistant acid phosphatase. Cell apoptosis and death induction were evidenced by a higher percentage of Bal2、BAX and caspase 3 expressions of Qilian formula-treated tumor tissues. Our study demonstrated a significant inhibitory effect of the Qilian formula on the progression of osteolytic invasion in vivo by suppressing osteoclastogenesis and promoting apoptotic cell death.

BackgroundPain is a common complication for patients with metastatic bone disease. Animal models suggest that the pain, in part, is driven by pathological sprouting and reorganization of the nerve fibers innervating the bone. Here, we investigate how these findings translate to humans.MethodsBone biopsies were collected from healthy volunteers (n = 7) and patients with breast cancer and metastatic bone disease (permissions H-15000679, S-20180057 and S-20110112). Cancer-infiltrated biopsies were from patients without recent anticancer treatment (n = 10), patients with recent anticancer treatment (n = 10), and patients with joint replacement surgery (n = 9). Adjacent bone sections were stained for (1) protein gene product 9.5 and CD34, and (2) cytokeratin 7 and 19. Histomorphometry was used to estimate the area of bone marrow and tumor burden. Nerve profiles were counted, and the nerve profile density calculated. The location of each nerve profile within 25 μm of a vascular structure and/or cancer cells was determined.ResultsCancer-infiltrated bone tissue demonstrated a significantly higher nerve profile density compared to healthy bone tissue. The percentage of nerve profiles found close to vascular structures was significantly lower in cancer-infiltrated bone tissue. No difference was found in the percentage of nerve profiles located close to cancer between the subgroups of cancer-infiltrated bone tissue. Interestingly, no correlation was found between nerve profile density and tumor burden.ConclusionsTogether, the increased nerve profile density and the decreased association of nerve profiles to vasculature strongly suggests that neuronal sprouting and reorganization occurs in human cancer-infiltrated bone tissue.

PD35-04 QUANTITATIVE PIFLUFOLASTAT F18 (PSMA) SCAN INDICES AS A RESPONSE IMAGING-BIOMARKER TO ANDROGEN DEPRIVATION THERAPY IN VETERANS WITH NEWLY DIAGNOSED METASTATIC PROSTATE CANCER

Simple SummaryThe alpha emitter 223Radium-dichloride (223Ra) and the beta emitter 177Lutetium (177Lu) targeting the prostate-specific membrane antigen (PSMA) are sequentially used for therapy of advanced bone-metastatic castration-resistant prostate cancer. Despite routine performance in patients who had received 223Ra, it is not clear whether disease sites refractory to alpha radiation can be effectively treated with 177Lu-PSMA-617. Secondly, it remains to be elucidated if therapy with 177Lu-PSMA-617 can be safely performed shortly after 223Ra, bearing in mind the myelotoxic potential of both treatments. The aim of our retrospective study was to evaluate safety and efficacy of 177Lu-PSMA-617 within less than 8 weeks after failing 223Ra. Radioligand therapy with 177Lu-PSMA-617 shortly after failing 223Ra is effective and can result in long-standing disease control even in patients with disseminated or diffuse bone involvement. Patients with oligo- and multifocal bone metastases show significantly longer overall survival with lower risk of significant hematotoxicity compared to patients with disseminated/diffuse involvement.Bone-seeking 223Radium-dichloride (223Ra) is an established treatment prolonging survival and reducing morbidity in selected patients with metastatic castration-resistant prostate cancer (mCRPC) with skeletal involvement. Radioligand therapy with 177Lutetium-PSMA-617 (177Lu-PSMA-617) has been increasingly implemented in patients with mCRPC failing conventional treatment options. In this study, the safety and efficacy of 177Lu-PSMA-617 in patients with progressive bone involvement under treatment with 223Ra was assessed. Twenty-eight men (median age 73 years, range 63–89 years) with progressive mCRPC, who started 177Lu-PSMA-617 within 8 weeks after the last 223Ra administration, received a median of 4 (IQR 3–6) and a total of 120 cycles of 223Ra and a median of 4 (IQR 2–7) cycles 177Lu-PSMA-617 with a mean treatment activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA response (≥50% PSA decline 12 weeks after the first 177Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients. Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6–14) months and median overall survival (OS) was 18 (95% CI, 14–22) months. Patients with low bone tumor burden (2–20 lesions) had a significantly longer OS (28 vs. 14 months, p < 0.045) compared to patients with a high tumor burden (>20 lesions). Grade ≥ 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively. In progressive bone-metastatic mCRPC patients, prompt initiation of 177Lu-PSMA-617 after failing 223Ra is effective with an acceptable toxicity profile.

Granulocyte colony stimulating factor (G-CSF), an essential cytokine regulating granulopoiesis, is expressed in a substantial proportion of breast cancers, and it has been implicated in cancer progression. Here, we examined effects of G-CSF on the development of bone metastases of breast cancer using immunocompetent mouse models. The expression of CXC chemokine ligand 12 (CXCL12) in bone marrow stromal cells, which plays a critical role in the maintenance of hematopoietic stem cells and also in cancer cell homing to bone, was markedly decreased in mice treated with G-CSF. Flow cytometric analysis revealed that pretreatment of mice with G-CSF reduced the number of bone-homing cancer cells. G-CSF also increased the population of myeloid-derived suppressor cells (MDSCs) in bone marrow. Depletion of MDSCs using anti-Gr-1 antibody treatment significantly decreased the metastatic tumor burden in bone. The overall effects of G-CSF on bone metastases were finally examined using two different treatment protocols. When mice were treated with G-CSF prior to the tumor cell inoculation, G-CSF did not change bone metastatic-tumor burden. In contrast, when G-CSF treatment was started after the tumor cells had homed to bone, G-CSF significantly accelerated bone metastases formation. These results suggest that G-CSF suppressed cancer cell homing to bone by downregulating CXCL12 expression in bone marrow stromal cells, whereas G-CSF stimulated the progression of bone metastases at least in part by MDSC-mediated mechanisms. IMPLICATIONS: G-CSF had opposing effects on the initiation and progression of bone metastases of breast cancer and the balance may regulate the metastatic tumor burden.

Simple SummaryAdult T-cell leukemia (ATL) Leukemia is an aggressive, peripheral blood (T-cell) neoplasm associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Recent studies have implicated dysregulated histone deacetylases in ATL pathogenesis. ATL modulates the bone microenvironment of patients and activates osteoclasts (bone resorbing cells) that cause severe bone loss. The objective of this study was to assess the individual and dual effects of AR-42 (HDACi) and zoledronic acid (Zol) on the growth of ATL cells in vitro and in vivo. AR-42 and Zol reduced the viability of ATL cells in vitro. Additionally, Zol and Zol/AR-42 decreased ATL tumor growth and halted osteolysis in bone tumor xenografts in immunodeficient mice in vivo. Our study suggests that dual targeting of ATL cells (using HDACi) and bone osteoclasts (using bisphosphonates) may be exploited as a valuable approach to reduce bone tumor burden and improve the life quality of ATL patients.Adult T-cell leukemia/lymphoma (ATL) is an intractable disease affecting nearly 4% of Human T-cell Leukemia Virus Type 1 (HTLV-1) carriers. Acute ATL has a unique interaction with bone characterized by aggressive bone invasion, osteolytic metastasis, and hypercalcemia. We hypothesized that dual tumor and bone-targeted therapies would decrease tumor burden in bone, the incidence of metastasis, and ATL-associated osteolysis. Our goal was to evaluate dual targeting of both ATL bone tumors and the bone microenvironment using an anti-tumor HDACi (AR-42) and an osteoclast inhibitor (zoledronic acid, Zol), alone and in combination. Our results showed that AR-42, Zol, and AR-42/Zol significantly decreased the viability of multiple ATL cancer cell lines in vitro. Zol and AR-42/Zol decreased tumor growth in vivo. Zol ± AR-42 significantly decreased ATL-associated bone resorption and promoted new bone formation. AR-42-treated ATL cells had increased mRNA levels of PTHrP, ENPP2 (autotaxin) and MIP-1α, and TAX viral gene expression. AR-42 alone had no significant effect on tumor growth or osteolysis in mice. These findings indicate that Zol adjuvant therapy has the potential to reduce growth of ATL in bone and its associated osteolysis.