Publications

5012 Background: NEPC is an aggressive form of prostate cancer with poor prognosis and no standard treatment approach. NEPC can be characterized by late, treatment-emergent transformation from adenocarcinoma to high-grade neuroendocrine carcinoma (NEC), in 10–15% of mCRPC patients (pts). DLL3 is overexpressed in high-grade NECs, including NEPC, and minimally expressed on normal tissue. Tarlatamab, a bispecific T-cell engager immunotherapy with clinical activity in small cell lung cancer (SCLC), binds DLL3 and CD3 resulting in T-cell mediated tumor lysis. Here, we report primary analysis data of tarlatamab in NEPC (NCT04702737). Methods: This is an open-label phase 1b study evaluating tarlatamab monotherapy in adult (≥18 years [y]) pts with metastatic de novo or treatment-emergent NEPC by histologic, genomic, or immunohistochemistry (IHC) criteria. The starting dose was the highest safe and tolerable dose in the phase 1 SCLC trial (NCT03319940). Safety was the primary objective; anti-tumor activity and pharmacokinetics were secondary objectives. Exploratory analysis of DLL3 expression was assessed by IHC using the Ventana SP347 assay. Results: As of 28 March 2023, 40 pts received ≥1 tarlatamab dose (1 mg step dose, 100 mg target dose). Median (range) age was 64.5 (43–83) y, prior lines of therapy was 3 (1–9), prostate specific antigen at baseline was 0.2 (0.0–5000.0) μg/L. Treatment-related adverse events (TRAE) occurred in all patients, with no fatal TRAE. Most common TRAEs were cytokine-release syndrome (CRS; 65.0%), pyrexia (52.5%) and dysgeusia (42.5%). CRS occurred primarily in treatment cycle 1; events were mostly grade 1–2 (one grade 3 event). Treatment discontinuation due to TRAE was low (7.5%). Tarlatamab serum exposures were consistent with tarlatamab SCLC studies. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was 10.5% (95% CI, 2.9, 24.8); median progression free survival (mPFS) was 1.9 months (m) (95% CI, 1.7, 3.5). Retrospective DLL3 IHC analysis showed that 18 of 32 (56.3%) biopsy evaluable pts had ≥1% DLL3 tumor positivity (DLL3+). As of 24 January 2024, ORR in DLL3+ pts was 22.2% (95% CI, 6.4, 47.6); durations of response in the 4 pts with response were 25.8 m, 9.2 m, 5.5 m, 3.7 m; mPFS in DLL3+ pts was 3.75 m (95% CI, 1.87, 11.01). Efficacy is shown in Table. Conclusions: Findings from this phase 1 study of tarlatamab in pts with NEPC demonstrated manageable safety with encouraging anti-tumor activity in DLL3 expressing NEPC. Further investigation is ongoing. Clinical trial information: NCT04702737 . [Table: see text]

Biological thin-walled cellular structures, such as hierarchical structures of bone, exhibit unique internal structures that offer lightweight characteristics and high energy absorption capabilities. The compact bone shell can protect against local damage during high-impact events, while the porous cancellous bone is essential in absorbing energy. This research proposed five novel bioinspired cellular structures inspired by the well-arranged structure of femur bones. These structures comprise four distinct cell types: hexagonal honeycomb, re-entrant, hybrid, and hierarchical hybrid cells. A comprehensive numerical model, validated with experimental data, was employed to assess the performance of these structures under uniaxial compression. Some key characteristics were revealed, including peak elastic load, plateau load, energy absorption capacity, Poisson's ratio, and the effect of hierarchical cell size. The results demonstrated that the novel bioinspired structures surpassed the energy absorption performance of traditional designs, such as hexagonal design, re-entrant, and trabecular-bone-inspired structures. This enhanced performance was due to the progressive buckling and collapse mechanisms, showing promising implications for future engineering applications, particularly where energy absorption is of paramount importance.

<div>Abstract<p>Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased <i>in vivo</i> growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition.</p></div>

Abstract Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased in vivo growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition. We have recently initiated a clinical trial combining CX-5461 with talazoparib in mCRPC patients (REPAIR trial, NCT05425862) to explore this combination in both HR proficient and deficient settings. Citation Format: Mitchell G. Lawrence, Laura H. Porter, Nicholas Choo, Elaine Sanij, Renea Taylor, Richard Pearson, Kaylene J. Simpson, Ross D. Hannan, Shahneen Sandhu, Luc Furic. CX-5461 sensitizes DNA damage repair-proficient castrate-resistant prostate cancer to PARP inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR005.

Molten salts play an important role in the renewable energy transition, serving as a thermal storage medium for concentrated solar power. This study presents a numerical investigation into the thermal and mechanical performance of a steel tank, of commercial size and setup, for molten salt storage. A 2D axisymmetric sequential thermal-stress model is developed. Input parameters are validated from the data of the Solar Two and Andasol plants. Thermal-mechanical stress analysis is performed considering the yield criterion and directionality. A sensitivity analysis is performed for inventory level, thermal gradient, friction coefficient, inventory temperature, and foundation stiffness. The transient operating condition with cyclic thermal and mechanical loads is simulated. Elastic–plastic analysis is performed to predict the damage location and residual stress during an operation cycle. From the stress analysis, mechanical stress as high as 268 MPa develops at the tank floor edge, which reduces to 197 MPa with the salt thermal load. At the center, a maximum stress of 157 MPa is generated, but only due to thermal loads. The temperature gradient and higher friction between the tank floor and foundation exacerbate the stress levels. These stresses exceed the yield strength limit of steel. During a cyclic transient operation, radial stress of 260 MPa develops at the floor edge where the elastic–plastic damage occurs. Residual stress of 82 MPa and 35 MPa is generated in radial and circumferential directions. The floor deforms plastically every operation cycle and can eventually crack. This study offers a comprehensive analysis of the tank’s thermal-mechanical behavior and offers insights to mitigate potential failures and optimize design. • Developed and validated a thermal-stress model of a commercial-size molten salt tank. • Analyzed stress on the tank floor, considering the yield criterion and directionality. • Studied stress on the tank floor under varying physical and operational parameters. • Simulated the tank’s transient operating condition. • Predicted elastic–plastic damage location and residual stress during a cyclic operation.

<h3>Background</h3> BEMPEG is a pegylated interleukin-2 (IL-2) cytokine prodrug engineered to deliver a controlled and sustained IL-2 pathway stimulation, with the goal of preferentially expanding CD8+ T and natural killer (NK) cells over immunosuppressive regulatory T cells (Tregs) in the tumor microenvironment. In the phase 3 PIVOT IO-001 clinical trial (NCT03635983), BEMPEG+NIVO demonstrated no added clinical benefit over NIVO. This first disclosure of comprehensive biomarker analysis from a randomized controlled trial comparing a next-generation IL-2 agonist+NIVO with NIVO aims to gain mechanistic insights underlying the efficacy results. <h3>Methods</h3> Patients with previously untreated, unresectable, or metastatic melanoma were randomized 1:1 to receive BEMPEG 0.006 mg/kg+NIVO 360 mg IV Q3W or NIVO 360 mg IV Q3W. Longitudinal changes within Cycle 1 (C1) and 5 (C5) in CD4+ and CD8+ T, NK, and Treg (CD4+CD25+FOXP3+) cell counts, and proliferating (Ki67+) populations, were characterized in blood by flow cytometry. Changes in systemic cytokines, including interferon gamma (IFNγ), were also evaluated. Changes in% tumor cell PD-L1 expression,% CD8+ tumor-infiltrating lymphocytes (TILs), and% FOXP3+ cells from baseline to C1 Day 21 (C1D21) were assessed in tumor biopsies by immunohistochemistry. <h3>Results</h3> In peripheral blood, BEMPEG+NIVO mediated statistically significant increases in CD8+ and CD4+ T, NK, and Treg cell counts, as well as IFNγ levels, from baseline to day 8 of C1 and C5, with limited changes observed with NIVO. Compared with NIVO, BEMPEG+NIVO led to significant increases in proliferating Tregs and NK cells from baseline to D8 of C1 and C5. While significant increases in proliferating CD8+ and CD4+ T cells were observed in C1 and C5 following BEMPEG+NIVO, these effects were attenuated in C5. Systemic IFNγ increases, although significant, were attenuated in C5 with BEMPEG+NIVO. Changes in biomarkers measured in the tumor, including increases in CD8+ TILs, from baseline to C1D21 were similar between treatment arms. <h3>Conclusions</h3> Observations in peripheral blood demonstrated that, in comparison with limited changes with NIVO, BEMPEG+NIVO increased all immune cell subsets interrogated. Despite greater expansion of peripheral CD8+ T cells within C1 following BEMPEG+NIVO vs NIVO, there was no substantive difference in CD8+ TIL increase between the two arms, suggesting no synergistic/additive tumor activity for BEMPEG+NIVO over NIVO. These observations, together with attenuation of peripheral T-cell proliferation over time, potentially explain the lack of added clinical benefit for BEMPEG+NIVO vs NIVO in PIVOT IO-001. Results from this study should be taken into consideration and interrogated further as next-generation IL-2 agonists are developed. <h3>Acknowledgements</h3> The authors would like to thank the patients who participated in this trial and their families; the investigators, study coordinators, and study teams; and Lisa Panting and Yongliang Sun for their flow cytometry work. Editorial support was provided by Emily Motola, PharmD, of Spark Medica Inc. <h3>Trial Registration</h3> NCT03635983 <h3>Ethics Approval</h3> The trial protocols were approved by site institutional review boards or independent ethics committees and conducted according to Good Clinical Practice guidelines, per the International Conference on Harmonisation. Patients provided written informed consent based on Declaration of Helsinki principles. <h3>Consent</h3> Not applicable – no patient-identifiable data reported in this abstract

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.

Abstract INTRODUCTION: Response assessment of bone metastases (BM) remains a challenge for drug development in metastatic castration resistant prostate cancer (mCRPC) as standard imaging techniques, computed tomography and bone scintigraphy, fail to characterize BM. Diffusion-weighted imaging (DWI) is a functional MRI technique that studies the motion of water molecules within a tissue informing on cellularity. We hypothesized that changes in whole body (WB) DWI informs on BM response to treatment in mCRPC. METHODS: We conducted a phase II trial of the PARP inhibitor olaparib in mCRPC (TOPARP-A; CRUK/11/029); the primary endpoint was response rate defined using RECIST 1.1, PSA falls of ≥50% and conversion of circulating tumour cell (CTC) counts from ≥5 to &amp;lt;5. Optional WB-DWI in patients (pt) was performed prior to starting olaparib and after 12 weeks (w) of treatment on a 1.5 T MRI (Siemens Avanto). Images were analyzed with open-access imaging software (Osirix v5.6). Areas of DWI signal abnormality consistent with BM in the axial skeleton (C4 to mid-thigh) were delineated. We estimated disease volume and apparent diffusion coefficient (ADC), a parameter derived from DWI correlated with cellularity. BM volume and median ADC (mADC) changes between baseline and 12w were associated with binary response to treatment using Mann-Whitney tests and logistic regression; associations with best percentage PSA and CTC change after treatment were assessed using Spearman's correlation. RESULTS: Overall, 33/42 pt consented to the WB-DWI substudy of whom 21 had WB-DWI at baseline and at 12w. Of these 29% (6/21) were classified as responders to olaparib as per the primary endpoint definition and had not progressed prior to 12w. At baseline, median CTC count was 46 CTC/7.5ml blood and median PSA was 411 ng/ml for this cohort. When assessing all the areas of DWI signal abnormality, median volume of BM per patient was 445ml and mADC was 782 x10-6 mm2/s. Baseline CTC counts and PSA were significantly associated with volume of BM (ρ = 0.59, p = 0.005; ρ = 0.64, p = 0.002 respectively). All pts who responded to olaparib showed a decrease in volume of BM (median -41.1%, range -58.8%, -6.3%), whilst in non-responders a decrease was not observed in any pt (median 20.7%, range 0.0%, 76.9%); the difference between responders and non-responders was statistically significant (p = 0.001). Increases in mADC after 12 weeks of treatment were associated with increased odds of response (Odds Ratio: 1.08, 95% CI 1.00, 1.15, p = 0.04). Additionally, we detected a significant positive association between changes in volume of BM estimated by DWI and best percentage change in PSA and CTC (ρ = 0.63, p = 0.002 and ρ = 0.77, p&amp;lt;0.001 respectively). CONCLUSION: Decrease in volume and increase in mADC of BM assessed by WB-DWI are indicators of response to olaparib in BM from mCRPC. These data require validation but support the use of WB-DWI for assessing BM during treatment. Citation Format: Raquel Perez-Lopez, Matthew D. Blackledge, Helen Mossop, Joaquin Mateo, David Collins, Veronica A. Morgan, Alison McDonald, Shahneen Sandhu, Aurelius Omlin, Diletta Bianchini, Zafeiris Zafeiriou, Pasquale Rescigno, Michael Kolinsky, Daniel Nava Rodrigues, Penny Flohr, Berni Ebbs, Gemma Fowler, Nuria Porta, Emma Hall, Martin Leach, Johann S. de Bono, Dow-Mu Koh, Nina Tunariu. Diffusion-weighted imaging of bone metastases as treatment response biomarker in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3973.

&lt;p&gt;Tables S1-S8 and Figures S1-S4&lt;/p&gt;

We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL).HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible).HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, -0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics.Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.

Abstract Castration-resistant prostate cancer is a heterogeneous disease with variable phenotypes commonly observed in later stages of the disease. These include cases that retain expression of luminal markers and those that lose hormone dependence and acquire neuroendocrine features. While there are distinct transcriptomic and epigenomic differences between castration-resistant adenocarcinoma and neuroendocrine prostate cancer, the extent of overlap and degree of diversity across tumor metastases in individual patients has not been fully characterized. Here we perform combined DNA methylation, RNA-sequencing, H3K27ac, and H3K27me3 profiling across metastatic lesions from patients with CRPC/NEPC. Integrative analyses identify DNA methylation-driven gene links based on location (H3K27ac, H3K27me3, promoters, gene bodies) pointing to mechanisms underlying dysregulation of genes involved in tumor lineage (ASCL1, AR ) and therapeutic targets (PSMA, DLL3, STEAP1, B7-H3). Overall, these data highlight how integration of DNA methylation with RNA-sequencing and histone marks can inform intraindividual epigenetic heterogeneity and identify putative mechanisms driving transcriptional reprogramming in castration-resistant prostate cancer.