Prostate Tumor Growth Research Articles (Page 1)

Addressing prostate cancer, particularly in its aggressive forms, poses challenges that call for innovative treatment modalities. Our research focuses on developing a nanotechnological solution to enhance targeted cancer therapy. We have synthesized advanced nanocapsules embedded with indocyanine green (ICG) and conjugated with the Anti-hPSMAEC domain to improve specificity towards prostate cancer cells. These nanocapsules are engineered to perform dual-mode phototherapy through photothermal and photodynamic mechanisms. In vitro experiments demonstrated the nanocapsules effectively target and induce apoptosis in prostate cancer cells upon exposure to near-infrared light. Furthermore, in vivo assessments in murine models revealed excellent tumor localization and a substantial reduction in tumor volume with minimal impact on healthy tissues. This innovative approach underscores the potential of nanotechnology to transform the therapeutic landscape of prostate cancer by achieving precise targeting and reducing systemic side effects. Such nanocapsule systems' continued development and refinement may substantially improve clinical outcomes and provide promising therapeutic strategies for treating complex cancers.

Commonly used in cancer therapy, topoisomerase II (TOP2) poisons are designed to stabilize the normally transient DNA TOP2 cleavage complexes in chromatin, leading to deleterious DNA double-strand breaks. TOP2 poisons are often associated with significant side effects, highlighting the need to identify strategies aimed at improving the efficacy of TOP2 poisons in order to lower the required dosage. Here, we demonstrated that inhibiting histone H4-lysine 20 (H4K20) methyltransferases SUV4-20H1 and SUV4-20H2 induced synthetic lethality in combination with the TOP2 poison etoposide in prostate cancer. Remarkably, the loss of the SUV4-20H enzymes, which prevents the conversion of H4K20 mono-methylation to higher methylation states, increased replication fork velocity without impacting prostate cancer cell behavior. However, these apparently innocuous epigenetic changes significantly enhanced the trapping of TOP2 complexes in chromatin and increased DNA damage in response to etoposide. Furthermore, SUV4-20H depletion and the subsequent changes in H4K20 methylation impaired the repair of TOP2-induced DNA breaks by disrupting BRCA1-mediated homologous recombination processes, ultimately leading to extensive cancer cell death and significant inhibition of prostate tumor growth in vivo. Overall, these findings demonstrate that targeting the epigenetic activity of SUV4-20H is a powerful strategy to enhance the efficacy of TOP2 poisons and may represent a therapeutic alternative in prostate cancer, where SUV4-20H2 expression emerges as a potential marker of aggressive disease and high metastatic risk.

Metastasis is the main cause of prostate cancer-associated deaths, highlighting the urgent need to determine the mechanisms underlying prostate cancer progression. TROP2 (also known as TACSTD2) is an oncogenic transmembrane surface protein that is highly expressed in metastatic prostate cancer. Naturally occurring cleavage of TROP2 leads to a release of the TROP2 extracellular domain (TECD) into the extracellular environment. In this study, we identified an important functional role of TECD in prostate cancer metastasis. TECD was detectable in media from prostate cancer cells and serum from patients with clinically significant prostate cancer. While shed TECD did not affect prostate cancer cell proliferation and tumor growth, it increased cell migration and invasion in vitro and promoted metastatic colonization and spontaneous metastasis in vivo. TECD interactome and proteomic studies revealed that TECD binds to EGFR and that shed TECD modulates a set of proteins associated with invasion, migration, mTOR signaling, and epithelial-to-mesenchymal transition. Furthermore, elevated shed TECD increased EGFR phosphorylation, resulting in activation of the EGFR-PI3K-AKT-mTOR pathway in prostate cancer. EGFR inhibitors suppressed the invasive ability of prostate cancer cells driven by TECD overexpression, further supporting the key role of EGFR in TECD-mediated prostate cancer progression. This study uncovers a function of TECD in driving prostate cancer progression and provides mechanistic insights into TECD signaling through EGFR.

Elucidating the correlation between polychlorinated dibenzo-p-dioxins and prostate cancer progression: Insights from gene expression and molecular docking.

LncRNA HANR promotes the aerobic glycolysis in prostate cancer by stabilizing TPI1.

Prostate cancer is one of the malignancies affecting men and contributes significantly to their increased mortality rates. Understanding the molecular mechanisms underlying the initiation and progression of prostate cancer is important for identifying potential drug targets. Here we showed that metalloproteinase TLL1 was positively associated with prostate cancer aggressiveness. Mechanistically, TLL1 promoted prostate cancer cells migration and metastasis through cleaving latent TGF-β1 to activate TGF-β signaling pathway. Moreover, LINC01179 interacted with Miz1 to attenuate TLL1 expression and LINC01179 impaired prostate cancer cell proliferation and migration ability by suppressing TLL1 expression to deactivate TGF-β signaling activity. Meanwhile, we observed that TLL1 increased the expression of PD-L1 by activating TGF-β signaling pathway and TLL1 depletion enhanced the antitumor efficacy by anti-PD-1 antibody via augmenting the infiltration proportions of CD8+ T cells in tumors. In addition, T cell-specific overexpression of TLL1 disrupted T cell development in the thymus. TLL1 overexpression in T cells accelerated RM-1 prostate tumor growth in mice by decreasing the infiltration of CD8+ T cells into tumors. Collectively, our results revealed that TLL1 may be a potential therapeutic target to alter prostate cancer progression.

Abstract Prostate cancer (PCa) is the most common cancer and a leading cause of cancer-related deaths among men globally, including in Singapore. The incidence of PCa has been increasing worldwide due to lifestyle changes, though there is a significant disparity in the incidence-to-mortality ratio between developed and developing countries, largely because of the advanced theragnostic approaches utilized in developed regions. While conventional treatments are effective for localized and metastatic PCa, treatment outcomes for metastatic castration-resistant prostate cancer (mCRPC), a more aggressive form of the disease, remain poor with current therapies failing to significantly extend survival. Hence, in the current study we investigated the potential role of artesunate (ART), a semisynthetic derivative of the malaria drug artemisinin in PCa cell lines. Interestingly, the ART found to inhibit the cell growth, invasion, migration, stemness and trigger the expression of apoptosis and autophagy-related proteins in PCa cell lines. In particular, ART inhibited the expression of Wnt/β-catenin pathway proteins responsible for the progression of prostate cancer to mCRPC. Moreover, inhibiting the ART induced autophagy resulted in the survival of the PCa cells to a greater extent. Furthermore, the ART treatment in a preclinical model of prostate cancer exhibited a significant reduction of prostate tumor growth along with the inhibition of lung and liver metastasis. Overall, our findings suggest that ART may activate a powerful antitumor mechanism, offering a new therapeutic approach for treating mCRPC. Citation Format: Chandra Sekhar Bhol, Muthu Kumaraswamy Shanmugam, Grace Chew, Goh Si Rui Eva, Sujit Kumar Bhutia, Gautam Sethi. Harnessing Antineoplastic Properties of Artesunate for Prostate Cancer Therapy [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P47.

Prostate cancer is the second leading cause of cancer-related deaths in men worldwide, with bone metastasis being the predominant driver of morbidity and mortality in advanced stages. This underscores the urgent need for innovative therapeutic strategies to address skeletal metastasis and improve patient outcomes. Niclosamide, a long-standing anthelminthic drug, has emerged as a promising multipathway modulator against cancer hallmarks. Here, we propose a nanotechnology-enabled repurposing of niclosamide, hypothesizing that its formulation into smart, targeted nanohybrids could not only suppress prostate tumor growth but also inhibit its dissemination to the skeletal system. We discuss the molecular rationale, design considerations, and translational outlook for nanoengineered niclosamide in the context of metastatic prostate cancer.

The long non-coding RNA PVT1 reportedly forms a circular RNA variant (circPVT1). As circPVT1 is expressed in various cancers and has been implicated in promoting cancer cell proliferation and tumor progression, it is considered a potential biomarker and therapeutic target. We previously confirmed that circPVT1 expression varies according to the Gleason pattern, a morphological indicator of malignancy in prostate cancer. In this study, we assessed the expression of circPVT1 using BaseScopeTM assay with prostate cancer tissues and evaluated the correlation with the Grade Group (based on Gleason pattern), an indicator used to morphologically evaluate the degree of malignancy of prostate cancer. The relationship between circPVT1 expression and tumor proliferation was evaluated using cells in which circPVT1 expression was suppressed using the clustered regularly interspaced short palindromic repeats (CRISPR)/RfxCas13d system. BaseScopeTM assay confirmed that circPVT1 expression was significantly higher in Grade Group 2–5 (intermediate- and high-grade groups) than Grade Group 1 (low-grade group). In vitro experiments using the CRISPR/RfxCas13d system showed that specific suppression of circPVT1 expression resulted in a significant reduction in the number of prostate cancer cells. The results of this study suggest that circPVT1 is involved in tumor growth in prostate cancer and may serve as a therapeutic target for moderately and highly malignant prostate cancers that express circPVT1.

Abstract Prostate cancer is the second most commonly diagnosed cancer in men, with 1 in 8 men being diagnosed with prostate cancer in his lifetime. AR is a hormone-activated transcription factor that promotes cell growth and survival in the normal prostate, and AR signaling is a key driver of cell proliferation in prostate cancer. Inhibition of AR signaling is a mainstay of current prostate cancer treatment, however, patients often develop resistance to these therapies through mechanisms that retain dependency on AR signaling. GDC-2992 (also known as RO7656594) is a potent, orally bioavailable, heterobifunctional molecule that inhibits AR signaling by binding to both AR and the E3 ubiquitin ligase cereblon (CRBN), resulting in ubiquitination and subsequent degradation of AR. GDC-2992 inhibits AR signaling in the context of wild-type AR and AR proteins with mutations associated with resistance to standard-of-care AR signaling inhibitors (ARSIs). Unlike ARSIs, GDC-2992 does not display evidence of agonism against any AR variants evaluated. Co-treatment of GDC-2992 with the CRBN ligand pomalidomide prevents AR degradation mediated by GDC-2992 in vitro, supporting the role of CRBN in GDC-2992-mediated AR degradation. Importantly however, anti-proliferative potential of GDC-2992 is maintained even when degradation is attenuated, suggesting that the mechanism of GDC-2992 includes competitive AR antagonism in addition to degradation. In vivo, GDC-2992 decreases circulating PSA and inhibits prostate tumor growth in a dose responsive manner. The totality of in vitro and in vivo preclinical data supports that GDC-2992 represents a compelling advance over standard-of-care ARSIs. An ongoing Phase I dose-escalation and expansion study will assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of GDC-2992 in patients with advanced or metastatic prostate cancer who have previously received AR-targeted therapy [NCT05800665]. By providing more complete and sustained AR inhibition, GDC-2992 has the potential to reduce the occurrence of treatment-resistance and disease relapse in prostate cancer. Citation Format: Ciara Metcalfe, Wei Zhou, Darlene Dela Cruz, Thomas Hunsaker, Pablo Saenz-Lopez Larrocha, Elizabeth Levy, Bu-Er Wang, Tonia Hafner, Nayan Chaudhary, Marc Hafner, Kalpit Shah, Elisia Villemure, Yuxiang Zheng, Jodie Pang, Udi Segal. GDC-2992: A heterobifunctional Androgen Receptor (AR) antagonist and degrader for the treatment of AR wild-type and mutant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND02.

An unmet clinical need requires the discovery of new treatments for men facing advanced prostate cancer. Aberrant glycosylation is a universal feature of cancer cells and plays a key role in tumour growth, immune evasion and metastasis. Alterations in tumour glycosylation are closely associated with prostate cancer progression, making glycans promising therapeutic targets. Fucosyltransferase 8 (FUT8) drives core fucosylation by adding α1,6-fucose to the innermost GlcNAc residue on N-glycans. While FUT8 is recognised as a crucial factor in cancer progression, its role in prostate cancer remains poorly understood. Here, we demonstrate using multiple independent clinical cohorts that FUT8 is upregulated in high grade and metastatic prostate tumours, and in the blood of prostate cancer patients with aggressive disease. Using novel tools, including PhosL lectin immunofluorescence and N-glycan MALDI mass spectrometry imaging (MALDI-MSI), we find FUT8 underpins the biosynthesis of malignant core fucosylated N-glycans in prostate cancer cells and using both invitro and invivo models, we find FUT8 promotes prostate tumour growth, cell motility and invasion. Mechanistically we show FUT8 regulates the expression of genes and signalling pathways linked to prostate cancer progression. Furthermore, we find that fucosylation inhibitors can inhibit the activity of FUT8 in prostate cancer to suppress the growth of prostate tumours. Our study cements FUT8-mediated core fucosylation as an important driver of prostate cancer progression and suggests targeting FUT8 activity for prostate cancer therapy as an exciting area to explore.

Abstract UNC45A is a key co-chaperone supporting cancer cell proliferation and tumorigenesis. Interestingly, UNC45A is essential for cancer cells but not for normal cell proliferation. However, the mechanism underlying UNC45A regulatory function is not well studied. We have previously shown that UNC45A functions as a glucocorticoid receptor (GR) co-activator to drive the mitotic kinase NEK7 gene transcription. NEK7 is essential for centrosome separation, mitotic spindle formation, and cytokinesis. GR has been implicated in promoting aggressive prostate tumor growth and resistance to therapy. Indeed, GR upregulation is an established mechanism to bypass the androgen receptor blockade therapy in metastatic-resistant prostate tumors. Here, we tested the hypothesis that UNC45A promotes GR-mediated resistance to hormonal therapy. To this end, we used shRNA-mediated gene silencing to evaluate the impact of UNC45A loss on PC3 prostate tumor progression. Our results show that silencing UNC45A reduces cell proliferation in vitro and tumor growth in vivo. TUNEL analysis and Ki67 staining show that loss of UNC45A triggers DNA damage, reduced cell proliferation, and apoptosis in PC3 tumors grown in the NOD SCID mice model. Immunofluorescence analysis shows a remarkable disorganization of centrosomes in tumor cells expressing UNC45A shRNA. The importance of UNC45A in promoting enzalutamide resistance is being tested in tridimensional spheroid culture and in vivo and will be discussed in this meeting. Overall, our results support the hypothesis that UNC45A is a promising cancer therapeutic target and highlight the need for developing UNC45A small molecule inhibitors to treat aggressive diseases such as prostate and breast cancers. Citation Format: Taoufik LLBIYI, Asif Elahi, Digvijay Singh, Nada Eisa, Yasmeen Jilani, Ahmed Chadli. The HSP90 Co-chaperone UNC45A is essential for prostate cancer cell proliferation in vitro and tumor growth in vivo [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 1386.

Abstract Background: Prostate cancer, despite advancements in early detection and therapies, remains an incurable disease when it transform to metastatic and castration-resistant. A significant knowledge gap exists in understanding the mechanistic insights that drives hormone-refractory progression and metastasis. The PI3-Kinase pathway, altered in over >50 % of metastatic prostate cancer cases, plays a pivotal role in oncogenesis and therapy resistant. Although PTEN deletions are well-characterized, the specific contributions of other PI3K pathway components, particularly PIK3R1 mutations, remain underexplored. Our previous study reported that PIK3R1 mutations are highly enriched in metastatic castration-resistant prostate cancer (mCRPC) and are associated with increased glucose uptake detected by FDG-PET scans. Therefore, these mutations are crucial for further investigation. Method: We generated 22 patients derived naturally occurring prostate cancer specific PIK3R1 mutations by site directed mutagenesis and verified their expression by western blotting. Using CRISPR and shRNA we have also established double PIK3R1-PTEN null prostate cancer cells. Prostasphere experiments was performed to analyzed the impact of these double loss on prostate cell growth in vitro Isogenic pairs of these double-knockout prostate cancer cells were treated with increasing concentrations of insulin in the under serum starvation to study the impact of PIK3R1-PTEN loss on reprogramming of insulin-glucose metabolism and oncogenic signaling pathways associated with this reprogramming Results: Our results reveal that PIK3R1 mutations exhibit distinct, mutation-specific effects on PI3K-AKT signaling, where some variants induce AKT phosphorylation and destabilize PTEN, while others inhibit AKT and stabilize PTEN, underscoring diverse roles of specific PIK3r1 mutation within the PI3K pathway. Interestingly, PIK3R1-KO cells displayed heightened androgen receptor (AR) pathway activity and enhanced tumor sphere formation, suggesting increased tumorigenic potential. Furthermore elevated levels phosphorylated mTOR in PIK3R1 knockout clones indicate potential mechanisms of oncogenesis, which may further drive metastatic progression. Our primary data also demonstrated that insulin treatment in PIK3R1-PTEN null cells alters androgen receptor (AR) function, indicating a direct association between PIK3R1-PTEN-glucose metabolisms and AR-signaling that is crucial for prostate tumor growth. Conclusion: Our findings emphasize the critical role of PIK3R1 in both AR and PI3K-AKT-mTOR signaling cascades, offering insights into the complex interplay of PIK3R1 mutations in therapy-resistant prostate cancer. This research underscores the need to explore mutation-specific PIK3R1 effects as we move toward more personalized therapies for lethal mCRPC. Citation Format: Prathiksha Prabhakaraalva, Nabila Zaman, Sarah Ann King, Goutam Chakraborty. Revealing the influence of reprogrammed PI3K and glucose metabolism on the progression of hormone-refractory and metastatic prostate cancer [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 5401.

Abstract Enhanced cholesterol synthesis and storage in lipid droplets are strongly associated with cancer aggressiveness, particularly in lipid-rich and hormone-sensitive cancers such as prostate cancer. While tumor cells tightly regulate cholesterol anabolism and catabolism in response to nutrient states, the mechanisms that sense nutrient status and drive these processes remain poorly understood. Emerging evidence highlights mitochondria as key hubs of signal transduction, with mitochondrial metabolites serving as pivotal signaling molecules. Our prior work identified that the propionate metabolism pathway is remodeled during metastasis, with metabolites from this pathway acting as signaling regulators. Notably, patient data reveal that elevated propionyl-carnitine levels in prostate tumor tissues correlate with increased tumor aggressiveness. To investigate the role of propionyl-CoA in prostate cancer progression, we manipulated its levels in prostate cancer cells and assessed its effects on proliferation, colonization, and lipid metabolism both in vitro and in vivo. We discovered that mitochondrial metabolism of branched-chain amino acids (BCAAs), specifically isoleucine and valine, is a major source of cellular propionyl-CoA. This metabolite drives the propionylation of sterol regulatory element-binding protein 2 (SREBP2), promoting cholesterol synthesis and storage. The accumulated cholesterol fuels steroidogenesis, facilitating prostate tumor growth, colonization, and therapeutic resistance. Our findings establish a direct link between amino acid metabolism and cholesterol anabolism, unveiling a novel mechanism of cholesterol regulation in prostate cancer progression. This study highlights the therapeutic potential of targeting propionyl-CoA production, particularly through the metabolism of isoleucine and valine, to disrupt cholesterol synthesis and combat prostate cancer progression. Citation Format: Zhongchi Li, Shuchen Liu, Olivia Kester, Wenbing Jin, Un In Chan, Zhucui Li, Nayah Bullen, John Blenis. Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism [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 3802.

Abstract UNC45A is a key co-chaperone supporting cancer cell proliferation and tumorigenesis. Interestingly, UNC45A is essential for cancer cells but not for normal cell proliferation. However, the mechanism underlying UNC45A regulatory function is not well studied. We have previously shown that UNC45A functions as a glucocorticoid receptor (GR) co-activator to drive the mitotic kinase NEK7 gene transcription. NEK7 is essential for centrosome separation, mitotic spindle formation, and cytokinesis. GR has been implicated in promoting aggressive prostate tumor growth and resistance to therapy. Indeed, GR upregulation is an established mechanism to bypass the androgen receptor blockade therapy in metastatic-resistant prostate tumors. Here, we tested the hypothesis that UNC45A promotes GR-mediated resistance to hormonal therapy. To this end, we used shRNA-mediated gene silencing to evaluate the impact of UNC45A loss on PC3 prostate tumor progression. Our results show that silencing UNC45A reduces cell proliferation in vitro and tumor growth in vivo. TUNEL analysis and Ki67 staining show that loss of UNC45A triggers DNA damage, reduced cell proliferation, and apoptosis in PC3 tumors grown in the NOD SCID mice model. Immunofluorescence analysis shows a remarkable disorganization of centrosomes in tumor cells expressing UNC45A shRNA. The importance of UNC45A in promoting enzalutamide resistance is being tested in tridimensional spheroid culture and in vivo and will be discussed in this meeting. Overall, our results support the hypothesis that UNC45A is a promising cancer therapeutic target and highlight the need for developing UNC45A small molecule inhibitors to treat aggressive diseases such as prostate and breast cancers. Citation Format: Asif Elahi, Taoufik Llbiyi, Vamsi Krishna Kommalapati, Yasmeen Jilani, Ahmed Chadli. The role of the Co-chaperone UNC45A in breast and prostate cancer [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 6720.

The androgen receptor (AR) is a member of the nuclear hormone receptor superfamily and a key driver of prostate tumor growth. Several androgen receptor pathway inhibitors (ARPIs) have been developed and approved for the treatment of locally advanced and metastatic prostate cancer, including the androgen synthesis inhibitor, abiraterone and the AR antagonists, enzalutamide, apalutamide and darolutamide. Despite initial success resistance does occur, often involving alterations in the receptor itself, such as AR amplification or point mutations in the ligand binding domain (LBD). Therefore, there remains an urgent need to develop alternative strategies to target the AR. Here we describe the characterization of AZD9750, a novel AR PROTAC that potently degrades AR (DC50 in LNCaP cells = 9.9nM) and shows good cross species oral bioavailability. In a panel of prostate cancer (PC) cells expressing different altered forms of the receptor, AZD9750 was shown to degrade wild type, amplified and LBD mutant AR. The reduced AR levels were confirmed to be a consequence of increased AR degradation with AZD9750 reducing the half-life of AR from 4.9 to 1.0 hr in LNCaP and from 4.6 to 0.4 hr in VCAP PC cells. Degradation was also shown to be mediated via a PROTAC mechanism that required CRBN binding and proteasomal activity. Additionally, AZD9750 decreased AR-regulated gene expression and inhibited the proliferation of AR-dependent PC cell lines with GI50s in the low nM range, which represents a 10-fold increase in potency compared to enzalutamide in the same cell lines. In vivo, in the C901 patient derived xenograft (PDX) model, AZD9750 caused a dose-dependent reduction in tumor AR levels with oral doses of 3, 10 and 30 mg/kg giving a statistically significant reduction of 72, 88 and 95%, respectively. Consistent with this, the mRNA expression of a panel of AR-regulated genes was also decreased. Anti-tumor efficacy studies demonstrated that AZD9750 reduced tumor growth and in some cases caused tumor regression in a range of AR positive PDX models that represent both hormone-sensitive and castration-resistant prostate cancer. The anti-tumor effect was dose-dependent and accompanied by reduced AR levels and AR-regulated gene expression, consistent with the observed efficacy being driven by AR degradation and inhibition of AR signaling. Furthermore, in several models, the efficacy achieved with AZD9750 was superior to the efficacy achieved with a clinical exposure matched dose of enzalutamide. These data confirm that AZD9750 is a potent oral degrader of AR that leads to anti-tumor efficacy in a range of hormone-sensitive and castrate-resistant PDX models. Through degradation of AR, including mutant and amplified forms of the receptor, it has the potential to overcome key resistance mechanisms arising to current standard of care therapies and provide benefit to patients with prostate cancer. Citation Format: Claire Crafter, Antonio Ramos-Montoya, Chrysiis Michaloglou, Ziyanda Shologu, Nuria Galeano-Dalmau, Gemma Hardman Fowler, Ana Quiroga, Pablo Morentin-Gutierrez, Andy Pike, Laura Evans, James S. Scott, Michael Niedbala. AZD9750, a novel androgen receptor proteolysis targeting chimera (AR-PROTAC) for the treatment of prostate cancer [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 4758.

RNA therapeutics offer a promising approach to cancer treatment by precisely regulating cancer-related genes. While lipid nanoparticles (LNPs) are currently the most advanced nonviral clinically approved vectors for RNA therapeutics, their antitumor efficacy is limited by their unspecific hepatic accumulation after systemic administration. Thus, there is an urgent need to enhance the delivery efficiency of LNPs to target tumor-residing tissues. Here, we conjugated the cluster of differentiation 44 (CD44)-specific targeting peptide A6 (KPSSPPEE) to the cholesterol of LNPs via PEG, named AKPC-LNP, enabling specific tumor delivery. This modification significantly improved delivery to breast cancer cells both in vitro and in vivo, as shown by flow cytometry and confocal microscopy. We further used AKPC-siYT to codeliver siRNAs targeting the transcriptional coactivators YAP and TAZ, achieving potent gene silencing and increased cell death in both 2D cultures and 3D tumor spheroids, outperforming unmodified LNPs. In a breast tumor cell xenografted zebrafish model, systemically administered AKPC-siYT induced robust silencing of YAP/TAZ and downstream genes and significantly enhanced tumor suppression compared to unmodified LNPs. Additionally, AKPC-siYT effectively reduced proliferation in prostate cancer organoids and tumor growth in a patient-derived xenograft (PDX) model. Overall, we developed highly efficient AKPC-LNPs carrying RNA therapeutics for targeted cancer therapy.

Cancer-associated fibroblasts are increasingly recognized to have a high impact on prostate tumor growth and drug resistance. Here, we bioengineered organotypic prostate cancer 3D in vitro models to better understand tumor-stroma interplay, the metabolomic profile underlying such interactions, and their impact on standard-of-care therapeutics performance. The assembly of robust and uniform spheroids was evaluated and compared in monotypic PC-3 and heterotypic microtumors comprised of either a healthy or malignant stroma and prostate cancer cells. Our findings demonstrate that the precise inclusion of prostate cancer stromal elements is crucial to generating robust PC-3 prostate cancer spheroids with reproducible morphology and size. The inclusion of cancer-associated fibroblasts promoted the establishment of more compact microtumors exhibiting characteristic expression of major proteins. Exometabolomic profile analysis also highlighted the impact of stromal cells on tumor models metabolism. The optimized heterotypic spheroidswere additionally exploited for screening standard-of-care therapeutics, exhibiting a higher resistance when compared to their monotypic counterparts. Our findings demonstrate that including stromal elements in PC-3 prostate cancer models is crucial for their use as increasingly organotypic testing platforms, being relevant for screening candidate anti-cancer therapeutics and for the discovery of potential combinations with emerging anti-stroma therapies.

IRAK2 overexpression restrains prostate cancer progression by regulation of TRAF6 ubiquitination.

Prostate cancer (PCa) is a major world-wide health concern. Current diagnostic methods involve Prostate-Specific Antigen (PSA) blood tests, biopsies, and Magnetic Resonance Imaging (MRI) to assess cancer aggressiveness and guide treatment decisions. MRI aligns with in silico medicine, as patient-specific image biomarkers can be obtained, contributing towards the development of digital twins for clinical practice. This work presents a novel framework to create a personalized PCa model by integrating clinical MRI data, such as the prostate and tumour geometry, the initial distribution of cells and the vasculature, so a full representation of the whole prostate is obtained. On top of the personalized model construction, our approach simulates and predicts temporal tumour growth in the prostate through the Finite Element Method, coupling the dynamics of tumour growth and the transport of oxygen, and incorporating cellular processes such as proliferation, differentiation, and apoptosis. In addition, our approach includes the simulation of the PSA dynamics, which allows to evaluate tumour growth through the PSA patient's levels. To obtain the model parameters, a multi-objective optimization process is performed to adjust the best parameters for two patients simultaneously. This framework is validated by means of data from four patients with several MRI follow-ups. The diagnosis MRI allows the model creation and initialization, while subsequent MRI-based data provide additional information to validate computational predictions. The model predicts prostate and tumour volumes growth, along with serum PSA levels. This work represents a preliminary step towards the creation of digital twins for PCa patients, providing personalized insights into tumour growth.