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The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry–based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. Significance: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.

Context Ductal adenocarcinoma (DAC) is relatively rare, but is nonetheless the second most common subtype of prostate cancer. First described in 1967, opinion is still divided regarding its biology, prognosis, and outcome. Objectives To systematically interrogate the literature to clarify the epidemiology, diagnosis, management, progression, and survival statistics of DAC. Materials and methods We conducted a literature search of five medical databases from inception to May 04 2020 according to PRISMA criteria using search terms “prostate ductal adenocarcinoma” OR “endometriod adenocarcinoma of prostate” and variations of each. Results Some 114 studies were eligible for inclusion, presenting 2 907 170 prostate cancer cases, of which 5911 were DAC. [Correction added on 16 January 2021 after the first online publication: the preceding statement has been corrected in this current version.] DAC accounts for 0.17% of prostate cancer on meta‐analysis (range 0.0837%‐13.4%). The majority of DAC cases were admixed with predominant acinar adenocarcinoma (AAC). Median Prostate Specific Antigen at diagnosis ranged from 4.2 to 9.6 ng/mL in the case series. DAC was more likely to present as T3 (RR1.71; 95%CI 1.53‐1.91) and T4 (RR7.56; 95%CI 5.19‐11.01) stages, with far higher likelihood of metastatic disease (RR4.62; 95%CI 3.84‐5.56; all P‐values < .0001), compared to AAC. Common first treatments included surgery (radical prostatectomy (RP) or cystoprostatectomy for select cases) or radiotherapy (RT) for localized disease, and hormonal or chemo‐therapy for metastatic disease. Few studies compared RP and RT modalities, and those that did present mixed findings, although cancer‐specific survival rates seem worse after RP. Biochemical recurrence rates were increased with DAC compared to AAC. Additionally, DAC metastasized to unusual sites, including penile and peritoneal metastases. Where compared, all studies reported worse survival for DAC compared to AAC. Conclusion When drawing conclusions about DAC it is important to note the heterogenous nature of the data. DAC is often diagnosed incidentally post‐treatment, perhaps due to lack of a single, universally applied histopathological definition. As such, DAC is likely underreported in clinical practice and the literature. Poorer prognosis and outcomes for DAC compared to AAC merit further research into genetic composition, evolution, diagnosis, and treatment of this surprisingly common prostate cancer sub‐type. Patient summary Ductal prostate cancer is a rare but important form of prostate cancer. This review demonstrates that it tends to be more serious at detection and more likely to spread to unusual parts of the body. Overall survival is worse with this type of prostate cancer and urologists need to be aware of the presence of ductal prostate cancer to alter management decisions and follow‐up.

Diagnosis of prostate cancer is based on histologic evaluation of tumor architecture using a system known as the “Gleason score.” This diagnostic paradigm, while the standard of care, is time-consuming, shows intraobserver variability, and provides no information about the altered metabolic pathways, which result in altered tissue architecture. Characterization of the molecular composition of prostate cancer and how it changes with respect to the Gleason score (GS) could enable a more objective and faster diagnosis. It may also aid in our understanding of disease onset and progression. In this work, we present mass spectrometry imaging for identification and mapping of lipids and metabolites in prostate tissue from patients with known prostate cancer with GS from 6 to 9. A gradient of changes in the intensity of various lipids was observed, which correlated with increasing GS. Interestingly, these changes were identified in both regions of high tumor cell density, and in regions of tissue that appeared histologically benign, possibly suggestive of precancerous metabolomic changes. A total of 31 lipids, including several phosphatidylcholines, phosphatidic acids, phosphatidylserines, phosphatidylinositols, and cardiolipins were detected with higher intensity in GS (4+3) compared with GS (3+4), suggesting they may be markers of prostate cancer aggression. Results obtained through mass spectrometry imaging studies were subsequently correlated with a fast, ambient mass spectrometry method for potential use as a clinical tool to support image-guided prostate biopsy. Implications: In this study, we suggest that metabolomic differences between prostate cancers with different Gleason scores can be detected by mass spectrometry imaging.

Prostate cancer (PCa) is the second leading cause of cancer-related death in the US. Androgen receptor (AR) signaling is the driver of both PCa development and progression and, thus, the major target of current in-use therapies. However, despite the survival benefit of second-generation inhibitors of AR signaling in the metastatic setting, resistance mechanisms inevitably occur. Thus, novel strategies are required to circumvent resistance occurrence and thereby to improve PCa survival. Among the key cellular processes that are regulated by androgens, metabolic reprogramming stands out because of its intricate links with cancer cell biology. In this review, we discuss how cancer metabolism and lipid metabolism in particular are regulated by androgens and contribute to the acquisition of resistance to endocrine therapy. We describe the interplay between genetic alterations, metabolic vulnerabilities and castration resistance. Since PCa cells adapt their metabolism to excess nutrient supply to promote cancer progression, we review our current knowledge on the association between diet/obesity and resistance to anti-androgen therapies. We briefly describe the metabolic symbiosis between PCa cells and tumor microenvironment and how this crosstalk might contribute to PCa progression. We discuss how tackling PCa metabolic vulnerabilities represents a potential approach of synthetic lethality to endocrine therapies. Finally, we describe how the continuous advances in analytical technologies and metabolic imaging have led to the identification of potential new prognostic and predictive biomarkers, and non-invasive approaches to monitor therapy response.

Significance Standard of care for metastatic castration-resistant prostate cancer (mCRPC) mainly relies on suppression of androgen receptor (AR) signaling. This approach has no lasting benefit due to the emergence of resistance mechanisms, such as ligand-independent splicing variant AR-V7. A metabolic feature of mCRPC is the upregulation of de novo lipogenesis to provide substrates and fuel for metastatic spread. Whether increased levels of fats affect AR signaling to promote an aggressive disease remains to be determined. Using a selective and potent inhibitor of fatty acid synthase we demonstrate that suppression of this key enzyme inhibits AR, most importantly AR-V7, and reduces mCRPC growth. Our findings offer a therapeutic opportunity for mCRPC and a potential mechanism to overcome resistance to AR inhibitors., A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119–mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7–driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal adult cancers with an average 5-year survival rate of less than 10% due in part to the limited number of effective therapies. Activation of TRAILR2 (Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand Receptor 2) has emerged as an important therapeutic concept in cancer treatment. Traditional TRAILR2 agonists have had limited clinical success due to lack of efficacy or, importantly, severe hepatotoxicity. Here we present anti-tumor activity in preclinical PDAC models for BI 905711, a first-in-class tetravalent bispecific antibody specifically designed to overcome the disadvantages of previous strategies targeting TRAILR2. BI 905711 serves as a uniquely specific, and liver-sparing therapeutic by targeting tumors that co-express TRAILR2 and another cell surface protein CDH17, which has ~40% prevalence in PDAC and is not expressed in normal liver. Working from a large cohort of molecularly characterized PDAC PDX models, we provide the first preclinical evidence of BI 905711 exhibiting robust anti-tumor activity in difficult to treat PDAC PDX models. Anti-tumor efficacy in responding models correlated with strong induction of Caspases 3/7 and 8 activation in tumors 24 hours after a single dose of BI 905711, and was associated with the presence and expression levels of TRAILR2 and CDH17 proteins. Evaluation of models with differential TRAILR2 and CDH17 expression profiles helped define the expression threshold for each target that is associated with response, upon which clinical assay development is in process for future patient stratification. Additionally, response was also associated with PDAC molecular subtypes utilizing a novel proprietary gene co-expression network developed from a curated cohort of PDAC PDX tumors. Responders to BI 905711 were identified primarily within the classical and quasi-basal/hybrid subtypes when TRAILR2 was adequately co-expressed. This correlates with an enrichment pattern of CDH17 gene expression that is mostly within the classical gene cluster and strongly anti-correlated with basal-like cluster enrichment. Robust preclinical anti-tumor activity of BI 905711 in TRAILR2 and CDH17-expressing PDAC PDX models, along with this antibody's potential for a favorable safety profile, has justified the enrollment of pancreatic cancer patients in the ongoing BI 905711 FIH Phase I clinical trial (NCT04137289). Citation Format: Jing Han, Annette A. Machado, Mikhila Mahendra, Joseph R. Daniele, Christopher A. Bristow, Justin Kwang-Lay Huang, Alessandro Carugo, Robert A. Mullinax, Benjamin J. Bivona, Ningping Feng, Poojabahen Gandhi, Norbert Schweifer, Paolo Maria Chetta, Juan Manuel Garcia-Martinez, Frank Hilberg, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek. BI 905711 selectively induces apoptosis and anti-tumor response in TRAILR2/CDH17- expressing pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 985.

Introduction: Stimulator of interferon genes (STING) is activated by cyclic dinucleotides that are generated by cyclic GMP-AMP synthase in the presence of cytosolic DNA, resulting in a type 1 interferon response and the secretion of pro-inflammatory cytokines. BI-STING mimics the natural ligand of STING and hijacks the STING signaling pathway to trigger a potent anti-tumor immune response. Here we report the pre-clinical characterization of BI-STING in human cells lines in vitro, in human ex vivo systems and in vivo mouse models. Methods: Activity and specificity of BI-STING were tested in vitro in the human monocytic leukemia cell line THP1. Target engagement was confirmed using ex vivo studies in human whole blood and in human precision cut colorectal cancer slices. For in vivo studies, BI-STING was administered intratumorally (i.tu.) in a range of subcutaneous, syngeneic murine tumor models. The modulation of cytokine secretion over time was recorded and the induction of a tumor-specific immune response demonstrated. Results: Using THP1 cells, activation of down-stream signaling events by BI-STING was seen specifically in STING wild type, but not STING knock out cells. Ex vivo treatment of human whole blood and human precision cut colorectal cancer slices with BI-STING resulted in the significant induction of cytokine secretion (including IFNβ) and in an array of transcriptional changes associated with the activation of STING signaling. Treatment of tumor-bearing mice with a single dose of BI-STING i.tu. led to a transient increase of cytokine levels in tumor and plasma. In all tested models, i.tu. administration of BI-STING resulted in dose-dependent local tumor control. Importantly, animals whose primary tumor was cured by BI-STING treatment did not develop tumors when re-challenged with the same tumor cell line and an abscopal delay in tumor growth was seen for non-injected (or anenestic) lesions in mice carrying bilateral tumors. Abscopal tumor control was further improved when combined with anti-PD-1. Finally, ELISpot analysis resulted in a significantly increased number of immunospots in splenocytes from BI-STING treated animals as compared to vehicle control mice, confirming the induction of a tumor-specific immune response. Conclusions: BI-STING is a potent and specific inducer of the STING signaling pathway. In addition to local tumor control, i.tu. treatment with BI-STING results in a systemic anti-tumor immune response in mice, which was enhanced upon anti-PD-1 combination. A clinical trial to evaluate i.tu. administration of BI-STING alone and in combination with anti-PD-1 in patients with advanced solid tumors is ongoing. Citation Format: Gabriela Gremel, Maria A. Impagnatiello, Sebastian Carotta, Otmar Schaaf, Paolo M. Chetta, Thorsten Oost, Thomas Zichner, Marco Hofmann, Sophia Blake, Tom Bretschneider, Martin Fleck, Achim Grube, Herbert Nar, Georg Rast, Esther Schmidt, Ute Klinkhardt, Kirsten Arndt-Schmitz, Thorsten Laux, Vittoria Zinzalla, Jonathon Sedgwick, Norbert Kraut. Potent induction of a tumor-specific immune response by a cyclic dinucleotide STING agonist [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4522.

The control region of TMPRSS2 fuses with ETS transcription factor family members, particularly ERG. This occurs in ~20-50% of human prostate cancers depending on the ethnicity. TMPRSS2-ERG (T2E) fusions, however, do not display a notable phenotype in genetically engineered mouse models (GEMM) recapitulating the fusion expression and T2E also has no prognostic significance in humans, despite its high incidence. Wnt signaling has been implicated in prostate cancer. Here, we report a discovery of a role for T2E fusion that impacts the prostate stroma in pre-clinical models. The composition of stromal cells within the microenvironment in T2E mice was studied by single cell RNAseq analysis. We identified stromal cell clusters in T2E mice that differed from wild type mice in the expression of Pdgfrβ, Pdgfrα and Col1a1. Interestingly, these clusters showed an increase of expression of Wnt receptors such as Lgr5 and Fzd7 as well as Wnt ligands such as Sfrp2, Wnt2 and Wnt6. T2E GEMMs also exhibited upregulation of the Wnt-secretion regulator porcupine (PORCN-Protein-serine O-palmitoleoyltransferase) in the stroma adjacent to the T2E-expression prostate epithelial cells. Furthermore, lineage-tracing with the Wnt reporter and epithelial stem cell marker Lgr5 showed that Wnt-active cells were increased in prostatic intraepithelial neoplasia (PIN) lesions in T2E;Pten+/- mice. Strikingly, Lgr5+ cells were also found in the prostate stroma surrounding these PINs. Since, TMPRSS2/ERG fusions represent an early event in prostate tumorigenesis, here we provide a mechanism whereby induction of Wnt signaling in the stroma by T2E-expressing prostate epithelial cells increases the stem cell compartments in both epithelial and stromal cells. These data suggest that aberrant ERG-expressing prostate epithelial cells activate upregulation of Wnt signaling in stromal cells, which provides a possible route for enhancing prostate carcinogenesis. Citation Format: Hubert Pakula, Caroline F. Ribeiro, Giuseppe N. Fanelli, Rory Kirchner, Sudeepa Syamala, Basudev Chowdhury, Giorgia Zadra, Paolo Chetta, Zhe Li, Massimo Loda. The role of TMPRSS2_ERG fusions in modulating tumor microenvironment in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2748.