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Journal articles on the topic 'Neuroendocrine transdifferentiation'

Author: Grafiati

Published: 21 September 2024

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1

Sergeant, Camille, Christel Jublanc, Delphine Leclercq, Anne-Laure Boch, Franck Bielle, Gerald Raverot, Adrian F. Daly, Jacqueline Trouillas, and Chiara Villa. "Transdifferentiation of Neuroendocrine Cells." American Journal of Surgical Pathology 41, no. 6 (June 2017): 849–53. http://dx.doi.org/10.1097/pas.0000000000000803.

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2

Stone, Louise. "A novel mechanism of neuroendocrine transdifferentiation." Nature Reviews Urology 15, no. 5 (March 20, 2018): 263. http://dx.doi.org/10.1038/nrurol.2018.40.

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3

Cordeiro-Rudnisky, Fernanda, Yue Sun, and Rayan Saade. "Prostate Carcinoma With Overlapping Features of Small Cell and Acinar Adenocarcinoma: A Case Report." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S66—S67. http://dx.doi.org/10.1093/ajcp/aqz113.072.

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Abstract Introduction Prostate neuroendocrine (NE) cells can stimulate prostate adenocarcinoma (PA) cell growth, but occasionally adenocarcinoma cells themselves acquire NE characteristics, a phenomenon known as NE transdifferentiation of prostate adenocarcinoma. During this process, tumor cells acquire small cell-like morphology and become positive for neuroendocrine markers. NE transdifferentiation is associated with decreased androgen receptor (AR) signaling, a mechanism of resistance to AR-targeted treatments. Case A 74-year-old male with a history of cirrhosis, splenomegaly, and thrombocytopenia presented with hematuria and urinary obstruction. PSA was 0.31 ng/mL. CT scan demonstrated bladder wall thickening. Surgery showed a bladder tumor, clinically diagnosed as urothelial tumor. Pathology revealed a poorly differentiated carcinoma, with small cell-like morphology. The tumor cells had high nuclear to cytoplasmic ratio, focal nuclear molding, and high mitotic rate, like small cell carcinoma. But the nucleoli were intermediate between small cell carcinoma and usual adenocarcinoma of the prostate. Immunostains showed that the tumor cells were positive for NKX3.1 and focally positive for NE markers, including chromogranin, synaptophysin, INSM1, and FOXA2. The tumor cells were negative for PSA and GATA3. The morphology and immunoprofile are consistent with Gleason pattern 5 PA in transdifferentiation to small cell carcinoma. Discussion The incidence of neuroendocrine phenotype is 1% in primary PA and 25% in metastatic castrate-resistant PA. Typically, NE transdifferentiation occurs in response to androgen deprivation therapy/AR inhibitors. Pretreatment NE transdifferentiation is relatively uncommon. PA depends on androgens for its progression, which is the basis for antiandrogen therapy. Decreased AR expression associated with NE transdifferentiation is a mechanism of resistance to AR-targeted therapy. These tumors are often more aggressive with worse prognosis. Conclusion Our patient has Gleason pattern 5 PA with NE transdifferentiation invading the bladder, which is a high-grade, aggressive tumor.

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4

Quintanal-Villalonga, Alvaro, Hirokazu Taniguchi, Yingqian A. Zhan, Jacklynn V. Egger, Umesh Bhanot, Juan Qiu, Elisa de Stanchina, et al. "AKT inhibition as a therapeutic strategy to constrain histological transdifferentiation in EGFR-mutant lung adenocarcinoma." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21166-e21166. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21166.

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e21166 Background: In lung adenocarcinomas (LUADs), lineage plasticity drives neuroendocrine (NE) and squamous cell (LUSC) transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is remarkably lower than those of LUAD or de novo LUSC patients. The paucity of transforming clinical specimens amenable for molecular analyses has hindered the identification of histological transformation drivers, and to date no specific therapies aimed to prevent or delay transdifferentiation-led therapy relapse are available for patients at high risk of transformation. Methods: We performed multi-omic profiling of LUAD-to-LUSC and LUAD-to-NE transdifferentiating clinical samples, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Clinical findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Results: Our data supports that histological transdifferentiation from LUAD to LUSC or NE tumors is driven by epigenetic remodeling rather than by mutational events, and indicate that transdifferentiated tumors retain epigenomic features of their previous LUAD state. Integrative epigenomic, transcriptomic and protein analysis revealed divergent biological pathways dysregulated for each histological outcome, such as downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses identified commonly dysregulated pathways in both NE- and LUSC-transdifferentiating tumors, including remarkable downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in different EGFR-mutant patient-derived xenograft transdifferentiation models. Conclusions: These results identify common and divergent dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation.

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5

Yuan, Ta-Chun, Suresh Veeramani, and Ming-Fong Lin. "Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells." Endocrine-Related Cancer 14, no. 3 (September 2007): 531–47. http://dx.doi.org/10.1677/erc-07-0061.

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Neuroendocrine (NE) cells represent a minor cell population in the epithelial compartment of normal prostate glands and may play a role in regulating the growth and differentiation of normal prostate epithelia. In prostate tumor lesions, the population of NE-like cells, i.e., cells exhibiting NE phenotypes and expressing NE markers, is increased that correlates with tumor progression, poor prognosis, and the androgen-independent state. However, the origin of those NE-like cells in prostate cancer (PCa) lesions and the underlying molecular mechanism of enrichment remain an enigma. In this review, we focus on discussing the distinction between NE-like PCa and normal NE cells, the potential origin of NE-like PCa cells, and in vitro and in vivo studies related to the molecular mechanism of NE transdifferentiation of PCa cells. The data together suggest that PCa cells undergo a transdifferentiation process to become NE-like cells, which acquire the NE phenotype and express NE markers. Thus, we propose that those NE-like cells in PCa lesions were originated from cancerous epithelial cells, but not from normal NE cells, and should be defined as ‘NE-like PCa cells’. We further describe the biochemical properties of newly established, stable NE-like lymph node carcinoma of the prostate (LNCaP) cell lines, transdifferentiated from androgen-sensitive LNCaP cells under androgen-deprived conditions. Knowledge of understanding NE-like PCa cells will help us to explore new therapeutic strategies for treating PCa.

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6

Von Amsberg, Gunhild, Sergey Dyshlovoy, Jessica Hauschild, Verena Sailer, Sven Perner, Anne Offermann, Lina Merkens, et al. "Long-term taxane exposure and transdifferentiation of prostate cancer in vitro." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 254. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.254.

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254 Background: Development of aggressive variants of metastatic castration-resistant prostate cancer (AVPC) is a major challenge in the course of therapy but the underlying mechanisms of aggressive transdifferentiation are not completely understood and appropriate tumor models are missing. Here, we investigated the consequences of long-term taxane exposure on hormone-independent, BRCA2-mutated, AR-V7-positive 22Rv1 cells. Methods: 22Rv1 cells were treated with stepwise increased taxane concentrations for 10 months. Individual clones were picked and further cultured in media containing either docetaxel (Doce) or cabazitaxel (Caba). Passage-matched cells were maintained in culture without treatment. Further characterization was carried out using proliferation, migration, metabolic, and colony formation assays as well as proteomics, RNAseq analyses and xenotransplantation in immunodeficient mice. Results: In total, three single cell 22Rv1-DR clones (50-100-fold resistance to Doce) and three 22Rv1-CR clones (80-150-fold resistance to Caba) were successfully established. All clones showed cross-resistance to either drug. Expectedly, treatment-induced overexpression of ABCB1 was detected and validated. Moreover, alteration of drug resistance related SLC7A5, SLC3A2, and SLC25A24 genes was observed. Additionally, an enrichment analyses identified, among others, neuroendocrine transdifferentiation (GO-term “Neuroendocrine tumors”, p=4.46e-5) to be stimulated in prostate 22Rv1 cells under long-term treatment with Doce or Caba. In line with this, the neuroendocrine features were validated in vitro as well as in xenotransplanted tumors in vivo with upregulation of synaptophysin, chromogranin and neuron specific enolase accompanied by downregulation of the androgen receptor (AR) and upregulation of AR spice variants. Additionally, neuritic morphology, shift to higher nuclear-plasma ratio, partial loss of adherent properties and growth slowdown, along with higher migratory activity were detected. Conclusions: Long-term taxane exposure of 22Rv1 cells resulted in the development of neuroendocrine traits in individual cell clones that have successfully been translated into stable cell lines. Thus, we provide a new cell line model for secondary therapy-induced neuroendocrine transdifferentiation. Further in-depth analysis to identify individual alterations in the course of therapy is currently ongoing.

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7

Quintanal-Villalonga, Alvaro, Hirokazu Taniguchi, Yingqian A. Zhan, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, et al. "Abstract 658: AKT pathway as a therapeutic target to constrain lineage plasticity leading to histological transdifferentiation." Cancer Research 82, no. 12_Supplement (June 15, 2022): 658. http://dx.doi.org/10.1158/1538-7445.am2022-658.

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Abstract Lineage plasticity contributes to therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon drives neuroendocrine (NE) and squamous cell (LUSC) histologic transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is lower than that of either LUAD or de novo LUSC patients. To date, little is known about the molecular effectors enhancing lineage plasticity and driving histological transdifferentiation due to the paucity of well annotated pre- and post-transdifferentiation clinical samples amenable for molecular analyses. Currently no specific therapies for LUSC or NE transdifferentiation prevention are available for patients at high risk of transformation. We performed multi-omic profiling of transdifferentiating clinical samples, as well as control never-transformed LUAD and de novo LUSC and small cell carcinomas, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Our data suggest that histological transdifferentiation is driven by epigenetic -rather than mutational- events, and indicate that transdifferentiated tumors retain molecular features of their previous LUAD state. Integrative analysis revealed biological pathways dysregulated specifically for distinct histological outcomes, including downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses revealed commonly dysregulated pathways for transdifferentiated tumors, including marked downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in EGFR-mutant patient-derived xenograft transdifferentiation models. These results identify common and histology-specific drivers and dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to constrain lineage plasticity and prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation. Citation Format: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yingqian A. Zhan, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, Umesh K. Bhanot, Jacklynn Egger, Juan Qiu, Elisa de Stanchina, Natasha Rekhtman, Brian Houck-Loomis, Richard P. Koche, Helena A. Yu, Triparna Sen, Charles M. Rudin. AKT pathway as a therapeutic target to constrain lineage plasticity leading to histological transdifferentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 658.

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8

Frigo, Daniel E., and Donald P. McDonnell. "Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation." Molecular Cancer Therapeutics 7, no. 3 (March 2008): 659–69. http://dx.doi.org/10.1158/1535-7163.mct-07-0480.

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9

Patel, Girijesh, Sayanika Dutta, Mosharaf Mahmud Syed, Sabarish Ramachandran, Monica Sharma, Venkatesh Rajamanickam, Vadivel Ganapathy, et al. "TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p." Cancers 13, no. 19 (October 7, 2021): 5020. http://dx.doi.org/10.3390/cancers13195020.

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Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype.

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10

Turner, Leo, Andrew Burbanks, and Marianna Cerasuolo. "Mathematical insights into neuroendocrine transdifferentiation of human prostate cancer cells." Nonlinear Analysis: Modelling and Control 26, no. 5 (September 1, 2021): 884–913. http://dx.doi.org/10.15388/namc.2021.26.24441.

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Prostate cancer represents the second most common cancer diagnosed in men and the fifth most common cause of death from cancer worldwide. In this paper, we consider a nonlinear mathematical model exploring the role of neuroendocrine transdifferentiation in human prostate cancer cell dynamics. Sufficient conditions are given for both the biological relevance of the model’s solutions and for the existence of its equilibria. By means of a suitable Liapunov functional the global asymptotic stability of the tumour-free equilibrium is proven, and through the use of sensitivity and bifurcation analyses we identify the parameters responsible for the occurrence of Hopf and saddle-node bifurcations. Numerical simulations are provided highlighting the behaviour discovered, and the results are discussed together with possible improvements to the model.

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11

Cerasuolo, Marianna, Debora Paris, Fabio A. Iannotti, Dominique Melck, Roberta Verde, Enrico Mazzarella, Andrea Motta, and Alessia Ligresti. "Neuroendocrine Transdifferentiation in Human Prostate Cancer Cells: An Integrated Approach." Cancer Research 75, no. 15 (June 11, 2015): 2975–86. http://dx.doi.org/10.1158/0008-5472.can-14-3830.

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12

Zhu, Shimiao, Hao Tian, Xiaodan Niu, Jiang Wang, Xing Li, Ning Jiang, Simeng Wen, et al. "Neurotensin and its receptors mediate neuroendocrine transdifferentiation in prostate cancer." Oncogene 38, no. 24 (February 15, 2019): 4875–84. http://dx.doi.org/10.1038/s41388-019-0750-5.

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13

Zamora, Irene, Michael R. Freeman, Ignacio J. Encío, and Mirja Rotinen. "Targeting Key Players of Neuroendocrine Differentiation in Prostate Cancer." International Journal of Molecular Sciences 24, no. 18 (September 5, 2023): 13673. http://dx.doi.org/10.3390/ijms241813673.

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Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to the development of novel therapeutic approaches that may enhance the clinical management and prognosis of this lethal disease. In the present review, we discuss molecular players involved in the neuroendocrine phenotype, and we explore therapeutic strategies that are currently under investigation for NEPC.

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Zhu, Shimiao, Hao Tian, Xiaodan Niu, Jiang Wang, Xing Li, Ning Jiang, Simeng Wen, et al. "Correction: Neurotensin and its receptors mediate neuroendocrine transdifferentiation in prostate cancer." Oncogene 38, no. 24 (May 2, 2019): 4885. http://dx.doi.org/10.1038/s41388-019-0827-1.

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15

Wright, Michael E., Ming-Jer Tsai, and Ruedi Aebersold. "Androgen Receptor Represses the Neuroendocrine Transdifferentiation Process in Prostate Cancer Cells." Molecular Endocrinology 17, no. 9 (September 2003): 1726–37. http://dx.doi.org/10.1210/me.2003-0031.

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Azur, Romie Angelo G., Kevin Christian V. Olarte, Weand S. Ybañez, Alessandria Maeve M. Ocampo, and Pia D. Bagamasbad. "CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer." PLOS ONE 19, no. 5 (May 13, 2024): e0300413. http://dx.doi.org/10.1371/journal.pone.0300413.

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Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found that CYB561 expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown of CYB561 in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways.

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Slabáková, Eva, Zuzana Kahounová, Jiřina Procházková, and Karel Souček. "Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs." Non-Coding RNA 7, no. 4 (December 2, 2021): 75. http://dx.doi.org/10.3390/ncrna7040075.

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Neuroendocrine prostate cancer (NEPC) represents a variant of prostate cancer that occurs in response to treatment resistance or, to a much lesser extent, de novo. Unravelling the molecular mechanisms behind transdifferentiation of cancer cells to neuroendocrine-like cancer cells is essential for development of new treatment opportunities. This review focuses on summarizing the role of small molecules, predominantly microRNAs, in this phenomenon. A published literature search was performed to identify microRNAs, which are reported and experimentally validated to modulate neuroendocrine markers and/or regulators and to affect the complex neuroendocrine phenotype. Next, available patients’ expression datasets were surveyed to identify deregulated microRNAs, and their effect on NEPC and prostate cancer progression is summarized. Finally, possibilities of miRNA detection and quantification in body fluids of prostate cancer patients and their possible use as liquid biopsy in prostate cancer monitoring are discussed. All the addressed clinical and experimental contexts point to an association of NEPC with upregulation of miR-375 and downregulation of miR-34a and miR-19b-3p. Together, this review provides an overview of different roles of non-coding RNAs in the emergence of neuroendocrine prostate cancer.

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Gopal, Priyanka, and Mohamed Abazeed. "Abstract 5830: A first-of-its-kind model that reconstitutes targeted drug-induced cellular transdifferentiation." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5830. http://dx.doi.org/10.1158/1538-7445.am2024-5830.

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Abstract Introduction: Lung tumors treated with targeted therapies ultimately relapse due to intra-genic resistance mutations, bypass pathway activation, or cellular lineage changes. Newer precision therapies have higher selectivity and potency against both resistant and activating gene mutations, resulting in a significant increase in incidence of cellular transdifferentiation. The most common form of transdifferentiation is the change from lung adenocarcinomas (LUADs) to small cell lung cancer (t-SCLC) upon drug treatment which remains very poorly understood. Methods: We have combined patient derived xenografts (PDX) and ex vivo lines with multi-omic characterization, high-content image-based morphometry and fluorescence tracking, and single-cell barcode tracing to better understand the process of lung tumor transdifferentiation. Results: We have developed a first-of-its-kind t-SCLC model that reconstitutes ex vivo LUAD to SCLC transdifferentiation. Genomic and transcriptomic analyses of our NSCLC PDX collection identified tumors with mutation in TP53 and RB1, two genes that are altered in virtually all de novo SCLCs. PDX sample CBX336 was identified as having mutations in both TP53 and RB1, in addition to expressing the KRASG12C oncogene. Upon treatment with Sotorasib, CBX336 tumors initially demonstrated slow tumor growth, followed by a dramatic increase in the growth after prolonged drug exposure. Our experimental and computational data suggest a highly coordinated procession toward transdifferentiation with the parallel upregulation of the neuroendocrine transcription factor NEUROD1 across numerous epithelial cellular clones. Conclusions: Our new experimental system allows characterization at the single-cell level. Ongoing work includes the integration of new resources to study lineage reprogramming, and advancing new therapeutic strategies. Citation Format: Priyanka Gopal, Mohamed Abazeed. A first-of-its-kind model that reconstitutes targeted drug-induced cellular transdifferentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5830.

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Marzioni, Marco, Stefania Saccomanno, Cinzia Candelaresi, Chiara Rychlicki, Laura Agostinelli, Kumar Shanmukhappa, Luciano Trozzi, Irene Pierantonelli, Samuele De Minicis, and Antonio Benedetti. "Pancreatic Duodenal Homeobox-1 de novo expression drives cholangiocyte neuroendocrine-like transdifferentiation." Journal of Hepatology 53, no. 4 (October 2010): 663–70. http://dx.doi.org/10.1016/j.jhep.2010.04.022.

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20

Zelivianski, Stanislav, Michael Verni, Carissa Moore, Dmitriy Kondrikov, Rodney Taylor, and Ming-Fong Lin. "Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1539, no. 1-2 (May 2001): 28–43. http://dx.doi.org/10.1016/s0167-4889(01)00087-8.

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21

Li, Yinan, Nilgun Donmez, Cenk Sahinalp, Ning Xie, Yuwei Wang, Hui Xue, Fan Mo, et al. "SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway Inhibition." European Urology 71, no. 1 (January 2017): 68–78. http://dx.doi.org/10.1016/j.eururo.2016.04.028.

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22

Clermont, Pier-Luc, Xinpei Ci, Hardev Pandha, Yuzhuo Wang, and Francesco Crea. "Treatment-emergent neuroendocrine prostate cancer: molecularly driven clinical guidelines." International Journal of Endocrine Oncology 6, no. 2 (September 1, 2019): IJE20. http://dx.doi.org/10.2217/ije-2019-0008.

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An increasingly recognized mechanism of prostate cancer resistance is the transdifferentiation from adenocarcinoma to treatment-emergent neuroendocrine prostate cancer (t-NEPC), an extremely aggressive malignancy. The incidence of t-NEPC has been increasing in recent years, in part due to novel treatments that target the androgen receptor pathway. While clinicians historically had very few options for t-NEPC detection and treatment, recent research has uncovered key diagnostic tools and therapeutic targets that can be translated into improved patient care. In this article, we will outline the clinical features of t-NEPC and its molecular pathogenesis. Importantly, we will also discuss recently uncovered molecularly based strategies aimed at improving the diagnosis and treatment of t-NEPC. Finally, we will propose a unified algorithm that integrates clinical and molecular information for the clinical management of t-NEPC.

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23

Ci, Xinpei, Jun Hao, Xin Dong, Hui Xue, Rebecca Wu, Stephen Yiu Chuen Choi, Anne M. Haegert, et al. "Conditionally Reprogrammed Cells from Patient-Derived Xenograft to Model Neuroendocrine Prostate Cancer Development." Cells 9, no. 6 (June 4, 2020): 1398. http://dx.doi.org/10.3390/cells9061398.

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Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. It develops mainly via NE transdifferentiation of prostate adenocarcinoma in response to androgen receptor (AR)-inhibition therapy. The study of NEPC development has been hampered by a lack of clinically relevant models. We previously established a unique and first-in-field patient-derived xenograft (PDX) model of adenocarcinoma (LTL331)-to-NEPC (LTL331R) transdifferentiation. In this study, we applied conditional reprogramming (CR) culture to establish a LTL331 PDX-derived cancer cell line named LTL331_CR_Cell. These cells retain the same genomic mutations as the LTL331 parental tumor. They can be continuously propagated in vitro and can be genetically manipulated. Androgen deprivation treatment on LTL331_CR_Cells had no effect on cell proliferation. Transcriptomic analyses comparing the LTL331_CR_Cell to its parental tumor revealed a profound downregulation of the androgen response pathway and an upregulation of stem and basal cell marker genes. The transcriptome of LTL331_CR_Cells partially resembles that of post-castrated LTL331 xenografts in mice. Notably, when grafted under the renal capsules of male NOD/SCID mice, LTL331_CR_Cells spontaneously gave rise to NEPC tumors. This is evidenced by the histological expression of the NE marker CD56 and the loss of adenocarcinoma markers such as PSA. Transcriptomic analyses of the newly developed NEPC tumors further demonstrate marked enrichment of NEPC signature genes and loss of AR signaling genes. This study provides a novel research tool derived from a unique PDX model. It allows for the investigation of mechanisms underlying NEPC development by enabling gene manipulations ex vivo and subsequent functional evaluations in vivo.

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Ostano, Paola, Maurizia Mello-Grand, Debora Sesia, Ilaria Gregnanin, Caterina Peraldo-Neia, Francesca Guana, Elena Jachetti, Antonella Farsetti, and Giovanna Chiorino. "Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma." International Journal of Molecular Sciences 21, no. 3 (February 6, 2020): 1078. http://dx.doi.org/10.3390/ijms21031078.

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Neuroendocrine prostate cancer (NEPC) can arise de novo, but much more commonly occurs as a consequence of a selective pressure from androgen deprivation therapy or androgen receptor antagonists used for prostate cancer (PCa) treatment. The process is known as neuroendocrine transdifferentiation. There is little molecular characterization of NEPCs and consequently there is no standard treatment for this kind of tumors, characterized by highly metastases rates and poor survival. For this purpose, we profiled 54 PCa samples with more than 10-years follow-up for gene and miRNA expression. We divided samples into two groups (NE-like vs. AdenoPCa), according to their clinical and molecular features. NE-like tumors were characterized by a neuroendocrine fingerprint made of known neuroendocrine markers and novel molecules, including long non-coding RNAs and components of the estrogen receptor signaling. A gene expression signature able to predict NEPC was built and tested on independently published datasets. This study identified molecular features (protein-coding, long non-coding, and microRNAs), at the time of surgery, that may anticipate the NE transformation process of prostate adenocarcinoma. Our results may contribute to improving the diagnosis and treatment of this subgroup of tumors for which traditional therapy regimens do not show beneficial effects.

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25

Fernandes, Rayzel C., John Toubia, Scott Townley, Adrienne R. Hanson, B. Kate Dredge, Katherine A. Pillman, Andrew G. Bert, et al. "Post-transcriptional Gene Regulation by MicroRNA-194 Promotes Neuroendocrine Transdifferentiation in Prostate Cancer." Cell Reports 34, no. 1 (January 2021): 108585. http://dx.doi.org/10.1016/j.celrep.2020.108585.

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Yao, Erica, Chuwen Lin, Qingzhe Wu, Kuan Zhang, Hai Song, and Pao-Tien Chuang. "Notch Signaling Controls Transdifferentiation of Pulmonary Neuroendocrine Cells in Response to Lung Injury." STEM CELLS 36, no. 3 (December 1, 2017): 377–91. http://dx.doi.org/10.1002/stem.2744.

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Pisani, David, Daniel Micallef, Jeanesse Scerri, Alexandra Betts, James Degaetano, and Shawn Baldacchino. "Neuroendocrine Transdifferentiation in Cutaneous Melanoma: A Case Report and Review of the Literature." American Journal of Dermatopathology 45, no. 4 (February 17, 2023): 264–68. http://dx.doi.org/10.1097/dad.0000000000002377.

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Moritz, Tom, Simone Venz, Heike Junker, Sarah Kreuz, Reinhard Walther, and Uwe Zimmermann. "Isoform 1 of TPD52 (PC-1) promotes neuroendocrine transdifferentiation in prostate cancer cells." Tumor Biology 37, no. 8 (February 5, 2016): 10435–46. http://dx.doi.org/10.1007/s13277-016-4925-1.

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Zhu, Shimiao, Zhiqun Shang, Hao Tian, Amilcar Flores-Morales, and Yuanjie Niu. "AB007. Neurotensin derived from cancer stroma contributes to castration resistance via promoting neuroendocrine transdifferentiation." Translational Andrology and Urology 5, S1 (April 2016): AB007. http://dx.doi.org/10.21037/tau.2016.s007.

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Mendieta, Irasema, Maricela Rodríguez-Nieto, Rosa Elvira Nuñez-Anita, Jorge Luis Menchaca-Arredondo, Guadalupe García-Alcocer, and Laura Cristina Berumen. "Ultrastructural changes associated to the neuroendocrine transdifferentiation of the lung adenocarcinoma cell line A549." Acta Histochemica 123, no. 8 (December 2021): 151797. http://dx.doi.org/10.1016/j.acthis.2021.151797.

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OELRICH, FELIX, HEIKE JUNKER, MATTHIAS B. STOPE, HOLGER H. H. ERB, REINHARD WALTHER, SIMONE VENZ, and UWE ZIMMERMANN. "Gelsolin Governs the Neuroendocrine Transdifferentiation of Prostate Cancer Cells and Suppresses the Apoptotic Machinery." Anticancer Research 41, no. 8 (July 19, 2021): 3717–29. http://dx.doi.org/10.21873/anticanres.15163.

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Turner, Leo, Andrew Burbanks, and Marianna Cerasuolo. "PCa dynamics with neuroendocrine differentiation and distributed delay." Mathematical Biosciences and Engineering 18, no. 6 (2021): 8577–602. http://dx.doi.org/10.3934/mbe.2021425.

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<abstract><p>Prostate cancer is the fifth most common cause of death from cancer, and the second most common diagnosed cancer in men. In the last few years many mathematical models have been proposed to describe the dynamics of prostate cancer under treatment. So far one of the major challenges has been the development of mathematical models that would represent <italic>in vivo</italic> conditions and therefore be suitable for clinical applications, while being mathematically treatable. In this paper, we take a step in this direction, by proposing a nonlinear distributed-delay dynamical system that explores neuroendocrine transdifferentiation in human prostate cancer <italic>in vivo</italic>. Sufficient conditions for the existence and the stability of a tumour-present equilibrium are given, and the occurrence of a Hopf bifurcation is proven for a uniform delay distribution. Numerical simulations are provided to explore differences in behaviour for uniform and exponential delay distributions. The results suggest that the choice of the delay distribution is key in defining the dynamics of the system and in determining the conditions for the onset of oscillations following a switch in the stability of the tumour-present equilibrium.</p></abstract>

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Dankert, Jaroslaw Thomas, Marc Wiesehöfer, Elena Dilara Czyrnik, Bernhard B. Singer, Nicola von Ostau, and Gunther Wennemuth. "The deregulation of miR-17/CCND1 axis during neuroendocrine transdifferentiation of LNCaP prostate cancer cells." PLOS ONE 13, no. 7 (July 12, 2018): e0200472. http://dx.doi.org/10.1371/journal.pone.0200472.

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34

Angelucci, A., P. Muzi, G. Pace, L. Cristiano, A. M. Cimini, M. P. Ceru, C. Vicentini, and M. Bologna. "513 NEUROENDOCRINE TRANSDIFFERENTIATION INDUCED BY HDAC INHIBITORS CONFERS RESISTANCE TO ANTIBLASTIC THERAPY IN PROSTATE CARCINOMA." European Urology Supplements 8, no. 4 (March 2009): 249. http://dx.doi.org/10.1016/s1569-9056(09)60509-1.

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BURCHARDT, TATJANA, MARTIN BURCHARDT, MIN-WEI CHEN, YICHEN CAO, ALEXANDRE DE LA TAILLE, AHMED SHABSIGH, OMAR HAYEK, THAMBI DORAI, and RALPH BUTTYAN. "TRANSDIFFERENTIATION OF PROSTATE CANCER CELLS TO A NEUROENDOCRINE CELL PHENOTYPE IN VITRO AND IN VIVO." Journal of Urology 162, no. 5 (November 1999): 1800–1805. http://dx.doi.org/10.1016/s0022-5347(05)68241-9.

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Braadland, Peder R., Håkon Ramberg, Helene Hartvedt Grytli, Alfonso Urbanucci, Heidi Kristin Nielsen, Ingrid Jenny Guldvik, Andreas Engedal, et al. "The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells." Molecular Cancer Research 17, no. 11 (August 8, 2019): 2154–68. http://dx.doi.org/10.1158/1541-7786.mcr-18-0605.

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Kim, Soojin, Daksh Thaper, Samir Bidnur, Paul Toren, Shusuke Akamatsu, Jennifer L. Bishop, Colin Colins, Sepideh Vahid, and Amina Zoubeidi. "PEG10 is associated with treatment-induced neuroendocrine prostate cancer." Journal of Molecular Endocrinology 63, no. 1 (July 2019): 39–49. http://dx.doi.org/10.1530/jme-18-0226.

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Neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy is becoming increasingly recognized. Several models of this transdifferentiation provide insight into its molecular pathogenesis and have highlighted the placental gene PEG10 for further study. Using our unique model of enzalutamide resistance (ENZR) and NE differentiation, we studied PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42DENZR and 42FENZR compared to LNCaP and castration-resistant 16DCRPC cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16DCRPC. Antagonism of AR activity increased PEG10 expression followed by an increase in terminal NE markers. Conversely, stimulating AR activity via androgen supplementation reversed PEG10 and NE marker expression in a time and dose-dependent manner. These results were supported by human data showing that PEG10 expression is highest in NEPC and that AR-dependent gene, PSA, is negatively correlated with PEG10 in adenocarcinoma. Further, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression. While PEG10 did not drive NEPC, its knockdown reduced NE markers in our cell lines. Moreover, PEG10 knockdown in vitro- and in vivo-attenuated tumor growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates NE markers in ENZR cells and targeting PEG10 in advanced prostate cancer with NE features is a rational and viable option.

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Inoue, Y., and W. Lockwood. "MA22.02 Activation of MAPK Suppresses Neuroendocrine Transcription Factors and Causes Transdifferentiation of Small Cell Lung Cancer." Journal of Thoracic Oncology 13, no. 10 (October 2018): S433—S434. http://dx.doi.org/10.1016/j.jtho.2018.08.502.

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Pernicová, Zuzana, Eva Slabáková, Radek Fedr, Šárka Šimečková, Josef Jaroš, Tereza Suchánková, Jan Bouchal, et al. "The role of high cell density in the promotion of neuroendocrine transdifferentiation of prostate cancer cells." Molecular Cancer 13, no. 1 (2014): 113. http://dx.doi.org/10.1186/1476-4598-13-113.

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Shen, Ruoqian, Thambi Dorai, Matthias Szaboles, Aaron E. Katz, Carl A. Olsson, and Ralph Buttyan. "Transdifferentiation of cultured human prostate cancer cells to a neuroendocrine cell phenotype in a hormone-depleted medium." Urologic Oncology: Seminars and Original Investigations 3, no. 2 (March 1997): 67–75. http://dx.doi.org/10.1016/s1078-1439(97)00039-2.

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41

Indo, Sebastián, Octavio Orellana-Serradell, María José Torres, Enrique A. Castellón, and Héctor R. Contreras. "Overexpression of REST Represses the Epithelial–Mesenchymal Transition Process and Decreases the Aggressiveness of Prostate Cancer Cells." International Journal of Molecular Sciences 25, no. 6 (March 15, 2024): 3332. http://dx.doi.org/10.3390/ijms25063332.

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The RE-1 silencing transcription factor (REST) is a repressor factor related to neuroendocrine prostate cancer (PCa) (NEPC), a poor prognostic stage mainly associated with castration-resistant PCa (CRPC). NEPC is associated with cell transdifferentiation and the epithelial–mesenchymal transition (EMT) in cells undergoing androgen deprivation therapy (ADT) and enzalutamide (ENZ). The effect of REST overexpression in the 22rv1 cell line (xenograft-derived prostate cancer) on EMT, migration, invasion, and the viability for ENZ was evaluated. EMT genes, Twist and Zeb1, and the androgen receptor (AR) were evaluated through an RT-qPCR and Western blot in nuclear and cytosolic fractions of REST-overexpressing 22rv1 cells (22rv1-REST). The migratory and invasive capacities of 22rv1-REST cells were evaluated via Transwell® assays with and without Matrigel, respectively, and their viability for enzalutamide via MTT assays. The 22rv1-REST cells showed decreased nuclear levels of Twist, Zeb1, and AR, and a decreased migration and invasion and a lower viability for ENZ compared to the control. Results were expressed as the mean + SD of three independent experiments (Mann–Whitney U test, Kruskal–Wallis, Tukey test). REST behaves like a tumor suppressor, decreasing the aggressiveness of 22rv1 cells, probably through the repression of EMT and the neuroendocrine phenotype. Furthermore, REST could represent a response marker to ENZ in PCa patients.

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Zhao, Kaihong. "Attractor of a nonlinear hybrid reaction–diffusion model of neuroendocrine transdifferentiation of human prostate cancer cells with time-lags." AIMS Mathematics 8, no. 6 (2023): 14426–48. http://dx.doi.org/10.3934/math.2023737.

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<abstract><p>Prostate cancer is a serious disease that endangers men's health. The genetic mechanism and treatment of prostate cancer have attracted the attention of scientists. In this paper, we focus on the nonlinear mixed reaction diffusion dynamics model of neuroendocrine transdifferentiation of prostate cancer cells with time delays, and reveal the evolutionary mechanism of cancer cells mathematically. By applying operator semigroup theory and the comparison principle of parabolic equation, we study the global existence, uniqueness and boundedness of the positive solution for the model. Additionally, the global invariant set and compact attractor of the positive solution are obtained by Kuratowski's measure of noncompactness. Finally, we use the Pdepe toolbox of MATLAB to carry out numerical calculations and simulations on an example to check the correctness and effectiveness of our main results. Our results show that the delay has no effect on the existence, uniqueness, boundedness and invariant set of the solution, but will affect the attractor.</p></abstract>

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Vlachostergios, Panagiotis J., Athanasios Karathanasis, and Vassilios Tzortzis. "Expression of Fibroblast Activation Protein Is Enriched in Neuroendocrine Prostate Cancer and Predicts Worse Survival." Genes 13, no. 1 (January 13, 2022): 135. http://dx.doi.org/10.3390/genes13010135.

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Background: Advanced prostate cancer (PC) may accumulate genomic alterations that hallmark lineage plasticity and transdifferentiation to a neuroendocrine (NE) phenotype. Fibroblast activation protein (FAP) is a key player in epithelial-to-mesenchymal transition (EMT). However, its clinical value and role in NE differentiation in advanced PC has not been fully investigated. Methods: Two hundred and eight patients from a multicenter, prospective cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with available RNA sequencing data were analyzed for tumor FAP mRNA expression, and its association with overall survival (OS) and NE tumor features was investigated. Results: Twenty-one patients (10%) were found to have high FAP mRNA expression. Compared to the rest, this subset had a proportionally higher exposure to taxanes and AR signaling inhibitors (abiraterone or enzalutamide) and was characterized by active NE signaling, evidenced by high NEPC- and low AR-gene expression scores. These patients with high tumor mRNA FAP expression had a more aggressive clinical course and significantly shorter survival (12 months) compared to those without altered FAP expression (28 months, log-rank p = 0.016). Conclusions: FAP expression may serve as a valuable NE marker indicating a worse prognosis in patients with metastatic CRPC.

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Bishop, Jennifer L., Alastair Davies, Kirsi Ketola, and Amina Zoubeidi. "Regulation of tumor cell plasticity by the androgen receptor in prostate cancer." Endocrine-Related Cancer 22, no. 3 (May 1, 2015): R165—R182. http://dx.doi.org/10.1530/erc-15-0137.

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Prostate cancer (PCa) has become the most common form of cancer in men in the developed world, and it ranks second in cancer-related deaths. Men that succumb to PCa have a disease that is resistant to hormonal therapies that suppress androgen receptor (AR) signaling, which plays a central role in tumor development and progression. Although AR continues to be a clinically relevant therapeutic target in PCa, selection pressures imposed by androgen-deprivation therapies promote the emergence of heterogeneous cell populations within tumors that dictate the severity of disease. This cellular plasticity, which is induced by androgen deprivation, is the focus of this review. More specifically, we address the emergence of cancer stem-like cells, epithelial–mesenchymal or myeloid plasticity, and neuroendocrine transdifferentiation as well as evidence that demonstrates how each is regulated by the AR. Importantly, because all of these cell phenotypes are associated with aggressive PCa, we examine novel therapeutic approaches for targeting therapy-induced cellular plasticity as a way of preventing PCa progression.

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Davidoff, Michail S., Ralf Middendorff, Grigori Enikolopov, Dieter Riethmacher, Adolf F. Holstein, and Dieter Müller. "Progenitor cells of the testosterone-producing Leydig cells revealed." Journal of Cell Biology 167, no. 5 (November 29, 2004): 935–44. http://dx.doi.org/10.1083/jcb.200409107.

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The cells responsible for production of the male sex hormone testosterone, the Leydig cells of the testis, are post-mitotic cells with neuroendocrine characteristics. Their origin during ontogeny and regeneration processes is still a matter of debate. Here, we show that cells of testicular blood vessels, namely vascular smooth muscle cells and pericytes, are the progenitors of Leydig cells. Resembling stem cells of the nervous system, the Leydig cell progenitors are characterized by the expression of nestin. Using an in vivo model to induce and monitor the synchronized generation of a completely new Leydig cell population in adult rats, we demonstrate specific proliferation of vascular progenitors and their subsequent transdifferentiation into steroidogenic Leydig cells which, in addition, rapidly acquire neuronal and glial properties. These findings, shown to be representative also for ontogenetic Leydig cell formation and for the human testis, provide further evidence that cellular components of blood vessels can act as progenitor cells for organogenesis and repair.

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46

Sivanandhan, Dhanalakshmi, Sridharan Rajagopal, Chandru Gajendran, Naveen Sadhu, Mohd Zainuddin, Ramachandraiah Gosu, and Luca Rastelli. "Abstract B029: LSD1-HDAC6 dual inhibitor JBI-802 is an epigenetic modulating agent with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B029. http://dx.doi.org/10.1158/1538-7445.cancepi22-b029.

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Abstract MYC is considered a master regulator of human cancers by modulating the transcription of numerous cancer-related genes. MYC amplification is reported in about 15% of all human cancers and is generally associated with poor prognosis and resistance to treatments. Focal amplification of MYC together with mutation in RB1 and p53 is an important event in the metastatic process of neuroendocrine tumor development. While limited options are available for direct targeting, transcriptional modulation via epigenetic modulating agent could be an attractive and viable option to target neuroendocrine cancers. JBI-802 inhibits the transcriptional regulator coREST via its component LSD1/HDAC6 therefore blocking neuroendocrine transdifferentiation and inducing cell death resulting in activity against neuroendocrine tumors. At the same time, this molecule has shown a good safety profile in toxicological studies. We have now identified a novel aspect of JBI-802 mechanism of action, the ability to induce downregulation of MYC RNA and degradation of MYC protein both in vitro and in animal models of two neuroendocrine tumors, small cell lung cancer and neuroendocrine prostate cancer JBI-802 showed significant anti-proliferative activity (0.2 to 1 µM) against several cancer cell lines as shown by Alamar blue or CTG assays. Sensitive ones included small cell lung cancer (SCLC), gastric cancer, breast cancer cell lines with RB1 mutation. Interestingly, dual inhibitor JBI-802 was also active in cell lines with MYC over-expression, while LSD1 selective inhibitors have been reported to be inactive in these cell lines. JBI-802 also inhibited MYC at RNA as well as protein level in hematological and solid tumors as assessed by RT-qPCR at RNA level and by Western blotting at protein level, while single agent LSD1 and HDAC6 inhibitors did not show significant modulation. JBI-802 also showed strong tumor growth inhibition of these tumors in mouse xenograft models. MYC levels showed a dose dependent inhibition in these tumors when tested at the end of the study. Only dual inhibition of both LSD1/HDAC6 with JBI-802 as opposed to single target inhibition is able to effectively downregulate MYC level and achieve efficacy in MYC amplified models in vivo and in vitro. This novel mechanism increases the potential population of neuroendocrine patients that could be sensitive to this compound, going beyond the proof of principle already established preclinically and clinically by single target LSD1 inhibitors. Therefore, by targeting 2 major pathways in neuroendocrine tumor development, JBI-802 novel mechanism of action is uniquely suited for the treatment of high unmet neuroendocrine tumors like small cell lung cancer, neuroendocrine prostate cancer and advanced, MYC amplified tumors. Based on this rationale, JBI-802 is being tested in phase 1/2 clinical trial focus on this type of tumors. Citation Format: Dhanalakshmi Sivanandhan, Sridharan Rajagopal, Chandru Gajendran, Naveen Sadhu, Mohd Zainuddin, Ramachandraiah Gosu, Luca Rastelli. LSD1-HDAC6 dual inhibitor JBI-802 is an epigenetic modulating agent with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B029.

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Qiao, Yuanyuan, Chungen Li, Yang Zheng, Xia Jiang, Sarah Nicole Yee, Caleb Cheng, Yi Bao, et al. "Abstract 2898: Development of the lipid kinase PIKfyve PROTAC degrader against neuroendocrine prostate cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2898. http://dx.doi.org/10.1158/1538-7445.am2024-2898.

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Abstract Therapies targeting the androgen receptor (AR) as the main driver of prostate cancer (PCa) can lead to various mechanisms of resistance and promote progression to castration-resistant PCa (CRPC), which has a median survival of only 13-23 months. Amongst recurrent CRPC, 17%-30% of patients develop neuroendocrine prostate cancer (NEPC), which is a PCa subtype characterized by a unique histology. NEPC exhibits a loss of AR signaling during neuroendocrine transdifferentiation which results in resistance to AR-targeted therapies and gain of cell characteristics resembling poorly differentiated neuroendocrine tumors. Despite advances in the understanding of NEPC development, treatment options remain limited, with platinum-based chemotherapy as the first-line treatment for both de novo and treatment-induced NEPC. However, response to first-line chemotherapy in NEPC is short, with a median survival of only seven months. The poor prognosis of NEPC is attributed in part to late diagnosis and a lack of effective therapeutic agents. Our previous work demonstrated that NEPC and AR-negative PCa exhibit higher dependency on the lipid kinase PIKfyve than AR-positive CRPC. Thus, development of PIKfyve inhibitory therapies targeting the emergent vulnerabilities of NEPC or AR-negative forms of PCa is a promising approach. Using a proteolysis targeting chimera (PROTAC) technology, we designed a class of PIKfyve specific degrader. The in vitro degradation efficiency were determined by immunoblotting, and DC50s (degradation concentration at 50%) were calculated for top candidates. Pharmacokinetic and pharmacodynamic were evaluated for in vivo study. In summary, we have developed a class of PIKfyve specific degrader using the E3 ligase von Hippel-Lindau (VHL) as a ligand via a diverse set of linkers. Mechanistic studies revealed that it induced PIKfyve degradation in a VHL- and proteasome-dependent manner. Citation Format: Yuanyuan Qiao, Chungen Li, Yang Zheng, Xia Jiang, Sarah Nicole Yee, Caleb Cheng, Yi Bao, Yuping Zhang, Yuzhuo Wang, Zhen Wang, Ke Ding, Arul Chinnaiyan. Development of the lipid kinase PIKfyve PROTAC degrader against neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2898.

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Bae, Song Yi, Hannah E. Bergom, Abderrahman Day, Joseph T. Greene, Tanya S. Freedman, Justin H. Hwang, and Justin M. Drake. "Abstract B057: ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer." Cancer Research 83, no. 11_Supplement (June 2, 2023): B057. http://dx.doi.org/10.1158/1538-7445.prca2023-b057.

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Abstract Neuroendocrine prostate cancer (NEPC) is a lethal variant of aggressive prostate cancer. Hallmarks of NEPC include the loss of androgen receptor (AR) signaling and transdifferentiation toward small-cell neuroendocrine (SCN) phenotypes, which result in resistance to AR-targeted therapy. NEPC resembles other SCN carcinomas clinically, histologically and genomically. Here, we leveraged SCN phenotype scores of various cancer cell lines and gene depletion screens from the Cancer Dependency Map (DepMap) to identify vulnerabilities in NEPC. We discovered ZBTB7A, a transcription factor, as a candidate promoting the progression of NEPC. Cancer cells with high SCN phenotype scores showed a strong dependency with RET kinase, an emerging therapeutic target of NEPC, suggesting the NEPC-like phenotype of the cells. Then, we observed a strong correlation between dependencies of RET and ZBTB7A in these cells. Utilizing informatic modeling of whole transcriptome sequencing data from patient samples, we revealed distinct gene networking patterns of ZBTB7A in NEPC versus prostate adenocarcinoma. Specifically, we observed a robust association of ZBTB7A with genes promoting cell cycle progression in NEPC, and this result was confirmed through Gene Set Enrichment Analysis. Furthermore, we showed a potential interaction of ZBTB7A with apoptosis regulating genes. Silencing ZBTB7A in a NEPC cell line confirmed the dependency of cells on ZBTB7A for cell growth, and the role of ZBTB7A in regulating G1/S transition in cell cycle and inducing apoptosis. Collectively, our results highlight the oncogenic function of ZBTB7A in NEPC, and emphasize the value of ZBTB7A as a promising therapeutic strategy for targeting NEPC tumors. Citation Format: Song Yi Bae, Hannah E. Bergom, Abderrahman Day, Joseph T. Greene, Tanya S. Freedman, Justin H. Hwang, Justin M. Drake. ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B057.

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Syder, A. J., S. M. Karam, J. C. Mills, J. E. Ippolito, H. R. Ansari, V. Farook, and J. I. Gordon. "A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype." Proceedings of the National Academy of Sciences 101, no. 13 (March 30, 2004): 4471–76. http://dx.doi.org/10.1073/pnas.0307983101.

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Angelucci, Adriano, Paola Muzi, Loredana Cristiano, Danilo Millimaggi, AnnaMaria Cimini, Vincenza Dolo, Roberto Miano, Carlo Vicentini, Maria Paola Cerù, and Mauro Bologna. "Neuroendocrine transdifferentiation induced by VPA is mediated by PPARγ activation and confers resistance to antiblastic therapy in prostate carcinoma." Prostate 68, no. 6 (May 1, 2008): 588–98. http://dx.doi.org/10.1002/pros.20708.

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