18 results on '"Mizuno, Kei"'
Search Results
2. Supplementary figure S4 from TREX1 Inactivation Unleashes Cancer Cell STING–Interferon Signaling and Promotes Antitumor Immunity
- Author
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Tani, Tetsuo, primary, Mathsyaraja, Haritha, primary, Campisi, Marco, primary, Li, Ze-Hua, primary, Haratani, Koji, primary, Fahey, Caroline G., primary, Ota, Keiichi, primary, Mahadevan, Navin R., primary, Shi, Yingxiao, primary, Saito, Shin, primary, Mizuno, Kei, primary, Thai, Tran C., primary, Sasaki, Nobunari, primary, Homme, Mizuki, primary, Yusuf, Choudhury Fabliha B., primary, Kashishian, Adam, primary, Panchal, Jipsa, primary, Wang, Min, primary, Wolf, Benjamin J., primary, Barbie, Thanh U., primary, Paweletz, Cloud P., primary, Gokhale, Prafulla C., primary, Liu, David, primary, Uppaluri, Ravindra, primary, Kitajima, Shunsuke, primary, Cain, Jennifer, primary, and Barbie, David A., primary
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- 2024
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3. Data from TREX1 Inactivation Unleashes Cancer Cell STING–Interferon Signaling and Promotes Antitumor Immunity
- Author
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Tani, Tetsuo, primary, Mathsyaraja, Haritha, primary, Campisi, Marco, primary, Li, Ze-Hua, primary, Haratani, Koji, primary, Fahey, Caroline G., primary, Ota, Keiichi, primary, Mahadevan, Navin R., primary, Shi, Yingxiao, primary, Saito, Shin, primary, Mizuno, Kei, primary, Thai, Tran C., primary, Sasaki, Nobunari, primary, Homme, Mizuki, primary, Yusuf, Choudhury Fabliha B., primary, Kashishian, Adam, primary, Panchal, Jipsa, primary, Wang, Min, primary, Wolf, Benjamin J., primary, Barbie, Thanh U., primary, Paweletz, Cloud P., primary, Gokhale, Prafulla C., primary, Liu, David, primary, Uppaluri, Ravindra, primary, Kitajima, Shunsuke, primary, Cain, Jennifer, primary, and Barbie, David A., primary
- Published
- 2024
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- View/download PDF
4. Supplementary Table S1 from TREX1 Inactivation Unleashes Cancer Cell STING–Interferon Signaling and Promotes Antitumor Immunity
- Author
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Tani, Tetsuo, primary, Mathsyaraja, Haritha, primary, Campisi, Marco, primary, Li, Ze-Hua, primary, Haratani, Koji, primary, Fahey, Caroline G., primary, Ota, Keiichi, primary, Mahadevan, Navin R., primary, Shi, Yingxiao, primary, Saito, Shin, primary, Mizuno, Kei, primary, Thai, Tran C., primary, Sasaki, Nobunari, primary, Homme, Mizuki, primary, Yusuf, Choudhury Fabliha B., primary, Kashishian, Adam, primary, Panchal, Jipsa, primary, Wang, Min, primary, Wolf, Benjamin J., primary, Barbie, Thanh U., primary, Paweletz, Cloud P., primary, Gokhale, Prafulla C., primary, Liu, David, primary, Uppaluri, Ravindra, primary, Kitajima, Shunsuke, primary, Cain, Jennifer, primary, and Barbie, David A., primary
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- 2024
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- View/download PDF
5. Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.
- Author
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Venkadakrishnan, Varadha Balaji, Presser, Adam G., Singh, Richa, Booker, Matthew A., Traphagen, Nicole A., Weng, Kenny, Voss, Nathaniel C. E., Mahadevan, Navin R., Mizuno, Kei, Puca, Loredana, Idahor, Osasenaga, Ku, Sheng-Yu, Bakht, Martin K., Borah, Ashir A., Herbert, Zachary T., Tolstorukov, Michael Y., Barbie, David A., Rickman, David S., Brown, Myles, and Beltran, Himisha
- Subjects
CASTRATION-resistant prostate cancer ,PROSTATE cancer ,NATURAL immunity ,HORMONE therapy ,DISEASE progression - Abstract
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition. Enhancer of zeste homolog 2 (EZH2) has been implicated as a driver of disease progression and resistance to hormonal therapies. Here, the authors focus on EZH2 in two subtypes of advanced prostate cancer and report how it modulates the bivalent genes thereby leading to forward differentiation after being targeted in neuroendocrine prostate cancer. [ABSTRACT FROM AUTHOR]
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- 2024
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- View/download PDF
6. Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes
- Author
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Beltran, Himisha, primary, Venkadakrishnan, Varadha Balaji, additional, Presser, Adam, additional, Singh, Richa, additional, Booker, Matthew, additional, Traphagen, Nicole, additional, Weng, Kenny, additional, Voss, Nathaniel, additional, Mahadevan, Navin, additional, Mizuno, Kei, additional, Puca, Loredana, additional, Idahor, Osasenaga, additional, Ku, Sheng Yu, additional, Bakht, Martin, additional, Borah, Ashir, additional, Herbert, Zachary, additional, Tolstorukov, Michael, additional, Barbie, David, additional, Rickman, David, additional, and Brown, Myles, additional
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- 2024
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- View/download PDF
7. Supplementary Tables S1-S10 from Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation
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Franceschini, Gian Marco, primary, Quaini, Orsetta, primary, Mizuno, Kei, primary, Orlando, Francesco, primary, Ciani, Yari, primary, Ku, Sheng-Yu, primary, Sigouros, Michael, primary, Rothmann, Emily, primary, Alonso, Alicia, primary, Benelli, Matteo, primary, Nardella, Caterina, primary, Auh, Joonghoon, primary, Freeman, Dory, primary, Hanratty, Brian, primary, Adil, Mohamed, primary, Elemento, Olivier, primary, Tagawa, Scott T., primary, Feng, Felix Y., primary, Caffo, Orazio, primary, Buttigliero, Consuelo, primary, Basso, Umberto, primary, Nelson, Peter S., primary, Corey, Eva, primary, Haffner, Michael C., primary, Attard, Gerhardt, primary, Aparicio, Ana, primary, Demichelis, Francesca, primary, and Beltran, Himisha, primary
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- 2024
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8. Data from Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation
- Author
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Franceschini, Gian Marco, primary, Quaini, Orsetta, primary, Mizuno, Kei, primary, Orlando, Francesco, primary, Ciani, Yari, primary, Ku, Sheng-Yu, primary, Sigouros, Michael, primary, Rothmann, Emily, primary, Alonso, Alicia, primary, Benelli, Matteo, primary, Nardella, Caterina, primary, Auh, Joonghoon, primary, Freeman, Dory, primary, Hanratty, Brian, primary, Adil, Mohamed, primary, Elemento, Olivier, primary, Tagawa, Scott T., primary, Feng, Felix Y., primary, Caffo, Orazio, primary, Buttigliero, Consuelo, primary, Basso, Umberto, primary, Nelson, Peter S., primary, Corey, Eva, primary, Haffner, Michael C., primary, Attard, Gerhardt, primary, Aparicio, Ana, primary, Demichelis, Francesca, primary, and Beltran, Himisha, primary
- Published
- 2024
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- View/download PDF
9. Supplementary Figures S1-S7 from Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation
- Author
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Franceschini, Gian Marco, primary, Quaini, Orsetta, primary, Mizuno, Kei, primary, Orlando, Francesco, primary, Ciani, Yari, primary, Ku, Sheng-Yu, primary, Sigouros, Michael, primary, Rothmann, Emily, primary, Alonso, Alicia, primary, Benelli, Matteo, primary, Nardella, Caterina, primary, Auh, Joonghoon, primary, Freeman, Dory, primary, Hanratty, Brian, primary, Adil, Mohamed, primary, Elemento, Olivier, primary, Tagawa, Scott T., primary, Feng, Felix Y., primary, Caffo, Orazio, primary, Buttigliero, Consuelo, primary, Basso, Umberto, primary, Nelson, Peter S., primary, Corey, Eva, primary, Haffner, Michael C., primary, Attard, Gerhardt, primary, Aparicio, Ana, primary, Demichelis, Francesca, primary, and Beltran, Himisha, primary
- Published
- 2024
- Full Text
- View/download PDF
10. TREX1 Inactivation Unleashes Cancer Cell STING–Interferon Signaling and Promotes Antitumor Immunity
- Author
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Tani, Tetsuo, primary, Mathsyaraja, Haritha, additional, Campisi, Marco, additional, Li, Ze-Hua, additional, Haratani, Koji, additional, Fahey, Caroline G., additional, Ota, Keiichi, additional, Mahadevan, Navin R., additional, Shi, Yingxiao, additional, Saito, Shin, additional, Mizuno, Kei, additional, Thai, Tran C., additional, Sasaki, Nobunari, additional, Homme, Mizuki, additional, Yusuf, Choudhury Fabliha B., additional, Kashishian, Adam, additional, Panchal, Jipsa, additional, Wang, Min, additional, Wolf, Benjamin J., additional, Barbie, Thanh U., additional, Paweletz, Cloud P., additional, Gokhale, Prafulla C., additional, Liu, David, additional, Uppaluri, Ravindra, additional, Kitajima, Shunsuke, additional, Cain, Jennifer, additional, and Barbie, David A., additional
- Published
- 2024
- Full Text
- View/download PDF
11. Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes
- Author
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Venkadakrishnan, Varadha Balaji, primary, Presser, Adam G., additional, Singh, Richa, additional, Booker, Matthew A., additional, Traphagen, Nicole A., additional, Weng, Kenny, additional, Voss, Nathaniel C., additional, Mahadevan, Navin R., additional, Mizuno, Kei, additional, Puca, Loredana, additional, Idahor, Osasenaga, additional, Ku, Sheng-Yu, additional, Bakht, Martin K., additional, Borah, Ashir A., additional, Herbert, Zachary T., additional, Tolstorukov, Michael Y., additional, Barbie, David A., additional, Rickman, David S., additional, Brown, Myles, additional, and Beltran, Himisha, additional
- Published
- 2024
- Full Text
- View/download PDF
12. Molecular features of prostate cancer after neoadjuvant therapy in the phase 3 CALGB 90203 trial.
- Author
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Sumiyoshi, Takayuki, Wang, Xiaofei, Warner, Evan W, Sboner, Andrea, Annala, Matti, Sigouros, Michael, Beja, Kevin, Mizuno, Kei, Ku, Shengyu, Fazli, Ladan, Eastham, James, Taplin, Mary-Ellen, Simko, Jeffrey, Halabi, Susan, Morris, Michael J, Gleave, Martin E, Wyatt, Alexander W, and Beltran, Himisha
- Subjects
PROSTATE cancer ,GENE expression ,NEOADJUVANT chemotherapy ,RADICAL prostatectomy ,ANDROGEN deprivation therapy ,DNA sequencing - Abstract
Background The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical outcomes to explore mechanisms of response and resistance to chemohormonal therapy. Methods We evaluated 471 radical prostatectomy tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy before radical prostatectomy and 177 samples from 97 patients in the control arm (radical prostatectomy alone). Targeted DNA sequencing and RNA expression of tumor foci and adjacent noncancer regions were analyzed in conjunction with pathologic changes and clinical outcomes. Results Tumor fraction estimated from DNA sequencing was significantly lower in post-treated tumor tissues after chemohormonal therapy compared with controls. Higher tumor fraction after chemohormonal therapy was associated with aggressive pathologic features and poor outcomes, including prostate-specific antigen–progression-free survival. SPOP alterations were infrequently detected after chemohormonal therapy, while TP53 alterations were enriched and associated with shorter overall survival. Residual tumor fraction after chemohormonal therapy was linked to higher expression of androgen receptor–regulated genes, cell cycle genes, and neuroendocrine genes, suggesting persistent populations of active prostate cancer cells. Supervised clustering of post–treated high-tumor-fraction tissues identified a group of patients with elevated cell cycle–related gene expression and poor clinical outcomes. Conclusions Distinct recurrent prostate cancer genomic and transcriptomic features are observed after exposure to docetaxel and androgen deprivation therapy. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 alterations and high cell cycle transcriptomic activity are linked to aggressive residual disease, despite potent chemohormonal therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
13. Newly developed preclinical models reveal broad‐spectrum CDK inhibitors as potent drugs for CRPC exhibiting primary resistance to enzalutamide.
- Author
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Matsuoka, Takashi, Sugiyama, Aiko, Miyawaki, Yoshifumi, Hidaka, Yusuke, Okuno, Yukiko, Sakai, Hiroaki, Tanaka, Hiroki, Yoshikawa, Kiyotsugu, Fukui, Tomohiro, Mizuno, Kei, Sumiyoshi, Takayuki, Goto, Takayuki, Inoue, Takahiro, Akamatsu, Shusuke, Kobayashi, Takashi, and Nakamura, Eijiro
- Abstract
Androgen‐deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration‐resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen‐deprived conditions. Unlike most pre‐existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate‐specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence‐based chemical screening. We identified flavopiridol, a broad‐spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81). Importantly, this broad‐spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient‐derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad‐spectrum CDK inhibitors might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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14. Cacao Polyphenol-Rich Dark Chocolate Intake Contributes to Efficient Brain Activity during Cognitive Tasks: A Randomized, Single-Blinded, Crossover, and Dose-Comparison fMRI Study.
- Author
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Sasaki, Akihiro, Kawai, Eriko, Watanabe, Kyosuke, Yamano, Emi, Oba, Chisato, Nakamura, Kentaro, Natsume, Midori, Mizuno, Kei, and Watanabe, Yasuyoshi
- Abstract
Cacao polyphenol-enriched dark chocolate may have beneficial effects on human health, such as facilitating maintaining good performance in long-lasting cognitive tasks. This study examined the effects of dark chocolate intake on improving brain function during cognitive tasks using functional magnetic resonance imaging (fMRI). In this randomized, single-blinded, crossover, and dose-comparison study, 26 healthy middle-aged participants ingested dark chocolate (25 g) either with a low concentration (LC) (211.7 mg) or a high concentration (HC) (635 mg) of cacao polyphenols. Thereafter, their brain activities were analyzed during continuous and effortful cognitive tasks relevant to executive functioning using fMRI in two consecutive 15 min sessions (25 and 50 min after ingestion). We observed significant interaction effects between chocolate consumption and brain activity measurement sessions in the left dorsolateral prefrontal cortex and left inferior parietal lobule. After HC chocolate ingestion, these areas showed lower brain activity in the second session than in the first session; however, these areas showed higher activity in the second session after LC chocolate ingestion. These results suggest that cacao polyphenol-enriched dark chocolate enhances the efficient use of cognitive resources by reducing the effort of brain activity. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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15. Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer.
- Author
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Ku SY, Wang Y, Garcia MM, Yamada Y, Mizuno K, Long MD, Rosario S, Chinnam M, Al Assaad M, Puca L, Kim MJ, Bakht MK, Venkadakrishnan VB, Robinson BD, Acosta AM, Wadosky KM, Mosquera JM, Goodrich DW, and Beltran H
- Subjects
- Male, Animals, Humans, Mice, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 immunology, Adenocarcinoma immunology, Adenocarcinoma pathology, Adenocarcinoma genetics, Adenocarcinoma metabolism, Neuroendocrine Cells pathology, Neuroendocrine Cells metabolism, Neuroendocrine Cells immunology, Receptors, Notch metabolism, Receptors, Notch genetics, Receptors, Notch immunology, Neuroendocrine Tumors immunology, Neuroendocrine Tumors pathology, Neuroendocrine Tumors genetics, Neuroendocrine Tumors metabolism, Cell Line, Tumor, Prostatic Neoplasms immunology, Prostatic Neoplasms pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Tumor Microenvironment immunology, Signal Transduction immunology, Cell Differentiation
- Abstract
Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME).
- Published
- 2024
- Full Text
- View/download PDF
16. Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.
- Author
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Venkadakrishnan VB, Presser AG, Singh R, Booker MA, Traphagen NA, Weng K, Voss NC, Mahadevan NR, Mizuno K, Puca L, Idahor O, Ku SY, Bakht MK, Borah AA, Herbert ZT, Tolstorukov MY, Barbie DA, Rickman DS, Brown M, and Beltran H
- Abstract
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma (PRAD) and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.
- Published
- 2024
- Full Text
- View/download PDF
17. Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.
- Author
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Franceschini GM, Quaini O, Mizuno K, Orlando F, Ciani Y, Ku SY, Sigouros M, Rothmann E, Alonso A, Benelli M, Nardella C, Auh J, Freeman D, Hanratty B, Adil M, Elemento O, Tagawa ST, Feng FY, Caffo O, Buttigliero C, Basso U, Nelson PS, Corey E, Haffner MC, Attard G, Aparicio A, Demichelis F, and Beltran H
- Subjects
- Male, Humans, DNA Methylation, Prospective Studies, Biopsy, Prostatic Neoplasms, Castration-Resistant diagnosis, Prostatic Neoplasms, Castration-Resistant genetics, Cell-Free Nucleic Acids genetics
- Abstract
Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n = 222 plasma samples) and qualified it achieving an AUC > 0.93 for detecting pathology-confirmed CRPC-NE (n = 136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification., Significance: Neuroendocrine prostate cancer is an aggressive subtype of treatment-resistant prostate cancer. Early detection is important, but the diagnosis currently relies on metastatic biopsy. We describe the development and validation of a plasma cell-free DNA targeted methylation panel that can quantify tumor fraction and identify patients with neuroendocrine prostate cancer noninvasively. This article is featured in Selected Articles from This Issue, p. 384., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
18. Molecular features of prostate cancer after neoadjuvant therapy in the phase 3 CALGB 90203 trial.
- Author
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Sumiyoshi T, Wang X, Warner EW, Sboner A, Annala M, Sigouros M, Beja K, Mizuno K, Ku S, Fazli L, Eastham J, Taplin ME, Simko J, Halabi S, Morris MJ, Gleave ME, Wyatt AW, and Beltran H
- Subjects
- Male, Humans, Neoadjuvant Therapy, Docetaxel, Androgen Antagonists therapeutic use, Androgens therapeutic use, Treatment Outcome, Neoplasm Recurrence, Local surgery, Prostate-Specific Antigen, Prostatectomy, Nuclear Proteins, Repressor Proteins, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms surgery
- Abstract
Background: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical outcomes to explore mechanisms of response and resistance to chemohormonal therapy., Methods: We evaluated 471 radical prostatectomy tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy before radical prostatectomy and 177 samples from 97 patients in the control arm (radical prostatectomy alone). Targeted DNA sequencing and RNA expression of tumor foci and adjacent noncancer regions were analyzed in conjunction with pathologic changes and clinical outcomes., Results: Tumor fraction estimated from DNA sequencing was significantly lower in post-treated tumor tissues after chemohormonal therapy compared with controls. Higher tumor fraction after chemohormonal therapy was associated with aggressive pathologic features and poor outcomes, including prostate-specific antigen-progression-free survival. SPOP alterations were infrequently detected after chemohormonal therapy, while TP53 alterations were enriched and associated with shorter overall survival. Residual tumor fraction after chemohormonal therapy was linked to higher expression of androgen receptor-regulated genes, cell cycle genes, and neuroendocrine genes, suggesting persistent populations of active prostate cancer cells. Supervised clustering of post-treated high-tumor-fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes., Conclusions: Distinct recurrent prostate cancer genomic and transcriptomic features are observed after exposure to docetaxel and androgen deprivation therapy. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 alterations and high cell cycle transcriptomic activity are linked to aggressive residual disease, despite potent chemohormonal therapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
- Full Text
- View/download PDF
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