A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers
Himisha Beltran,Himisha Beltran,Clara Oromendia,Daniel C. Danila,Daniel C. Danila,Bruce Montgomery,Christopher J. Hoimes,Russell Z. Szmulewitz,Ulka N. Vaishampayan,Andrew J. Armstrong,Mark N. Stein,Jacek Pinski,Juan Miguel Mosquera,Juan Miguel Mosquera,Verena Sailer,Rohan Bareja,Alessandro Romanel,Naveen Gumpeni,Andrea Sboner,Andrea Sboner,Etienne Dardenne,Loredana Puca,Loredana Puca,Davide Prandi,Mark A. Rubin,Mark A. Rubin,Howard I. Scher,Howard I. Scher,David S. Rickman,David S. Rickman,Francesca Demichelis,Francesca Demichelis,David M. Nanus,David M. Nanus,Karla V. Ballman,Scott T. Tagawa,Scott T. Tagawa +36 more
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Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.Abstract:
Purpose: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. Patients and Methods: Sixty men were treated with alisertib 50 mg twice daily for 7 days every 21 days. Eligibility included metastatic prostate cancer and at least one: small-cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; or elevated serum neuroendocrine markers. The primary endpoint was 6-month radiographic progression-free survival (rPFS). Pretreatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed. Results: Median PSA was 1.13 ng/mL (0.01–514.2), number of prior therapies was 3, and 68% had visceral metastases. Genomic alterations involved RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%), and AR (27%), and there was a range of androgen receptor signaling and NEPC marker expression. Six-month rPFS was 13.4% and median overall survival was 9.5 months (7.3–13). Exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity. Patient organoids exhibited concordant responses to alisertib and allowed for the dynamic testing of Aurora–N-myc complex disruption. Conclusions: Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.read more
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Genomic correlates of clinical outcome in advanced prostate cancer.
Wassim Abida,Joanna Cyrta,Joanna Cyrta,Glenn Heller,Davide Prandi,Joshua Armenia,Ilsa Coleman,Marcin Cieslik,Matteo Benelli,Dan R. Robinson,Eliezer M. Van Allen,Eliezer M. Van Allen,Andrea Sboner,Tarcisio Fedrizzi,Juan Miguel Mosquera,Brian D. Robinson,Navonil De Sarkar,Lakshmi P. Kunju,Scott A. Tomlins,Yi-Mi Wu,Daniel Nava Rodrigues,Massimo Loda,Massimo Loda,Anuradha Gopalan,Victor E. Reuter,Colin C. Pritchard,Joaquin Mateo,Diletta Bianchini,Susana Miranda,Suzanne Carreira,Pasquale Rescigno,Julie Filipenko,Jacob Vinson,Robert B. Montgomery,Himisha Beltran,Himisha Beltran,Elisabeth I. Heath,Howard I. Scher,Philip W. Kantoff,Mary-Ellen Taplin,Nikolaus Schultz,J. De-Bono,Francesca Demichelis,Peter S. Nelson,Mark A. Rubin,Mark A. Rubin,Arul M. Chinnaiyan,Charles L. Sawyers +47 more
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The role of lineage plasticity in prostate cancer therapy resistance
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Genomic and phenotypic heterogeneity in prostate cancer.
Michael C. Haffner,Michael C. Haffner,Michael C. Haffner,Wilbert Zwart,Martine Roudier,Lawrence D. True,William G. Nelson,Jonathan I. Epstein,Angelo M. De Marzo,Peter S. Nelson,Srinivasan Yegnasubramanian +10 more
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TL;DR: New consensus criteria for eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone are defined, with increasing emphasis on time-to-event end points as decision aids in proceeding from phase II to phase III trials.
Journal ArticleDOI
Organoid cultures derived from patients with advanced prostate cancer
Dong Gao,Ian Vela,Andrea Sboner,Phillip J. Iaquinta,Wouter R. Karthaus,Anuradha Gopalan,Catherine Dowling,Jackline Wanjala,Eva Undvall,Vivek K. Arora,John Wongvipat,Myriam Kossai,Sinan Ramazanoglu,Luendreo P Barboza,Wei Di,Zhen Cao,Qi Fan Zhang,Inna Sirota,Leili Ran,Theresa Y MacDonald,Himisha Beltran,Juan Miguel Mosquera,Karim Touijer,Peter T. Scardino,Vincent P. Laudone,Kristen Rebecca Curtis,Dana E. Rathkopf,Michael J. Morris,Michael J. Morris,Daniel C. Danila,Daniel C. Danila,Susan F. Slovin,Susan F. Slovin,Stephen B. Solomon,James A. Eastham,Ping Chi,Brett S. Carver,Mark A. Rubin,Howard I. Scher,Howard I. Scher,Hans Clevers,Charles L. Sawyers,Charles L. Sawyers,Yu Chen,Yu Chen +44 more
TL;DR: Using a 3D organoid system, this paper reported success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss.
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Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer
Himisha Beltran,Himisha Beltran,Davide Prandi,Juan Miguel Mosquera,Juan Miguel Mosquera,Matteo Benelli,Loredana Puca,Joanna Cyrta,Clarisse Marotz,Eugenia G. Giannopoulou,Balabhadrapatruni V. S. K. Chakravarthi,Sooryanarayana Varambally,Scott A. Tomlins,David M. Nanus,Scott T. Tagawa,Eliezer M. Van Allen,Eliezer M. Van Allen,Olivier Elemento,Olivier Elemento,Andrea Sboner,Andrea Sboner,Levi A. Garraway,Levi A. Garraway,Levi A. Garraway,Mark A. Rubin,Mark A. Rubin,Francesca Demichelis,Francesca Demichelis,Francesca Demichelis +28 more
TL;DR: Analysis of whole-exome sequencing data of metastatic biopsies from patients observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas and neuroendocrine prostate cancer (CRPC-NE), supporting the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.
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