1032 poster MLN8054, A NOVEL INHIBITOR OF AURORA KINASE A SENSITIZES ANDROGEN-RESISTANT PROSTATE CANCER MODELS TO RADIATION

2011 ◽  
Vol 99 ◽  
pp. S386
Author(s):  
L. Moretti ◽  
K. Niermann ◽  
S. Schleicher ◽  
K.W. Kim ◽  
P. Kopsombut ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Aurora Kinase ◽  
Aurora Kinase A ◽  
Cancer Models ◽  
Kinase A

scholarly journals miR-199a-3p Inhibits Aurora Kinase A and Attenuates Prostate Cancer Growth

2014 ◽  
Vol 184 (5) ◽  
pp. 1541-1549 ◽  
Author(s):  
Yi Qu ◽  
Xiang Huang ◽  
Zhiqing Li ◽  
Junyan Liu ◽  
Jinlin Wu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Aurora Kinase ◽  
Cancer Growth ◽  
Aurora Kinase A ◽  
Kinase A

A phase II trial of the aurora kinase A inhibitor MLN8237 in patients with metastatic castrate resistant and neuroendocrine prostate cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS5096-TPS5096 ◽  
Author(s):  
Himisha Beltran ◽  
Mark A. Rubin ◽  
Juan Miguel Mosquera ◽  
Paul J. Christos ◽  
Olivera Calukovic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Neuron Specific Enolase ◽  
Aurora Kinase ◽  
Response To Therapy ◽  
Aurora Kinase A ◽  
Kinase A

TPS5096 Background: NEPC can rarely arise de novo but more commonly arises as a mechanism of resistance in the setting of advanced prostate cancer. Transformation to NEPC is likely promoted by potent hormonal therapies and is currently under-recognized. There is no effective therapy for NEPC and most patients (pts) survive less than one year. We have found that Aurora kinase A (AURKA) and N-myc (MYCN) are significantly overexpressed and amplified in NEPC compared to prostate adenocarcinoma, and cooperate to induce neuroendocrine (NE) differentiation in prostate cancer (Beltran et al, Cancer Disc 2011). In preclinical models, aurora kinase inhibition results in dramatic and preferential anti-tumor activity in NEPC. Methods: In this single arm, multi-institutional Phase II trial, pts with metastatic prostate cancer need to meet at least one NEPC entry criterion: 1) histologic diagnosis of small cell or NEPC, 2) >50% immunohistochemical staining for NE markers, 3) development of liver metastases in absence of PSA progression, or 4) serum chromogranin >5x normal or neuron specific enolase >2x normal. Study will be open at 10 institutions including PCCTC sites. After a mandatory on-study research biopsy, pts will be treated with MLN8237, an orally administered Aurora kinase A inhibitor at 50 mg twice daily for 7 days repeated every 21 days. The primary endpoint is objective response rate (ORR). Secondary endpoints include overall survival, progression free survival, PSA response rate, circulating tumor cell response, and serum NE marker response to therapy. A number of correlative studies including AURKA, MYCN, AR, and exome and RNAseq are embedded in this trial in order to molecularly define this aggressive and poorly characterized disease. A Simon 2-stage design will be employed with up to 60 subjects providing 80% power to determine if the true ORR is >30% and 95% power if the true ORR is <15%, assuming a 5% level of significance. A subset of at least 20% meeting histologic entry criteria is embedded.

scholarly journals Effects of DNAzymes targeting Aurora kinase A on the growth of human prostate cancer

2008 ◽  
Vol 15 (8) ◽  
pp. 517-525 ◽  
Author(s):  
Y Qu ◽  
L Zhang ◽  
M Mao ◽  
F Zhao ◽  
X Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Aurora Kinase ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Aurora Kinase A ◽  
Kinase A

scholarly journals A phase 2 study of the aurora kinase A inhibitor alisertib for patients with neuroendocrine prostate cancer (NEPC)

2016 ◽  
Vol 27 ◽  
pp. vi565 ◽  
Author(s):  
H. Beltran ◽  
D. Danila ◽  
B. Montgomery ◽  
R. Szmulewitz ◽  
U. Vaishampayan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Aurora Kinase ◽  
Phase 2 ◽  
Aurora Kinase A ◽  
Neuroendocrine Prostate Cancer ◽  
Phase 2 Study ◽  
Kinase A

MLN8054, A Small Molecule Inhibitor of Aurora Kinase A, Sensitizes Androgen-Resistant Prostate Cancer to Radiation

2011 ◽  
Vol 80 (4) ◽  
pp. 1189-1197 ◽  
Author(s):  
Luigi Moretti ◽  
Kenneth Niermann ◽  
Stephen Schleicher ◽  
Nicholas J. Giacalone ◽  
Vinod Varki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Aurora Kinase ◽  
Small Molecule Inhibitor ◽  
Aurora Kinase A ◽  
Molecule Inhibitor ◽  
Kinase A

scholarly journals Aurora Kinase A-YBX1 Synergy Fuels Aggressive Oncogenic Phenotypes and Chemoresistance in Castration-Resistant Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 660 ◽  
Author(s):  
Kumar Nikhil ◽  
Asif Raza ◽  
Hanan S. Haymour ◽  
Benjamin V. Flueckiger ◽  
Jiachong Chu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Aurora Kinase ◽  
Mrna Levels ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Aurora Kinase A ◽  
Castration Resistant ◽  
Kinase A

Multifunctional protein YBX1 upregulation promotes castration-resistant prostate cancer (CRPC). However, YBX1 protein abundance, but not its DNA status or mRNA levels, predicts CRPC recurrence, although the mechanism remains unknown. Similarly, the mechanism by which YBX1 regulates androgen receptor (AR) signaling remains unclear. We uncovered the first molecular mechanism of YBX1 upregulation at a post-translational level. YBX1 was identified as an Aurora Kinase-A (AURKA) substrate using a chemical screen. AURKA phosphorylates YBX1 at two key residues, which stabilizes it and promotes its nuclear translocation. YBX1 reciprocates and stabilizes AURKA, thereby initiating a synergistic loop. Notably, phospho-resistant YBX1 is dominant-negative and fully inhibits epithelial to mesenchymal transition, chemoresistance, drug-resistance and tumorigenesis in vivo. Unexpectedly, we further observed that YBX1 upregulates AR post-translationally by preventing its ubiquitylation, but not by increasing its transcription as reported before. Uncovering YBX1-mediated AR stabilization is highly significant due to AR’s critical role in both androgen-sensitive prostate cancer and CRPC. As YBX1 inhibitors are unknown, AURKA inhibitors provide a potent tool to degrade both YBX1 and AR simultaneously. Finally, this is the first study to show a reciprocal loop between YBX1 and its kinase, indicating that their concomitant inhibition will be act synergistically for CRPC therapy.

scholarly journals Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

2021 ◽  
Author(s):  
Gary K. L. Chan ◽  
Samantha Maisel ◽  
Yeonjoo C. Hwang ◽  
Rebecca R. B. Wolber ◽  
Phuong Vu ◽  
...  
Keyword(s):  
Drug Targets ◽  
Human Cancer ◽  
Aurora Kinase ◽  
Genetic Alterations ◽  
Genetic Changes ◽  
Aurora Kinase A ◽  
Protein Levels ◽  
Cancer Models ◽  
Tumor Types ◽  
Kinase A

AbstractGenetic alterations that activate protein kinase A (PKA) signaling are found across many tumor types, but their downstream oncogenic mechanisms are poorly understood. We used global phosphoproteomics and kinome activity profiling to map the conserved signaling outputs driven by diverse genetic changes that activate PKA in human cancer, including melanoma and fibrolamellar carcinoma (FLC). We define two consensus networks of effectors downstream of PKA in cancer models. One is centered on RAS/MAPK components, and a second involves Aurora Kinase A (AURKA). We find that AURKA stabilizes c-MYC and n-MYC protein levels and expression programs in PKA-dependent tumor models, in part via a positive feedback loop mediated by the oncogenic kinase PIM2. This process can be suppressed by conformation-disrupting AURKA inhibitors such as CD-532. Our findings elucidate two independent mechanisms of PKA-driven tumor cell growth and offer insight into drug targets for study in FLC and other PKA-dependent malignancies.

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