Open‐label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors

Graff, Julie N.; Higano, Celestia S.; Hahn, Noah M.; Taylor, Matthew H.; Zhang, Bin; Zhou, Xiaofei; Venkatakrishnan, Karthik; Leonard, E. Jane; Sarantopoulos, John

doi:10.1002/cncr.30073

Cited by 28 publications

(19 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…49 In our study, this was exemplified by patient #35153 where some of the emerging somatic alterations, such as loss of PTEN or RB1 and the novel gain of 20q13, which harbors the AURKA gene, have been reported as frequent changes in t-NEPC [50][51][52][53][54] and represent a potential therapeutic target. 55 AR antagonism may induce lineage alterations and thus promote enhanced lineage plasticity, 19,[52][53][54]56 as previously reported by us and others. 11,19 Furthermore, we describe several cases in which genomic alterations evolve with disease progression, but at present it is unclear whether these are associated with response/resistance to abiraterone/ enzalutamide.…”

Section: Discussionsupporting

confidence: 78%

“…In the present study, this was exemplified by patient #35153 where some of the emerging somatic alterations, such as loss of PTEN or RB1 and the novel gain of 20q13, which harbors the AURKA gene, have been reported as frequent changes in t-NEPC 50–54 and represent a potential therapeutic target 55 . AR antagonism may induce lineage alterations and thus promote enhanced lineage plasticity 19, 52–54, 56 , as previously reported by us and others 11, 19 .…”

Section: Discussionmentioning

confidence: 82%

See 1 more Smart Citation

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Belic

Graf

Bauernhofer

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

In patients with metastatic castrate resistant prostate cancer (mCRPC), circulating tumor DNA (ctDNA) analysis offers novel opportunities for the development of non-invasive biomarkers informative of treatment response with novel agents targeting the androgen-receptor (AR) pathway, such as abiraterone or enzalutamide. However, the relationship between ctDNA abundance, detectable somatic genomic alterations and clinical progression of mCRPC remains unexplored. Our study aimed to investigate changes in plasma DNA during disease progression and their associations with clinical variables in mCRPC patients. We analyzed ctDNA in two cohorts including 94 plasma samples from 25 treatment courses (23 patients) and 334 plasma samples from 125 patients, respectively. We conducted whole-genome sequencing (plasma-Seq) for genome-wide profiling of somatic copy number alterations and targeted sequencing of 31 prostate cancer-associated genes. The combination of plasma-Seq with targeted AR analyses identified prostate cancer-related genomic alterations in 16 of 25 (64%) treatment courses in the first cohort, in which we demonstrated that AR amplification does not always correlate with poor abiraterone and enzalutamide therapy outcome. As we observed a wide variability of ctDNA levels, we evaluated ctDNA levels and their association with clinical parameters and included the second, larger cohort for these analyses. Employing altogether 428 longitudinal plasma samples from 148 patients, we identified the presence of bone metastases, increased lactate dehydrogenase and prostate-specific antigen (PSA) as having the strongest association with high ctDNA levels. In summary, ctDNA alterations are observable in the majority of patients with mCRPC and may eventually be useful to guide clinical decision-making in this setting.

show abstract

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 82%

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Belic

Graf

Bauernhofer

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Our analysis of MCF10A cells showed that non-transformed cells do display nuclear abnormalities and arrested proliferation in response to alisertib treatment, which warrants an assessment of long-term effects on normal tissues. Clinically, antitumor effects of alisertib were reported in solid and hematological cancers [43–45], and long-term progression-free survival or complete response was observed in some cases in patients with solid cancers or in patients with recurrent ovarian cancer [46, 47].…”

Section: Discussionmentioning

confidence: 99%

TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells

et al. 2018

View full text Add to dashboard Cite

Genomic instability is a hallmark feature of cancer cells, and can be caused by defective DNA repair, for instance due to inactivation of BRCA2. Paradoxically, loss of Brca2 in mice results in embryonic lethality, whereas cancer cells can tolerate BRCA2 loss. This holds true for multiple DNA repair genes, and suggests that cancer cells are molecularly "rewired" to cope with defective DNA repair and the resulting high levels of genomic instability. In this study, we aim to identify genes that genomically unstable cancer cells rely on for their survival. Using functional genomic mRNA (FGmRNA) profiling, 16,172 cancer samples were previously ranked based on their degree of genomic instability. We analyzed the top 250 genes that showed a positive correlation between FGmRNA levels and the degree of genomic instability, in a co-functionality network. Within this co-functionality network, a strong cluster of 11 cell cycle-related genes was identified, including TPX2. We then assessed the dependency on these 11 genes in the context of survival of genomically unstable cancer cells, induced by BRCA2 inactivation. Depletion of TPX2 or its associated kinase Aurora-A preferentially reduced cell viability in a panel of BRCA2-deficient cancer cells. In line with these findings, BRCA2-depleted and BRCA2-mutant human cell lines, or tumor cell lines derived from Brca2;p53 mice showed increased sensitivity to the Aurora-A kinase inhibitor alisertib, with delayed mitotic progression and frequent mitotic failure. Our findings reveal that BRCA2-deficient cancer cells show enhanced sensitivity to inactivation of TPX2 or its partner Aurora-A, which points at an actionable dependency of genomically unstable cancers.

show abstract

“…Alisertib (MLN8237) is an orally available ATP-competitive, highly selective inhibitor of AURKA (40-fold selective for AURKA compared with AURKB) [24]. Clinical trials testing Alisertib as a single agent or in combination with conventional chemotherapies are ongoing for the treatment of various malignancies [14,[25][26][27][28][29][30][31][32][33]. Of the entire AURKA inhibitors, only Alisertib has proceeded to phase III evaluation [34].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma

et al. 2020

View full text Add to dashboard Cite

Background: Cholangiocarcinoma is a highly lethal neoplasm for which the currently available chemotherapeutic agents are suboptimal. Numerous studies show that alterations in expression of genes related to mitotic spindle and mitotic checkpoint are involved in chromosomal instability and tumor progression in various malignancies. This study aimed to evaluate these genes in cholangiocarcinoma patients. Material and methods: Different public datasets were analyzed to examine the expression of 76 selected mitotic spindle checkpoint genes including Aurora Kinase A (AURKA) in cholangiocarcinoma. Afterwards, cell number counting, CCK-8 assay, and Caspase 3/7 assay were used to explore the antitumor effect of AURKA inhibitor Alisertib in vitro. In addition, xenograft model was used to evaluate the antitumor effect of Alisertib in vivo. Furthermore, siRNA mediated silencing of AURKA was used to verify the function of AURKA in cholangiocarcinoma. Results: Components of the mitotic spindle checkpoint, including AURKA, were broadly dysregulated in human cholangiocarcinoma. High AURKA mRNA expression was associated with poor survival in cholangiocarcinoma patients within different datasets. AURKA specific inhibitor Alisertib, inhibited cell growth, induced cell cycle arrest in G2/M phase, and promoted apoptosis in cholangiocarcinoma cell lines. Additionally, Alisertib also inhibited tumor growth in a cholangiocarcinoma xenograft mouse model. Furthermore, AURKA knockdown by siRNA recapitulated the antitumor effect of Alisertib. AURKA expression was also highly correlated with its interaction proteins Polo-like kinase 1(PLK1) and Targeting protein for xenopus kinesin-like protein2 (TPX2) in different cholangiocarcinoma datasets. Conclusions: Highly expressed AURKA confers poor outcomes in cholangiocarcinoma and may represent a rational therapeutic target.

show abstract

Open‐label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors

Abstract: Alisertib at 20 mg twice daily on days 1 to 7 with intravenous docetaxel at 75 mg/m(2) on day 1 in a 21-day cycle was well tolerated, and the combination demonstrated antitumor activity. Cancer 2016;122:2524-33. © 2016 American Cancer Society.

Cited by 28 publications

References 33 publications

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells

Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma

Contact Info

Product

Resources

About