mln-8237 and Liposarcoma

Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor.. This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1-d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design.. Seventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3-4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%).. Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising.. NCT01653028.

Topics: Adult; Aged; Aged, 80 and over; Aurora Kinase A; Azepines; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leiomyosarcoma; Liposarcoma; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrimidines

Liposarcoma (LPS) is one of the most frequently reported type of soft‑tissue sarcoma (STS). Well‑differentiated (WD) LPS and dedifferentiated (DD) LPS are the two most common subtypes. Chemotherapy has been considered to be ineffective in LPS, and novel treatment agents are thus necessary. In this study, we reanalyzed two published microarray data sets of LPS. By comparing the top 50 upregulated genes in DD LPS in both sets of data, we identified 12 overlapping genes. Of note, the top five gene sets enriched in DD LPS in both sets of data were involved in cell cycle regulation. Among the 12 overlapping genes, aurora kinase A (AURKA) is a well‑known gene involved in cell cycle regulation; we thus further investigated this gene. AURKA was significantly upregulated in DD LPS, compared with WD LPS. Among 40 cases of DD LPS in GSE30929, patients with high AURKA expression in tumors had significantly worse distant recurrence‑free survival than those with low expression. In an in vitro model, MLN8237, an AURKA inhibitor, could inhibit AURKA in LPS cell lines with a resultant G2/M arrest. MLN8237 was also reported to exert a cytotoxic effect by inducing apoptosis in LPS cell lines. Furthermore, except for cisplatin, MLN8237 had a significantly synergistic effect with chemotherapy agents against LPS. MLN8237 induced cellular senescence in LPS cell lines with increased expression of DcR2, a senescence biomarker, and upregulated expression of cytokines associated with the senescence‑associated secretory phenotype, including interleukin (IL)‑1α, IL‑6 and IL‑8. Our study identified AURKA as a potential biomarker for predicting poor prognosis in LPS. The findings of the present study suggested the potential of AURKA as a therapeutic target in LPS cell line models, while the novel combination of AURKA inhibitors and chemotherapy requires further investigation.

Topics: Aurora Kinase A; Azepines; Cell Dedifferentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Drug Therapy; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Liposarcoma; Oligonucleotide Array Sequence Analysis; Pyrimidines; Up-Regulation

Aurora kinases have become an attractive target in cancer therapy due to their deregulated expression in human tumors. Liposarcoma, a type of soft tissue sarcoma in adults, account for approximately 20% of all adult soft tissue sarcomas. There are no effective chemotherapies for majority of these tumors. Efforts made to define the molecular basis of liposarcomas lead to the finding that besides the amplifications of CDK4 and MDM2, Aurora Kinase A, also was shown to be overexpressed. Based on these as well as mathematic modeling, we have carried out a successful preclinical study using CDK4 and IGF1R inhibitors in liposarcoma. MLN8237 has been shown to be a potent and selective inhibitor of Aurora A. MLN-8237, as per our results, induces a differential inhibition of Aurora A and B in a dose dependent manner. At a low nanomolar dose, cellular effects such as induction of phospho-Histone H3 (Ser10) mimicked as that of the inhibition of Aurora kinase A followed by apoptosis. However, micromolar dose of MLN-8237 induced polyploidy, a hallmark effect of Aurora B inhibition. The dose dependent selectivity of inhibition was further confirmed by using siRNA specific inhibition of Aurora A and B. This was further tested by time lapse microscopy of GFP-H2B labelled cells treated with MLN-8237. LS141 xenograft model at a dose of 30 mg/kg also showed efficient growth suppression by selective inhibition of Aurora Kinase A. Based on our data, a dose that can target only Aurora A will be more beneficial in tumor suppression.

Topics: Animals; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Aurora Kinase B; Azepines; Cell Proliferation; Humans; Liposarcoma; Mice; Mice, Nude; Protein Kinase Inhibitors; Pyrimidines; Soft Tissue Neoplasms; Xenograft Model Antitumor Assays