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Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma.

ABSTRACT: Myxoid liposarcoma is a rare form of soft-tissue sarcoma. Although most patients initially respond well to treatment, approximately 21% relapse, highlighting the need for alternative treatments. To identify novel treatment regimens and gain a better understanding of myxoid liposarcoma tumor biology, we screened various candidate and approved targeted therapeutics and chemotherapeutics against myxoid liposarcoma cell lines. Therapeutics that target angiogenesis showed antitumor activity. The small molecule inhibitor axitinib, which targets angiogenesis by inhibiting the VEGFR and PDGFR families and c-Kit, inhibited cell cycle progression and induced apoptosis in vitro, as well as having significant antitumor activity against MLS 1765 myxoid liposarcoma xenografts in mice. Axitinib also displayed synergistic antitumor activity in vitro when combined with the potassium channel ionophore salinomycin or the BH3 mimetic ABT-737. Another angiogenesis-targeting therapeutic, 4EGI-1, which targets the oncoprotein eIF4E, significantly decreased angiogenic ligand expression by myxoid liposarcoma cells and reduced tumor cell growth. To verify this oncogenic addiction to angiogenic pathways, we utilized VEGFR-derived ligand traps and found that autocrine VEGFR signaling was crucial to myxoid liposarcoma cell survival. Overall, these findings suggest that autocrine angiogenic signaling through the VEGFR family is critical to myxoid liposarcoma cell survival and that further study of axitinib as a potential anticancer therapy is warranted.

SUBMITTER: Kerr LT

PROVIDER: S-EPMC5086398 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma.

Kerr Lauren T LT Donoghue Jacqueline F JF Wilding Alexander L AL Johns Terrance G TG

Sarcoma 20161016

Myxoid liposarcoma is a rare form of soft-tissue sarcoma. Although most patients initially respond well to treatment, approximately 21% relapse, highlighting the need for alternative treatments. To identify novel treatment regimens and gain a better understanding of myxoid liposarcoma tumor biology, we screened various candidate and approved targeted therapeutics and chemotherapeutics against myxoid liposarcoma cell lines. Therapeutics that target angiogenesis showed antitumor activity. The smal ...[more]

PMID: 27822137

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Project description:Myxoid liposarcoma (MLS) is a subtype of liposarcoma characterized morphologically by lipomatous differentiation with a myxoid stroma. The purpose of this study was to review clinical and pathological information for patients treated for MLS at our institution to better understand neoadjuvant and adjuvant therapy. An institutional database of sarcomas was queried for patients who were treated for MLS at our institution between 1992 and 2013. Survival curves were constructed using Kaplan-Meier analysis, and univariate and multivariate statistics were performed using the Cox-proportional hazards model and using linear regression. A total of 85 patients with myxoid liposarcoma were identified. The mean and median histologic response rate to treatment for patients who received preoperative radiation therapy was 77.6%. Five-year disease-free survival, distant metastasis-free survival, local recurrence-free survival, and overall survival were 78.6% (95% CI: 67.8-86.1), 84.7% (95% CI: 74.5-91.0), 95.6% (95% CI: 86.9-98.6), and 87.5% (95% CI: 77.2-93.3) respectively. On univariate analysis, there was a trend towards higher necrosis or treatment response rates in patients who received concurrent chemotherapy, 84.7% (95% CI: 75.9-93.4) and 69.5% (95% CI: 55.1-83.8), p=0.061. Tumor size was associated with inferior disease-free and overall survival. Hazard ratio for disease-free survival is 1.08 (per cm) (95% CI: 1.01-1.16), p=0.019. Myxoid liposarcoma exhibits histological response to chemotherapy and radiation therapy. Tumor size appears to be greatest predictor of long-term disease control and overall survival. We were not able to show that chemotherapy provides a clinical benefit with regard to local control, disease-free survival, or overall survival. However, it is important to note that the selected usage of chemotherapy in the highest risk patients confounds this analysis. Further investigation is needed to help better determine the optimal use of chemotherapy in this group of patients.

Project description:Myxoid liposarcoma (LS), the most common subtype of LS, is known to be characterized by the specific t(12;16) resulting in a TLS-CHOP fusion in almost all cases. We wished to address the following questions: (i) Is this genetic hallmark also present in other types of LS with predominant myxoid change? (ii) What is the proportion of cases with the variant EWS-CHOP fusion? (iii) What is the optimal approach for Southern blot detection of TLS breakpoints? We identified 59 LS characterized histologically by >90% myxoid component, in which frozen tissue tumor was available for DNA extraction. These 59 LS with myxoid features were divided into 2 groups: 42 LS with classic myxoid/round cell appearance (myxoid LS) and 17 well-differentiated LS (WDLS) with a predominant (>90%) myxoid component. Within the myxoid LS group, 29 tumors were low grade and 13 high grade (>20% round cell component). Among the 17 predominantly myxoid WDLS, there were 15 low grade and 2 focally high grade tumors. In addition, we selected as control group, 20 LS of other histological types with minimal or no myxoid change (17 WDLS and 3 pleomorphic LS) and 13 myxofibrosarcomas. Southern blot analysis was performed in all cases using a CHOP cDNA probe, and in all CHOP rearranged cases using a TLS cDNA probe. Probe/enzyme combinations for Southern blot analysis were CHOP exon 3-4 cDNA probe with BamHI or SacI, TLS exon 3-6 cDNA probe with BclI. All 42 cases of myxoid LS showed a CHOP rearrangement and 38 of them also had a TLS rearrangement. Among the 4 myxoid LS without Southern blot evidence of TLS rearrangement, 1 showed an EWS-CHOP fusion by Southern blotting and reverse transcriptase-polymerase chain reaction and in another case, reverse transcriptase-polymerase chain reaction detected a TLS-CHOP fusion transcript. None of the predominantly myxoid WDLS and none of the tumors included in the control group showed rearranegements with CHOP probe. In addition, 12 predominantly myxoid WDLS, 10 other LS, and 5 myxofibrosarcoma from the control group were also tested for TLS rearrangement; all were negative. The TLS-CHOP fusion is highly sensitive and specific for the entity of classic myxoid/round cell LS. Other types of LS, even with a predominant myxoid component, lack the TLS-CHOP rearrangement, confirming that they represent a genetically distinct group of LS. The prevalence of the EWS-CHOP variant fusion was approximately 2% in this series. The optimal enzyme for TLS genomic breakpoint detection is BclI.

Dataset Information

Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma.

Publications

Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma.

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