Cell Liposarcoma Research Articles

Lipoblastoma-like tumor of the vulva: a clinicopathologic, immunohistochemical, fluorescence in situ hybridization and genomic copy number profiling study of seven cases

Lipoblastoma-like tumor of the vulva was first described as a benign mesenchymal neoplasm of adipocytic differentiation having features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma. Prior studies of lipoblastoma-like tumor have evaluated PLAG1, HMGA2, and RB1 immunohistochemistry and DDIT3 rearrangement status, with results supporting its distinction from lipoblastoma and myxoid liposarcoma. However, absent RB1 expression was reported in a majority of tested cases, suggesting that lipoblastoma-like tumor may have underlying 13q alterations and be related to RB1-deleted soft tissue tumors. To further understand the molecular genetics of lipoblastoma-like tumor, we examined 7 cases by RB1 immunohistochemistry, DDIT3 and PLAG1 break apart FISH probes, RB1 enumeration FISH probe, and genomic copy number analysis by microarray. Patient age ranged from 21 to 56 years (median 35 years). Clinical follow up was available for 5 patients (71%) ranging 3–264 months (median 74 months). Microscopically, lipoblastoma-like tumor formed large lobules separated by thin and/or thick bands of fibrous tissue and had a prominent network of thin-walled vessels. Each tumor was predominantly composed of spindle cells and lipoblasts with variable quantities of mature adipocytes. RB1 immunohistochemistry exhibited a heterogeneous or “mosaic” pattern of weak and negative nuclear expression in all seven cases. DDIT3 and PLAG1 FISH were negative in each case. No evidence of RB1 regional gain or loss was identified by FISH. Genomic copy number analysis by chromosomal microarray showed a normal diploid profile in six tumors (86%). One tumor had copy number abnormalities consisting of an 11.9 megabase deletion from 1p13.3 to 1p11.2 and monosomy 14. Although lipoblastoma-like tumor has features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma, it is genetically different from these tumors. Furthermore, lipoblastoma-like tumor does not appear to have structural abnormalities of 13q resulting in deletion of RB1.

Establishment of a Novel PDX Mouse Model and Evaluation of the Tumor Suppression Efficacy of Bortezomib Against Liposarcoma

The patient-derived xenograft (PDX) model has been adopted as a major tool for studying tumorigenesis and differentiation in various carcinomas. In addition, it has been used in the development of anticancer agents. PDX models have been among the most meaningful tools used to understand the role of stromal cells and vascular cells in the body, which are major factors in cancer development and the application of therapeutic agents. Also, the establishment of PDX models from liposarcoma patients is considered to be important for understanding lipomagenesis and following drugs development. For these reasons, we developed patient-derived cell (PDC) and PDX models derived from 20 liposarcoma patients. The tissues of these patients were obtained in accordance with the principles of the Samsung Medical Center's ethics policy, and cell culture and xenografting onto the mice were performed under these principles. High-throughput drug screening (HTS) was carried out using established PDCs to select candidate drugs. Among the different candidate anticancer drugs, we tested the effect of bortezomib, which was expected to inhibit MDM2 amplification. First, we confirmed that the PDCs maintained the characteristics of liposarcoma cells by assessing MDM2 amplification and CDK4 overexpression using fluorescence in situ hybridization. Analysis of short tandem repeats and an array using comparative genomic hybridization confirmed that the PDX model exhibited the same genomic profile as that of the patient. Immunohistochemistry for MDM2 and CDK4 showed that the overexpression patterns of both proteins were similar in the PDX models and the PDCs. Specifically, MDM2 amplification was observed to be significantly correlated with the successful establishment of PDX mouse models. However, CDK4 expression did not show such a correlation. Of the anticancer drugs selected through HTS, bortezomib showed a strong anticancer effect against PDC. In addition, we observed that bortezomib suppressed MDM2 expression in a dose-dependent manner. In contrast, p21 tended to elicit an increase in PDC expression. Treatment of the PDX model with bortezomib resulted in an anticancer effect similar to that seen in the PDCs. These results support that PDCs and PDX models are among the most powerful tools for the development and clinical application of anticancer drugs for the treatment of liposarcoma patients.

Status of programmed death-ligand 1 expression in sarcomas

BackgroundSarcomas are challenging to study because of their rarity and histomorphological complexity. PD1 and PD-L1 inhibitors showed a promising anti-tumor effect in solid tumors, where a relationship between PD-L1 expression and the objective response has been evidenced.MethodsIn this study, we examined PD-L1 expression in 16 bone and soft tissue sarcoma cell lines of 11 different subtypes by means of western blot, flow cytometry and immunocytochemistry, and in 230 FFPE patient-derived tumor tissues by means of immunohistochemistry using three different antibody clones. The association between PD-L1 expression and clinicopathological features was evaluated.ResultsWe demonstrated that PD-L1 protein is highly expressed in pleomorphic rhabdomyosarcoma, fibrosarcoma, and dedifferentiated liposarcoma (DDLPS) cell lines. From the tissue microarray, undifferentiated pleomorphic sarcoma showed ≥ 1% immunoreactivity in 20%, 17.6%, and 16.3% of the cases with PD-L1 22C3, SP263, and SP142 antibodies, respectively. In whole sections stained with a PD-L1 22C3 antibody, DDLPS showed ≥ 1% immunoreactivity in 21.9% of the cases. In DDLPS group, cases with ≥ 1% PD-L1 expression showed statistically significantly worse recurrence-free survival (P = 0.027) and overall survival (P = 0.017) rates. Upon interferon–gamma treatment, the mRNA expression levels of PD-L1 were elevated in the HS-RMS-1, LIPO-224B, MLS1765, RH30, and RH41 cell lines.ConclusionsWe found that the expression of PD-L1 in sarcoma differs depending on the histologic subtype and the PD-L1 antibody clones. These results may serve as primary data for the selection of appropriate patients when applying PD1/PD-L1 inhibitor therapy in sarcoma.

The Use of Adjuvant or Neoadjuvant Chemotherapy in Extremity and Truncal Sarcoma

Although neoadjuvant chemotherapy has been an established component of multimodality cancer care for patients with pediatric sarcomas for the past 25 years, the role of adjuvant or neoadjuvant chemotherapy in the management of adult patients with soft tissue sarcoma (STS) amenable to treatment with curative intent remains controversial. Overall, meta-analyses have revealed modest improvements in survival outcomes with the use of adjuvant or neoadjuvant chemotherapy, but individual trials have demonstrated inconsistent results leading some to question the robustness and external validity of the results. A recent randomized trial using anthracycline- and ifosfamide-based chemotherapy has provided further positive evidence in support of neoadjuvant chemotherapy for adult STS patients, but concerns persist regarding the risks of chemotherapy-related toxicities and the generalizability of the findings. Given the substantial risk of distant recurrence and disease-specific death for adult STS patients with tumors greater than 10 cm, especially those with synovial sarcoma and myxoid or round liposarcoma histologies, these patients should be strongly considered for neoadjuvant chemotherapy as part of a combined modality approach. The impact of recent level I data on the broader implementation of adjuvant or neoadjuvant chemotherapy in adult STS remains to be seen. This review contains 5 figures and 34 references Key Words: chemotherapy, limb salvage, myxoid/round cell liposarcoma, multimodality therapy, soft tissue sarcoma, surgery, survival, synovial sarcoma, undifferentiated pleomorphic sarcoma

The Use of Adjuvant or Neoadjuvant Chemotherapy in Extremity and Truncal Sarcoma

Although neoadjuvant chemotherapy has been an established component of multimodality cancer care for patients with pediatric sarcomas for the past 25 years, the role of adjuvant or neoadjuvant chemotherapy in the management of adult patients with soft tissue sarcoma (STS) amenable to treatment with curative intent remains controversial. Overall, meta-analyses have revealed modest improvements in survival outcomes with the use of adjuvant or neoadjuvant chemotherapy, but individual trials have demonstrated inconsistent results leading some to question the robustness and external validity of the results. A recent randomized trial using anthracycline- and ifosfamide-based chemotherapy has provided further positive evidence in support of neoadjuvant chemotherapy for adult STS patients, but concerns persist regarding the risks of chemotherapy-related toxicities and the generalizability of the findings. Given the substantial risk of distant recurrence and disease-specific death for adult STS patients with tumors greater than 10 cm, especially those with synovial sarcoma and myxoid or round liposarcoma histologies, these patients should be strongly considered for neoadjuvant chemotherapy as part of a combined modality approach. The impact of recent level I data on the broader implementation of adjuvant or neoadjuvant chemotherapy in adult STS remains to be seen. This review contains 5 figures and 34 references Key Words: chemotherapy, limb salvage, myxoid/round cell liposarcoma, multimodality therapy, soft tissue sarcoma, surgery, survival, synovial sarcoma, undifferentiated pleomorphic sarcoma

SBF-1 preferentially inhibits growth of highly malignant human liposarcoma cells

Frequent local recurrence and metastasis are generally involved in human liposarcoma, but the management is a challenge. There is an urgent need for improved effective therapy. In the present study, we reported that SBF-1, a steroidal glycoside, inhibited the growth of cultured highly malignant human liposarcoma SW872-S cells in vitro and in vivo. SBF-1 down-regulated the phosphorylation of protein kinase B (AKT) and thus reduced cell adhesion to fibronectin and laminin. Then we found that SBF-1 inhibited the expression of oxysterol binding protein (OSBP) in SW872-S cells, indicating that OSBP may be involved in malignant liposarcoma cell survival. Cancer cell growth and AKT phosphorylation were inhibited significantly upon knockdown of OSBP in SW872-S cells in vitro. Taken together, these results suggest that SBF-1 causes an apparent loss of OSBP function in SW872-S cells, resulting in growth inhibition. Based on our findings, OSBP serves as a potential therapeutic target for human liposarcoma.

Periplocin, the most anti-proliferative constituent of Periploca sepium, specifically kills liposarcoma cells by death receptor mediated apoptosis

Background: During a screening of Chinese plants traditionally used for the treatment of cancer and related diseases, extracts of the root bark of Periploca sepium Bunge showed strong cytotoxic activity.Purpose: Isolate and identify cytotoxic compounds from P. sepium and investigate the effects and mechanism of action on different cancer cell lines.Methods: Extracts obtained with solvents of different polarities of the root bark of P. sepium were tested for their anti-proliferative effects. The most active extract was subjected to activity-guided fractionation using different chromatographic methods. The most active compound was further investigated on sarcoma cell lines regarding its effects concerning apoptosis, DNA damage and death receptor expression.Results: We isolated the cardiac glycosides periplocin, glucosyl divostroside, periplogenin, periplocymarin and periplocoside M with periplocin exhibiting the lowest IC50 value against leukemia and liposarcoma cells. Liposarcomas are rare tumors within the heterogeneous group of soft tissue sarcomas and respond poorly to conventional treatments. Periplocin led to growth inhibition and apoptosis induction by changing the expression of death receptors and inducing DNA double strand breaks in SW-872 cells.Conclusion: Periplocin displays a promising mechanism of action in sarcoma cells because altering the death receptor expression is an interesting target in sarcoma treatment especially to overcome TRAIL resistance.

1659P - Combination of eribulin plus gemcitabine in L-sarcomas

Background: Eribulin (Halaven®; Eisai Co., Tokyo, Japan) is a synthetic analogue of halichondrin B that was approved for advanced liposarcoma. Eribulin, besides its well stablished cytotoxic activity, induces vascular remodelling and increased tumor perfusion, as well as inhibits pericyte- and endothelial-driven angiogenesis, which could facilitate the distribution of other drugs within the tumor. Altogether, we hypothesize that eribulin and gemcitabine, acting in different cell cycle phases and modulating distintly tumour microenvironment, could be synergistic, without overlapping toxicity. Methods: CP0024 human leiomyosarcoma primary cell line, SK-UT-1 human leiomyosarcoma cell line and, 93T449 and 94T778 human liposarcoma cell lines were treated with increased concentrations of eribulin (1x10-7M to 1x10-11M) or gemcitabine (1x10-9M to 1x10-13M) to determine IC50 values. Combination index values of eribulin plus gemcitabine were calculated, after treating L-sarcoma cell lines with both drugs using the following administration sequences: concomitant (E+G), eribulin followed by gemcitabine (E→G) and gemcitabine followed by eribulin (G→E). Cell viability, at 72 hours, was measured by MTS cell proliferation assay. Results: The IC50 values determined for eribulin ranged between 0.28nM (SK-UT-1) and 1.98nM (94T778), while IC50 values of gemcitabine ranged between 2.10nM (SK-UT-1) and 7.02nM (94T778). The combination index values at ED50 (the effective doses at which 50% of cell killing occurred) ranged: between 0.27 (SK-UT-1) and 0.89 (94T778), when cell lines were treated with E+G; between <0.10 (SK-UT-1) and 0.33 (CP0024) when treated with G→E; and between <0.10 (SK-UT-1) and 0.20 (CP0024) when cells were treated with E→G. All the cell lines showed a higher synergism when treated using the E→G administration sequence. Conclusions: Eribulin and gemcitabine combination is synergic in L-sarcoma cell lines. The administration of eribulin, followed by gemcitabine is the recommended administration sequence for further studies. The mechanisms underlying eribulin plus gemcitabine synergy, as well as predictive biomarkers of response to the combination, will be evaluated in in vitro and in vivo models of L-sarcoma. Legal entity responsible for the study: Instituto de Biomedicina de Sevilla. Funding: Eisai Co., Ltd. Disclosure: D.S. Moura: Corporate-sponsored research fees: Eisai. Co. Ltd. J. Martin-Broto: Corporate-sponsored research fees: Eisai. Co., Ltd., Novartis, PharmaMar; Honoraria or consultation fees: Lilly, Novartis, PharmaMar; Company sponsored speaker’s bureau: PharmaMar. All other authors have declared no conflicts of interest.

Silencing of perilipin by short hairpin RNA inhibits proliferation and induces apoptosis in liposarcoma cells.

Previous studies have identified that perilipin-1 (PLIN1) is a highly specific marker for liposarcoma. However, its functions have yet to be fully elucidated. The aim of the present study was to investigate the potential role of PLIN1 in the proliferation, migration and apoptosis of liposarcoma cells. Short hairpin RNA was designed to inhibit PLIN1 levels. Cell proliferation was monitored by Cell Counting Kit‑8 assay and cell migration determined by wound healing assay. Flow cytometry was performed to assess the cell cycle distributions and apoptosis in liposarcoma cells. The results demonstrated that the expression of PLIN1 was significantly upregulated in liposarcoma tumor tissues compared with normal adipose tissues. Silencing of PLIN1 by short hairpin RNA significantly inhibited proliferation and migration and induced G1 phase cell cycle arrest and apoptosis in liposarcoma cell lines. It was identified that PLIN1 serves a crucial role in the pathogenesis and progression of liposarcoma and may be a potential therapeutic target for its clinical management.

MiR-409 Inhibits Human Non-Small-Cell Lung Cancer Progression by Directly Targeting SPIN1

Lung cancers, the leading cause of cancer mortality worldwide, are characterized by a high metastatic potential. Growing evidence reveals that Spindlin 1 (SPIN1) is involved in tumor progression and carcinogenesis. However, the role of SPIN1 in non-small-cell lung cancer (NSCLC) and the molecular mechanisms underlying SPIN1 in human NSCLC remain undetermined. Here we examined the function of SPIN1 in human NSCLC and found that the expression of SPIN1 was closely correlated with the overall survival and poor prognosis of NSCLC patients. Aberrant regulation of microRNAs (miRNAs) has an important role in cancer progression. We revealed that miR-409 inhibits the expression of SPIN1 by binding directly to the 3′ UTR of SPIN1 using dual-luciferase reporter assays. Overexpression of miR-409 significantly suppressed cell migration, growth, and proliferation by inhibiting SPIN1 in vitro and in vivo. SPIN1 overexpression in miR-409-transfected NSCLC cells effectively rescued the suppression of cell migration, growth, and proliferation regulated by miR-409. miR-409 regulates the PI3K/AKT (protein kinase B) pathway in NSCLC. Moreover, clinical data showed that NSCLC patients with high levels of miR-409 experienced significantly better survival. miR-409 expression was also negatively associated with SPIN1 expression. Taken together, these findings highlight that the miR-409/SPIN1 axis is a useful pleiotropic regulatory network and could predict the metastatic potential in NSCLC patients early, indicating the possibility that miR-409 and SPIN1 might be attractive prognostic markers for treating NSCLC patients.

Next frontiers in systemic therapy for soft tissue sarcoma

Soft tissue sarcoma (STS) is a heterogeneous disease with more than 50 subtypes. Once the disease reached locally advanced or metastatic status, the standard treatment remains to be chemotherapy. Current understanding of the underlying molecular and genomic mechanisms of different histology subtypes have led to encouraging development of new drugs in treating STS. Besides molecular targeted therapy, immunotherapy have also shown promising advancement in solid tumor treatments. This review will be in two parts. The first part will focus on the molecular targeted agents aiming at molecular or genetic alterations that are more specific in STS, including antiangiogenic molecules, plate-derived growth factor receptor alpha (PDGFRA) monoclonal antibody, colony-stimulating factor-1 receptor (CSF-1R), selective inhibitors of nuclear export (SINE), cyclin-dependent kinase 4/6 (CDK 4/6), mdm2, and epigenetic regulators. We also discussed in depth about how current precision medicine influences the treatment paradigm in STS. In the second part, we focus on the landscape of immunotherapy in STS including immune checkpoint inhibitors (ICIs) and the combinations of immunotherapies or with other molecules that could modulate the tumor microenvironment. These included the program cell death-1 receptor and its ligand (PD-1/PD-L1), cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the combination with anti-angiogenic agents that could facilitate the trafficking of T cells. Strategies targeting the tumor-associated antigen NY-ESO-1, which is commonly observed in synovial sarcoma and myxoid round cell liposarcoma, via viral vaccines and adoptive T cells will also be discussed. These new frontiers of treatment that are developed with better insights into sarcoma and immune biology hopefully will change the treatment paradigm of advanced STS in the future.

Enhancement of Soft Tissue Sarcoma Cell Radiosensitivity by Poly(ADP-ribose) Polymerase-1 Inhibitors.

Soft tissue sarcomas (STS) are aggressive tumors with a poor prognosis. Poly(ADP-ribose) polymerase (PARP)-1 inhibitors (PARPi) enhance the cytotoxic effects of radiation. In this study, we evaluated the effect of PARPi on survival and DNA damage of irradiated STS cells. For clonogenic assays, STS cell lines were irradiated with or without olaparib, iniparib or veliparib pretreatment. The effect of PARP inhibition on γ-H2AX and Rad51 foci formation, on PARP-1, phospho-ERK and cleaved caspase-3 protein expression and on cell cycle progression was evaluated on irradiated rhabdomyosarcoma cells pretreated with olaparib. The results from this work showed that PARPi induced significant radiosensitization in STS cells. Rhabdomyosarcoma cells showed the highest increase in radiosensitivity, with a radiosensitization enhancement ratio at 50% survival (ER50) of 3.41 with veliparib. All PARPi exerted a synergistic effect when combined with radiation. Fibrosarcoma cells showed an ER50 of 2.29 with olaparib. Leiomyosarcoma and liposarcoma cells showed their highest ER50 with veliparib (1.71 and 1.84, respectively). In rhabdomyosarcoma, olaparib enhanced the formation of radiation-induced γ-H2AX/Rad51 foci and PARP-1 cleavage, induced slightly increased expression of cleaved caspase-3 and reduced phospho-ERK expression. Moreover, the combination of olaparib and radiation resulted in a significantly enhanced cell cycle arrest in the G2/M phase compared to the two treatments alone. In conclusion, we have shown that PARPi are potent radiosensitizers of human STS cells. These results support the pursuit of further investigations into the effects of PARPi combined with radiation on STS.

HMGA1/E2F1 axis and NFkB pathways regulate LPS progression and trabectedin resistance

Although the medical treatments of sarcoma have evolved in the last years, a significant portion of patients develops recurrence after therapies suggesting the need to identify novel targets to improve the treatments. By the use of patient-derived and established cell lines from liposarcoma, as well as specimens from patient biopsies, we found that HMGA1 is involved in the progression of dedifferentiated and myxoid liposarcoma. The immunohistochemical and RT-PCR analyses of 68 liposarcoma specimens revealed a significant high expression of HMGA1, at the protein and RNA levels, both in myxoid and dedifferentiated liposarcoma subtypes compared with differentiated ones. Loss- and gain-of-function experiments by HMGA1-specific depletion and overexpression in dedifferentiated and myxoid liposarcoma cells showed the contribution of this oncogenic factor in cell proliferation, motility, invasion, and drug resistance. The in vitro and in vivo treatment of myxoid liposarcoma with trabectedin, a drug with a potent anti-tumor activity, revealed downregulation of HMGA1, E2F1, and its-downstream targets, vimentin and ZEB1, indicating a critical role of trabectedin in inhibiting the mesenchymal markers of these tumors through the HMGA1/E2F1 axis. These data were also confirmed in patients’ tumor biopsies being HMGA1, E2F1, and vimentin expression significantly reduced upon trabectedin therapy, administered as neo-adjuvant chemotherapy. Furthermore, trabectedin treatment inhibits in vitro NFkB pathway in mixoyd liposarcoma sensitive but not in resistant counterparts, and the inhibition of NFkB pathway re-sensitizes the resistant cells to trabectedin treatment. These data support the rational for combining NFkB inhibitors with trabectedin in liposarcoma patients, who have become resistant to the drug.

Abstract 616: Interferon gamma induced transformation of the cold tumor microenvironment in patients with NY-ESO-1 expressing sarcomas

Abstract Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) cells homogeneously express high levels of NY-ESO-1 and other cancer/testis antigens, which makes these sarcoma types good candidates for T cell immunotherapy. However, these tumors demonstrate a “cold” microenvironment, with low cell surface expression of human leukocyte antigen (HLA) molecules and few infiltrating T cells. Interferon gamma (IFNγ) has been used both as a single agent and in combination with other immunotherapies in cancers with “hot”, highly inflamed tumor microenvironments such as melanoma. To date, little work has explored its impact on immunologically quiet tumors. In order to increase the expression of HLA on the tumor cell surface and improve the T cell recognition and cytotoxicity, we initiated a pilot “window of opportunity” clinical trial, 6 SS/MRCL patients were treated with subcutaneous systemic interferon gamma (IFNγ) weekly for 2 or 4 weeks at a dose of 100 mcg/m2. The primary objective of the study was to determine if HLA expression increased on post-treatment biopsies in comparison to pre-treatment biopsies. The treatment was relatively well-tolerated, patients experienced flu-like symptoms with no severe adverse effects. Patients' sera, PBMCs and tumor biopsies were collected pre- and post-IFNγ treatment for further analysis. Several cytokines including interleukin-16, microphage migration inhibitory factor and CXCL-10 etc. changed considerably in patients' periphery. Transcriptome profiling on the PBMCs showed significant changes in some immune regulatory genes in T cells and monocytes. Flow cytometry analysis of the tumor biopsies showed significant increase of both class I and class II HLA on the tumor surface in all treated patients. Tumor infiltrating immune cell frequencies increased by 3-10 times, of which, the majority were T cells. Functional assay of expanded tumor infiltrating lymphocytes (TIL) showed an increased and broadened tumor-associated peptide recognition capability. However, in all evaluable tumors there was an increase in PD-L1 either on tumor or on infiltrating macrophages. In conclusion, weekly IFNγ treatment is well tolerated in SS/MRCL patients and it can significantly enhance the expression of HLA on tumor surface, and increase T cell infiltration; however, increased PD-L1 expression on tumor cells and infiltrating immune cells may help tumors evade T cell elimination. Strategies combining PD-1 blockade and IFNγ should be explored. Citation Format: Shihong Zhang, Sara Cooper, Bailey Donahue, Venu G. Pillarisetty, Robin L. Jones, Stanley R. Riddell, Brian A. Van Tine, Seth M. Pollack. Interferon gamma induced transformation of the cold tumor microenvironment in patients with NY-ESO-1 expressing sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 616.

Pilot study of NY-ESO-1c259 T cells in advanced myxoid/round cell liposarcoma.

3005Background: Metastatic myxoid/round cell liposarcoma (MRCLS) has a poor prognosis. NY-ESO-1 is expressed in 80-90% of MRCLS tumors. This study evaluates affinity enhanced autologous NY-ESO-1c25...

Trabectedin modulates the senescence-associated secretory phenotype and promotes cell death in senescent tumor cells by targeting NF-κB.

Therapy-induced senescence is a major cellular response to chemotherapy in solid tumors. Senescent tumor cells acquire a secretory phenotype, or SASP, and produce pro-inflammatory factors, whose expression is largely under NF-κB transcriptional control. Secreted factors play a positive role in driving antitumor immunity, but also exert negative influences on the microenvironment, and promote tumor growth and metastasis. Moreover, subsets of cancer cells can escape the senescence arrest, driving tumor recurrence after treatments. Hence, removal the senescent tumor cells, or reprogramming of the senescent secretome, have become attractive therapeutic options.The marine drug trabectedin was shown to inhibit the production of pro-inflammatory mediators by tumor-infiltrating immune cells and by myxoid liposarcoma cells. Here, we demonstrate that trabectedin inhibits the SASP, thus limiting the pro-tumoral activities of senescent tumor cells in vitro. We show that trabectedin modulates NF-κB transcriptional activity in senescent tumor cells. This results in disruption of the balance between antiapoptotic and proapoptotic signals, and sensitization of cells to Fas-mediated apoptosis. Further, we found that trabectedin inhibits escape from therapy-induced senescence, at concentrations that do not affect the viability of bulk tumor population.Overall, our data demonstrate that trabectedin has the potential to inhibit multiple detrimental effects of therapy-induced senescence.

Case Report: An incidental finding of an metastases noted in a "cancer to cancer adrenal tumor " from a large malignant nerve sheath tumor of the thigh.

Current guidelines are vague for the management of soft tissue sarcomas, specifically malignant peripheral nerve sheath tumors (MPNST), regarding staging the disease with the use of routine abdominal imaging. The most recent guidelines from the National Comprehensive Cancer Network (NCCN) recommends to "consider" abdominal/pelvic CT imaging for certain sub groups of sarcomas (e.g., myxoid/round cell liposarcoma, epithelial sarcoma, angiosarcoma, leiomyosarcoma), but provide no guidance on other sarcoma subtypes regardless of tumor size. We report a case of a very large large MPNST in a 40 year-old-female with neurofibromatosis type 1 who was incidentally found to have adrenal metastasis.

Optical mapping reveals a higher level of genomic architecture of chained fusions in cancer.

Genomic rearrangements are common in cancer, with demonstrated links to disease progression and treatment response. These rearrangements can be complex, resulting in fusions of multiple chromosomal fragments and generation of derivative chromosomes. Although methods exist for detecting individual fusions, they are generally unable to reconstruct complex chained events. To overcome these limitations, we adopted a new optical mapping approach, allowing megabase-length genome maps to be reconstructed and rearranged genomes to be visualized without loss of integrity. Whole-genome mapping (Bionano Genomics) of a well-studied highly rearranged liposarcoma cell line resulted in 3338 assembled consensus genome maps, including 72 fusion maps. These fusion maps represent 112.3 Mb of highly rearranged genomic regions, illuminating the complex architecture of chained fusions, including content, order, orientation, and size. Spanning the junction of 147 chromosomal translocations, we found a total of 28 Mb of interspersed sequences that could not be aligned to the reference genome. Traversing these interspersed sequences using short-read sequencing breakpoint calls, we were able to identify and place 399 sequencing fragments within the optical mapping gaps, thus illustrating the complementary nature of optical mapping and short-read sequencing. We demonstrate that optical mapping provides a powerful new approach for capturing a higher level of complex genomic architecture, creating a scaffold for renewed interpretation of sequencing data of particular relevance to human cancer.

Homogeneous myxoid liposarcomas mimicking cysts on MRI: A challenging diagnosis

ObjectivesMyxoid liposarcoma (M-LPS) is the second most frequent subtype of liposarcoma. Foci of fat on MRI are strongly suggestive of this diagnosis. The aims of this study are to (i) assess the prevalence of perfectly homogeneous M-LPS-mimicking cyst and characterize their associated clinical and pathological features and to (ii) identify helpful clues to prevent misdiagnosis when encountered with a cyst-like lesion in soft tissue parts. MethodsMR images from 32 consecutive pathologically proven M-LPS and round cell liposarcomas (RC-LPS) were retrospectively reviewed independently by two radiologists at our institution. Location, morphology, signals, lesion architecture, heterogeneity, margins and periphery were systematically assessed in each case. Medical records were checked for initial and definitive histopathological diagnosis, therapeutic managements and outcomes. Histopathological specimens of cyst-like M-LPS were reviewed for the study. ResultsWe have identified seven perfectly homogeneous well-defined cyst mimickers (21.9%) located on the limbs, all but one being deep-seated. These tumors were significantly smaller than the conventional M-LPS (p = 0.0005). Six lesions were initially diagnosed as benign; 4 patients underwent marginal surgical resection without prior diagnosis and 2 cases were put under medical surveillance, one of which progressed towards classical RC-LPS on follow-up MRI. No specific pathological features could be identified nor were any clinical adverse outcomes recorded. Conclusion“Cyst” on MRI, without pathological adjacent joint, necessitates ultrasonography with Doppler and intravenous Gadolinium agent injections as subsets of M-LPS can mimic cyst on MRI. Cyst-like M-LPS, due to their smaller size and relative favorable outcome, could have better prognosis.

Abstract B09: Novel sarcoma treatments identified via drug sensitivity/resistance screening of sarcoma cell lines

Abstract Sarcomas comprise a plethora of subtypes and each should be regarded as ultra-orphan malignancy. Over the last century incremental improvements of sarcoma therapies have provided better survival; however, treatment options appear to have been exhausted and new alternatives beyond traditional chemotherapeutic regimens are much needed. To broaden the repertoire of antisarcoma drugs, we applied a direct drug testing approach. Using a library of 349 anticancer compounds (FDA-approved/under clinical trial) and panels of liposarcoma and osteosarcoma cell lines, we selected a group of potential novel antisarcoma therapeutics and retested them against cells from primary tumors. We are also investigating genomic and molecular features to find potential drug response biomarkers. Since all those compounds have been approved or are under clinical trials, they present a unique shortcut repurposing opportunity for personalized sarcoma treatment. Citation Format: Iwona Grad, Pilar Ayuda, Robert Hanes, Jorrit Enserink, Ola Myklebost. Novel sarcoma treatments identified via drug sensitivity/resistance screening of sarcoma cell lines [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B09.