bims-myxlip 2021-03-07 papers

Issue of 2021–03–07
six papers selected by
Laura Mannarino, Humanitas Research

J Exp Clin Cancer Res. 2021 Mar 01. 40(1): 83

Selinexor versus doxorubicin in dedifferentiated liposarcoma PDXs: evidence of greater activity and apoptotic response dependent on p53 nuclear accumulation and survivin down-regulation.

Valentina Zuco, Sandro Pasquali, Monica Tortoreto, Silvia Brich, Stefano Percio, Gian Paolo Dagrada, Chiara Colombo, Roberta Sanfilippo, Calogero Lauricella, Mrinal Gounder, Rihan El Bezawy, Marta Barisella, Angelo Paolo Dei Tos, Paolo Giovanni Casali, Alessandro Gronchi, Silvia Stacchiotti, Nadia Zaffaroni.

BACKGROUND: Dedifferentiated liposarcoma (DDLPS), a tumor that lacks effective treatment strategies and is associated with poor outcomes, expresses amplified MDM2 in the presence of wild-type p53. MDM2 ubiquitination of p53 facilitates its XPO1-mediated nuclear export, thus limiting p53 tumor suppressor functions. Consequently, nuclear export is a rational target in DDLPS. We directly compared the antitumor activity of the first-in class XPO1 inhibitor selinexor and doxorubicin, the standard front-line therapy in sarcomas, in DDLPS patient-derived xenografts (PDXs) and primary cell lines.
METHODS: Drug activity was assessed in three PDXs (and two corresponding cell lines) established from the dedifferentiated component of primary untreated retroperitoneal DDLPS with myogenic (N = 2) and rhabdomyoblastic (N = 1) differentiation from patients who underwent surgery. These models were marked by amplification of MDM2, CDK4 and HMGA2 genes.
RESULTS: Selinexor was moderately active in the three PDXs but achieved greater tumor response compared to doxorubicin (maximum tumor volume inhibition: 46-80 % vs. 37-60 %). The PDX harboring rhabdomyoblastic dedifferentiation showed the highest sensitivity to both agents. PDX response to selinexor and doxorubicin was not associated with the extent of MDM2 and CDK4 gene amplification. Interestingly, the most chemosensitive PDX model showed the lowest extent of HMGA2 amplification. Selinexor was also more efficient than doxorubicinin in inducing an apoptotic response in PDXs and cell lines. Consistently, an increased nuclear accumulation of p53 was seen in all selinexor-treated models. In addition, a time-dependent decrease of survivin expression, with an almost complete abrogation of the cytoplasmic anti-apoptotic pool of this protein, was observed as a consequence of the decreased acetylation/activation of STAT3 and the increased ubiquitination of nuclear survivin.
CONCLUSIONS: Selinexor showed a moderate antitumor activity in three DDLPS PDXs, which was, however, consistently higher than doxorubicin across all different models regardless the extent of MDM2 amplification and the histological differentiation. The depletion of survivin protein seems to significantly contribute to the induction of apoptosis through which selinexor exerts its antitumor activity.

Keywords: Dedifferentiated liposarcoma; Doxorubicin; PDX; Primary cell culture; Selinexor; Survivin; XPO1

DOI: https://doi.org/10.1186/s13046-021-01886-x

Fac Rev. 2021 ;10 1

Recent advances in the understanding and management of liposarcoma.

Candace L Haddox, Richard F Riedel.

Liposarcomas are a common subfamily of soft tissue sarcoma with several subtypes recognized by the World Health Organization: atypical lipomatous tumors (ALT)/well-differentiated liposarcoma (WDLPS), dedifferentiated liposarcoma (DDLPS), myxoid liposarcoma (MLPS), pleomorphic liposarcoma (PLPS), and myxoid pleomorphic liposarcoma (MPLPS). Despite shared adipocytic features among liposarcomas, the clinical approach to each subtype differs based on histology, location, clinical behavior, and specific oncogenic drivers. In this review, we highlight subtype-specific molecular features with the potential to generate novel therapies. We discuss recent clinical trials investigating the use of preoperative radiation therapy for retroperitoneal liposarcoma, chemotherapy, small molecule inhibitors, and innovative immunotherapy approaches and describe how we incorporate these advancements into the management of liposarcoma.

Keywords: Clinical Trials; Dedifferentiated; Immunotherapy; Liposarcoma; Myxoid/Round cell; Pleomorphic; Targeted therapy; Well-differentiated

DOI: https://doi.org/10.12703/r/10-1

Cancers (Basel). 2021 Feb 14. pii: 792. [Epub ahead of print]13(4):

A Growth Modulation Index-Based GEISTRA Score as a New Prognostic Tool for Trabectedin Efficacy in Patients with Advanced Soft Tissue Sarcomas: A Spanish Group for Sarcoma Research (GEIS) Retrospective Study.

The aim of this study was to identify an easily reliable prognostic score that selects the subset of advanced soft tissue sarcoma (ASTS) patients with a higher benefit with trabectedin in terms of time to progression and overall survival. A retrospective series of 357 patients with ASTS treated with trabectedin as second- or further-line in 19 centers across Spain was analyzed. First, it was confirmed that patients with high growth modulation index (GMI > 1.33) were associated with the better clinical outcome. Univariate and multivariate analyses were performed to identify factors associated with a GMI > 1.33. Thus, GEISTRA score was based on metastasis free-interval (MFI ≤ 9.7 months), Karnofsky < 80%, Non L-sarcomas and better response in the previous systemic line. The median GMI was 0.82 (0-69), with 198 patients (55%) with a GMI < 1, 41 (11.5%) with a GMI 1-1.33 and 118 (33.1%) with a GMI > 1.33. The lowest GEISTRA score showed a median of time-to-progression (TTP) and overall survival (OS) of 5.7 and 19.5 months, respectively, whereas it was 1.8 and 3.1 months for TTP and OS, respectively, for the GEISTRA 4 score. This prognostic tool can contribute to better selecting candidates for trabectedin treatment in ASTS.

Keywords: GEISTRA; L-sarcoma; growth modulation index; prognostic score; sarcoma; trabectedin

DOI: https://doi.org/10.3390/cancers13040792

NPJ Precis Oncol. 2021 Mar 05. 5(1): 17

Predictive and prognostic transcriptomic biomarkers in soft tissue sarcomas.

Eve Merry, Khin Thway, Robin L Jones, Paul H Huang.

Soft tissue sarcomas (STS) are rare and heterogeneous tumours comprising over 80 different histological subtypes. Treatment options remain limited in advanced STS with high rates of recurrence following resection of localised disease. Prognostication in clinical practice relies predominantly on histological grading systems as well as sarcoma nomograms. Rapid developments in gene expression profiling technologies presented opportunities for applications in sarcoma. Molecular profiling of sarcomas has improved our understanding of the cancer biology of these rare cancers and identified potential novel therapeutic targets. In particular, transcriptomic signatures could play a role in risk classification in sarcoma to aid prognostication. Unlike other solid and haematological malignancies, transcriptomic signatures have not yet reached routine clinical use in sarcomas. Herein, we evaluate early developments in gene expression profiling in sarcomas that laid the foundations for transcriptomic signature development. We discuss the development and clinical evaluation of key transcriptomic biomarker signatures in sarcomas, including Complexity INdex in SARComas (CINSARC), Genomic Grade Index, and hypoxia-associated signatures. Prospective validation of these transcriptomic signatures is required, and prospective trials are in progress to evaluate reliability for clinical application. We anticipate that integration of these gene expression signatures alongside existing prognosticators and other Omics methodologies, including proteomics and DNA methylation analysis, could improve the identification of 'high-risk' patients who would benefit from more aggressive or selective treatment strategies. Moving forward, the incorporation of these transcriptomic prognostication signatures in clinical practice will undoubtedly advance precision medicine in the routine clinical management of sarcoma patients.

DOI: https://doi.org/10.1038/s41698-021-00157-4

Int J Mol Sci. 2021 Feb 21. pii: 2142. [Epub ahead of print]22(4):

Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level?

Rola El Sayed, Yolla Haibe, Ghid Amhaz, Youssef Bouferraa, Ali Shamseddine.

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain "hot" or "immune-sensitive" tumors become "cold" or "immune-resistant", with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.

Keywords: OXPHOS; adaptation; checkpoint inhibitors; glycolysis; immune-metabolism; immunotherapy; metabolic modulation; tumor microenvironment

DOI: https://doi.org/10.3390/ijms22042142

Int J Mol Sci. 2021 Feb 23. pii: 2210. [Epub ahead of print]22(4):

Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment.

Rebecca Raue, Ann-Christin Frank, Shahzad Nawaz Syed, Bernhard Brüne.

The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside.

Keywords: RNA therapy; breast cancer; inflammation; macrophage; microRNA

DOI: https://doi.org/10.3390/ijms22042210