Targeting EZH2 in SMARCB1-deficient sarcomas: Advances and opportunities to potentiate the efficacy of EZH2 inhibitors.

Soft tissue sarcomas (STSs) are rare mesechymal malignancies characterized by distintive molecular, histological and clinical features. Many STSs are considered as predominatly epigenetic diseases due to underlying chromatin deregulation. Discovery of deregulated functional antagonism between the chromatin remodeling BRG1/BRM-associated (BAFs) and the histone modifying Polycomb repressor complexes (PRCs) has provided novel actionable targets.

Beyond targeting amplified MDM2 and CDK4 in well differentiated and dedifferentiated liposarcomas: From promise and clinical applications towards identification of progression drivers.

Well differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS) are tumors of the adipose tissue poorly responsive to conventional cytotoxic chemotherapy which currently remains the standard-of-care. The dismal prognosis of the DDLPS subtype indicates an urgent need to identify new therapeutic targets to improve the patient outcome. The amplification of the two driver genes and , shared by WDLPD and DDLPS, has provided the rationale to explore targeting the encoded ubiquitin-protein ligase and cell cycle regulating kinase as a therapeutic approach.

Combinatorial strategies to potentiate the efficacy of HDAC inhibitors in fusion-positive sarcomas.

Fusion positive (FP) sarcomas are characterized by chromosomal rearrangements generating pathognomonic fusion transcripts and oncoproteins. In Ewing's sarcoma family of tumors (ESFTs), FP-rhabdomyosarcomas (FP-RMS) and synovial sarcomas (SS), the most common and aggressive forms of sarcomas in childhood and adolescence, the oncogenic rearrangements involve transcription cofactors causing widespread epigenetic rewiring and aberrant gene expression. Through the cooperation with histone deacetylases (HDACs) in transcription regulatory complexes, the fusion oncoproteins affect histone acetylation and chromatin remodeling.

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma.

Background: Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies.

Receptor tyrosine kinases and heparan sulfate proteoglycans: Interplay providing anticancer targeting strategies and new therapeutic opportunities.

The development of pharmacological and biological inhibitors of receptor tyrosine kinases (RTKs) has changed the treatment paradigm of several neoplastic diseases. However, the occurrence of intrinsic and acquired resistance represents a limit to the efficacy of these drugs even in RTK-addicted cancers. The identification of innovative therapeutic approaches and rationale-based drug combinations remains a primary need to improve patients' outcome.

Heparanase: A Potential Therapeutic Target in Sarcomas.

Sarcomas comprise a heterogeneous group of rare malignancies of mesenchymal origin including more than 70 subtypes. They may arise in muscle, bone, cartilage and other connective tissues. Their high histological and genetic heterogeneity makes diagnosis and treatment very challenging.

Overactive IGF1/Insulin Receptors and NRASQ61R Mutation Drive Mechanisms of Resistance to Pazopanib and Define Rational Combination Strategies to Treat Synovial Sarcoma.

Pazopanib is approved for treatment of advanced soft tissue sarcomas, but primary and secondary drug resistance limits its clinical utility. We investigated the molecular mechanisms mediating pazopanib resistance in human synovial sarcoma (SS) models. We found reduced cell sensitivity to pazopanib associated with inefficient inhibition of the two critical signaling nodes, AKT and ERKs, despite strong inhibition of the main drug target, PDGFRα.

Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity.

Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS-binding proteins with pivotal roles in cancer growth and progression. The definition of structural/functional determinants and the introduction of chemical modifications enabled heparin derivatives to be identified with greatly reduced or absent anticoagulant activity, but conserved/enhanced anticancer activity. These studies paved the way for the disclosure of structural requirements for the inhibitory effects of HS mimetics on heparanase, selectins, and growth factor receptor signaling, as well as for the limitation of side effects.

Supersulfated low-molecular weight heparin synergizes with IGF1R/IR inhibitor to suppress synovial sarcoma growth and metastases.

Synovial sarcoma (SS) is an aggressive tumor with propensity for lung metastases which significantly impact patients' prognosis. New therapeutic approaches are needed to improve treatment outcome. Targeting the heparanase/heparan sulfate proteoglycan system by heparin derivatives which act as heparanase inhibitors/heparan sulfate mimetics is emerging as a therapeutic approach that can sensitize the tumor response to chemotherapy.

Axl molecular targeting counteracts aggressiveness but not platinum-resistance of ovarian carcinoma cells.

Ovarian carcinoma, the most common gynaecological cancer, is characterized by high lethality mainly due to late diagnosis and treatment failure. The efficacy of platinum drug-based therapy in the disease is limited by the occurrence of drug resistance, a phenomenon often associated with increased metastatic potential. Because the Tyr-kinase receptor Axl can be deregulated in ovarian carcinoma and plays a pro-metastatic/anti-apoptotic role, the aim of this study was to examine if Axl inhibition modulates drug resistance and aggressive features of ovarian carcinoma cells, using various pairs of cisplatin-sensitive and -resistant cell lines.

Targeting Heparan Sulfate Proteoglycans and their Modifying Enzymes to Enhance Anticancer Chemotherapy Efficacy and Overcome Drug Resistance.

Targeting heparan sulfate proteoglycans (HSPGs) and enzymes involved in heparan sulfate (HS) chain editing is emerging as a new anticancer strategy. The involvement of HSPGs in tumor cell signaling, inflammation, angiogenesis and metastasis indicates that agents able to inhibit aberrant HSPG functions can potentially act as multitarget drugs affecting both tumor cell growth and the supportive boost provided by the microenvironment. Moreover, accumulating evidence supports that an altered expression or function of HSPGs, or of the complex enzyme system regulating their activities, can also depress the tumor response to anticancer treatments in several tumor types.

The heparanase/heparan sulfate proteoglycan axis: A potential new therapeutic target in sarcomas.

Heparanase, the only known mammalian endoglycosidase degrading heparan sulfate (HS) chains of HS proteoglycans (HSPG), is a highly versatile protein affecting multiple events in tumor cells and their microenvironment. In several malignancies, deregulation of the heparanase/HSPG system has been implicated in tumor progression, hence representing a valuable therapeutic target. Currently, multiple agents interfering with the heparanase/HSPG axis are under clinical investigation.

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases.

The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes.

Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer.

Medullary thyroid cancer (MTC) relies on the aberrant activation of RET proto-oncogene. Though targeted approaches (i.e.

Synthetic sulfoglycolipids targeting the serine-threonine protein kinase Akt.

The serine-threonine protein kinase Akt, also known as protein kinase B, is a key component of the phosphoinositide 3-kinase (PI3K)-Akt-mTOR axis. Deregulated activation of this pathway is frequent in human tumors and Akt-dependent signaling appears to be critical in cell survival. PI3K activation generates 3-phosphorylated phosphatidylinositols that bind Akt pleckstrin homology (PH) domain.

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells.

Aberrant expression and activation of receptor tyrosine kinases (RTK) is a frequent feature of tumor cells that may underlie tumor aggressiveness. Among RTK, Axl, a member of the Tyro3-Axl-Mer family, represents a potential therapeutic target in different tumor types given its over-expression which leads to activation of oncogenic signaling promoting cell proliferation and survival, as well as migration and invasion. Axl can promote aggressiveness of various cell types through PI3K/Akt and/or MAPK/ERK, and its expression can be transcriptionally regulated by multiple factors.

New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants.

Platinum drugs have been widely used for the treatment of several solid tumors. Although DNA has been recognized as the primary cellular target for these agents, there are unresolved issues concerning their effects and the molecular mechanisms underlying the antitumor efficacy. These cytotoxic agents interact with sub-cellular compartments other than the nucleus.

PLK1 is a critical determinant of tumor cell sensitivity to CPT11 and its inhibition enhances the drug antitumor efficacy in squamous cell carcinoma models sensitive and resistant to camptothecins.

Intrinsic and acquired tumor drug resistance limits the therapeutic efficacy of camptothecins (CPTs). Downregulation of the mitotic kinase PLK1 was found associated with apoptosis induced by SN38 (CPT11 active metabolite). We investigated the role of PLK1 in the cell response to CPTs in squamous cell carcinoma (SCC) and pediatric sarcoma cell lines and explored the therapeutic potential of the combination of CPT11 and the PLK1 inhibitor BI2536 in CPT-sensitive and -resistant tumor models.

Targeting the invasive phenotype of cisplatin-resistant non-small cell lung cancer cells by a novel histone deacetylase inhibitor.

Non-Small Cell Lung Cancer (NSCLC) remains an aggressive and fatal disease with low responsiveness to chemotherapy, frequent drug resistance development and metastatic behavior. Platinum-based therapy is the standard of care for NSCLC with limited benefits. Since epigenetic alterations have been implicated in the aggressive behavior of lung cancer, the purpose of the present study was to examine the capability of the pan-histone deacetylase inhibitor SAHA and of ST3595, a novel hydroxamate-based compound, to interfere with the proliferative and invasive potential of NSCLC cells.

miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma.

Thyroid cancer incidence is rapidly increasing. Papillary Thyroid Carcinoma (PTC), the most frequent hystotype, usually displays good prognosis, but no effective therapeutic options are available for the fraction of progressive PTC patients. BRAF and RET/PTC are the most frequent driving genetic lesions identified in PTC.

Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells.

Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6).