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The axis CXCL12-CXCR4 is highly expressed in ovarian cancer where contributes to disease progression. Aim of the work was to evaluate the effect of the newly developed CXCR4 antagonist R54 on human ovarian cancer cells aggressiveness. CXCL12-CXCR4 axis was evaluated in human ovarian cancer cells through proliferation, migration and signaling CXCL12-dependents. Epithelial to mesenchymal transition (EMT) was analyzed through E-CADHERIN , N-CADHERIN , VIMENTIN , SNAIL1 and ΒETA-CATENIN by qRT-PCR, immunofluorescence and immunoblotting. R54 inhibited ovarian cancer cells proliferation and migration CXCL12-induced. Moreover, R54 inhibited CXCL12 dependent pERK1/2 and pAKT and reversed the CXCL12 induced EMT in ovarian cancer cells. Targeting CXCR4 with the new antagonist R54 consistently reverted the mesenchymal transition in human ovarian cancer cells reducing migratory and chemoresistance features.

Epithelial ovarian cancer is the most lethal gynecologic malignancy; it is highly aggressive and causes almost 125,000 deaths yearly. Despite advances in detection and cytotoxic therapies, a low percentage of patients with advanced stage disease survive 5 y after the initial diagnosis. The high mortality of this disease is mainly caused by resistance to the available therapies. Here, we profiled microRNA (miR) expression in serous epithelial ovarian carcinomas to assess the possibility of a miR signature associated with chemoresistance. We analyzed tumor samples from 198 patients (86 patients as a training set and 112 patients as a validation set) for human miRs. A signature of 23 miRs associated with chemoresistance was generated by array analysis in the training set. Quantitative RT-PCR in the validation set confirmed that three miRs (miR-484, -642, and -217) were able to predict chemoresistance of these tumors. Additional analysis of miR-484 revealed that the sensitive phenotype is caused by a modulation of tumor vasculature through the regulation of the VEGFB and VEGFR2 pathways. We present compelling evidence that three miRs can classify the response to chemotherapy of ovarian cancer patients in a large multicenter cohort and that one of these three miRs is involved in the control of tumor angiogenesis, indicating an option in the treatment of these patients. Our results suggest, in fact, that blockage of VEGF through the use of an anti-VEGFA antibody may not be sufficient to improve survival in ovarian cancer patients unless VEGFB signaling is also blocked.

Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum‐based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro , in xenografts in vivo , and in primary tumor cells derived from platinum‐treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients. Synopsis In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum‐induced cell death. CDK6 in complex with cyclin D3 participates in the control of DNA damage response. CDK6 binds and phosphorylates FOXO3 on serine 325 to control ATR expression. High CDK6 expression predicts poor survival of EOC patients. A combination of platinum‐based chemotherapy with pharmacological CDK6 inhibition might be a new therapeutic option for EOC patients. Graphical Abstract In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum‐induced cell death.

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called “kynurenine (Kyn) pathway”, which converts the essential amino acid l -tryptophan into the immunosuppressive metabolite l -kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endometrial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors. Keywords: endometrial cancer, PARP inhibitors, PTEN mutation, P53 mutation, homologous recombination deficiency, immune checkpoint inhibitors

Background Treatment with PARP inhibitors (PARPi) is primarily effective against high-grade serous ovarian cancers (HGSOC) with BRCA1/2 mutations or other deficiencies in homologous recombination (HR) repair mechanisms. However, resistance to PARPi frequently develops, mostly as a result of BRCA1/2 reversion mutations. The tumour suppressor CCDC6 is involved in HR repair by regulating the PP4c phosphatase activity on γH2AX. In this work, we reported that in ovarian cancer cells, a physical or functional loss of CCDC6 results synthetic lethal with the PARP-inhibitors drugs, by affecting the HR repair. We also unravelled a role for CCDC6 as predictive marker of PARPi sensitivity in ovarian cancer, and the impact of CCDC6 downregulation in overcoming PARPi resistance in these tumours. Methods A panel of HGSOC cell lines (either BRCA -wild type or mutant) were treated with PARPi after CCDC6 was attenuated by silencing or by inhibiting USP7, a CCDC6-deubiquitinating enzyme, and the effects on cell survival were assessed. At the cellular and molecular levels, the processes underlying the CCDC6-dependent modification of drugs’ sensitivity were examined. Patient-derived xenografts (PDXs) were immunostained for CCDC6, and the expression of the protein was analysed statistically after digital or visual means. Results HGSOC cells acquired PARPi sensitivity after CCDC6 depletion. Notably, CCDC6 downregulation restored the PARPi sensitivity in newly generated or spontaneously resistant cells containing either wild type- or mutant- BRCA2 . When in an un-phosphorylated state, the CCDC6 residue threonine 427 is crucial for effective CCDC6-PP4 complex formation and PP4 sequestration, which maintains high γH2AX levels and effective HR. Remarkably, the PP4-dependent control of HR repair is influenced by the CCDC6 constitutively phosphorylated mutant T427D or by the CCDC6 loss, favouring PARPi sensitivity. As a result, the PP4 regulatory component PP4R3α showed to be essential for both the activity of the PP4 complex and the CCDC6 dependent PARPi sensitivity. It's interesting to note that immunohistochemistry revealed an intense CCDC6 protein staining in olaparib-resistant HGSOC cells and PDXs. Conclusions Our findings suggest that the physical loss or the functional impairment of CCDC6 enhances the PP4c complex activity, which causes BRCAness and PARPi sensitivity in HGSOC cells. Moreover, CCDC6 downregulation might overcome PARPi resistance in HGSOCs, thus supporting the potential of targeting CCDC6 by USP7 inhibitors to tackle PARPi resistance.

Ovarian clear cell carcinoma (OCCC) is a rare, aggressive epithelial ovarian cancer subtype, accounting for approximately 10% of cases and associated with a poor prognosis due to chemoresistance and unique tumor biology. OCCC is frequently linked to endometriosis and characterized by mutations in ARID1A and PIK3CA , hyperactivation of the PI3K/Akt/mTOR pathway, and overexpression of VEGF, HIF-1α, and IL-6. These features drive tumor proliferation, angiogenesis, immune evasion, and resistance to platinum-based chemotherapy. The tumor microenvironment of OCCC is highly immunosuppressive, with infiltration of regulatory T cells, tumor-associated macrophages, and upregulation of immune checkpoint molecules, such as PD-1, PD-L1, and LAG-3. These characteristics suggest that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and could be an attractive target for therapeutic intervention. Despite the typical composition of the immunosuppressive tumor microenvironment in ovarian cancer, until now overall the results of trials testing immune checkpoint inhibitors so far have been disappointing. It is interesting to note instead that several subgroup analyses reported exceptional OCCC sensitivity to ICIs. Indeed, current and preliminary trials exploring ICIs, anti-angiogenic agents, and combinatorial therapies in OCCC show promising outcomes. Strategies targeting multiple pathways, including VEGF, IL-6, HIF-1α, and HDAC6, alongside ICIs, are under investigation to overcome resistance mechanisms. Additionally, IL-10 inhibition or ferroptosis pathway activation offers novel therapeutic potential. Personalized, biomarker-driven approaches, targeting ARID1A and PIK3CA mutations or combining immune and anti-angiogenic agents, are gaining traction in OCCC management. This review highlights OCCC molecular underpinnings and therapeutic challenges, emphasizing the need for innovative, multi-targeted strategies. Advances in understanding genetic-immunological interplay in OCCC may enable more effective and durable treatments and improved patient outcomes.

Background Validated prognostic biomarkers for anti-angiogenic therapy using the anti-VEGF antibody Bevacizumab in ovarian cancer (OC) patients are still an unmet clinical need. The EGFR can contribute to cancer-associated biological mechanisms in OC cells including angiogenesis, but its targeting gave disappointing results with less than 10% of OC patients treated with anti-EGFR compounds showing a positive response, likely due to a non adequate selection and stratification of EGFR-expressing OC patients. Methods EGFR membrane expression was evaluated by immunohistochemistry in a cohort of 310 OC patients from the MITO-16A/MANGO-OV2A trial, designed to identify prognostic biomarkers of survival in patients treated with first line standard chemotherapy plus bevacizumab. Statistical analyses assessed the association between EGFR and clinical prognostic factors and survival outcomes. A single sample Gene Set Enrichment-like and Ingenuity Pathway Analyses were applied to the gene expression profile of 195 OC samples from the same cohort. In an OC in vitro model, biological experiments were performed to assess specific EGFR activation. Results Based on EGFR-membrane expression, three OC subgroups of patients were identified being the subgroup with strong and homogeneous EGFR membrane localization, indicative of possible EGFR out/in signalling activation, an independent negative prognostic factor for overall survival of patients treated with an anti-angiogenic agent. This OC subgroup resulted statistically enriched of tumors of histotypes different than high grade serous lacking angiogenic molecular characteristics. At molecular level, among the EGFR-related molecular traits identified to be activated only in this patients’ subgroup the crosstalk between EGFR with other RTKs also emerged. In vitro, we also showed a functional cross-talk between EGFR and AXL RTK; upon AXL silencing, the cells resulted more sensitive to EGFR targeting with erlotinib. Conclusions Strong and homogeneous cell membrane localization of EGFR, associated with specific transcriptional traits, can be considered a prognostic biomarker in OC patients and could be useful for a better OC patients’ stratification and the identification of alternative therapeutic target/s in a personalized therapeutic approach.

The treatment of Epithelial Ovarian cancer (EOC) could benefit from the addition of bevacizumab (BEV) to standard chemotherapy in selected patients. Gene expression (GE) profiling and the evaluation of immune infiltration are used to define patients’ prognosis. However, their role as prognostic and/or predictive biomarkers for the efficacy of antiangiogenic therapy efficacy remains uncertain. In this study, we combined GE profiling and multiplex immunofluorescence (MIF) analyses on material from patients enrolled in the phase IV MITO16A/MaNGO OV-2 trial, assessing associations between immune infiltrate and patients’ prognosis. Patients were stratified into four molecular subtypes, and CIBERSORTx was applied to infer the cell-type-specific expression pattern of immune populations. MIF evaluated the presence of immune cells in the tumor and stromal compartments. These complementary experimental approaches revealed that immune infiltration is associated with shorter progression-free survival in BEV-treated patients, warranting future investigation to evaluate its use as a viable biomarker for patient stratification. Trial registration: NCT01706120, EudraCT number: 2012-003043-29, Date of registration 24 September 2012.