Selinexor, a selective inhibitor of nuclear export, enhances the anti-tumor activity of olaparib in triple negative breast cancer regardless of BRCA1 mutation status.

Triple negative breast cancer (TNBC) is a deadly disease with limited treatment options. Selinexor is a selective inhibitor of nuclear export that binds covalently to exportin 1 thereby reactivating tumor suppressor proteins and downregulating expression of oncogenes and DNA damage repair (DDR) proteins. Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor approved for the treatment of patients with breast cancer harboring BRCA mutations. We examined the effects of co-treatment with selinexor and olaparib in TNBC cell lines. BRCA1 wildtype (BRCA1-wt) and BRCA1 mutant (BRCA1-mut) TNBC cell lines were treated with selinexor and/or olaparib and effects on cell viability and cell cycle were evaluated. The effects of treatment were also evaluated in mouse xenograft models generated with BRCA1-wt and BRCA1-mut TNBC cell lines. Treatment with selinexor inhibited cell proliferation and survival of all TNBC cell lines tested in vitro. This effect was enhanced following treatment of the cells with the combination of selinexor and olaparib, which showed synergistic effects on tumor growth inhibition in MDA-MB-468-derived (BRCA1-wt) and MDA-MB-436-derived (BRCA1-mut) xenografts. As co-treatment with selinexor and olaparib exhibits anti-tumor activity regardless of BRCA1 mutation status, the clinical implications of the combination warrant further investigation.

FOLFIRI3-aflibercept in previously treated patients with metastatic colorectal cancer.

AIM: To evaluate the efficacy and safety of the modified FOLFIRI3-aflibercept as second-line therapy in patients with metastatic colorectal cancer. METHODS: This is a retrospective multicenter cohort, evaluating the efficacy and safety of the association of aflibercept with FOLFIRI3 (day 1: aflibercept 4 mg/kg, folinic acid 400 mg/m2, irinotecan 90 mg/m2, 5-fluorouracil infusion 2400 mg/m2 per 46 h; day 3: irinotecan 90 mg/m2) in patients with previously treated metastatic colorectal cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Among 74 patients treated in four French centers, nine were excluded due to prior use of aflibercept (n = 3), more than one prior treatment line in irinotecan-naïve patients (n = 3), and inadequate liver function (n = 3). In the "irinotecan-naïve" patients (n = 30), ORR was 43.3% and DCR was 76.7%. Median PFS and OS were 11.3 mo (95%CI: 6.1-29.0) and 17.0 mo (95%CI: 13.0-17.3), respectively. The most common (> 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), and hypertension (6.7%). In the "pre-exposed irinotecan" patients (n = 35), 20 (57.1%) received ≥ 2 prior lines of treatment. ORR was 34.3% and DCR was 60.0%. Median PFS and OS were 5.7 mo (95%CI: 3.9-10.4) and 14.3 mo (95%CI: 12.8-19.5), respectively. CONCLUSION: Minimally modified FOLFIRI has improvement dramatically the FOLFIRI3-aflibercept efficacy, whatever prior use of irinotecan. A prospective randomized trial is warranted to compare FOLFIRI-aflibercept to FOLFIRI3-aflibercept.

Co-targeting poly(ADP-ribose) polymerase (PARP) and histone deacetylase (HDAC) in triple-negative breast cancer: Higher synergism in BRCA mutated cells.

PURPOSE: Despite similarities with BRCA-mutated breast cancers, triple-negative breast cancers (TNBC) remain resistant to poly(ADP-ribose) polymerase (PARP) inhibitors as single agents. Histone deacetylase inhibitors (HDACi) can decrease expression of proteins involved in DNA repair. We thus hypothesized that a HDACi (suberoylanilide hydroxamic acid (SAHA) or belinostat) could sensitize TNBC to the PARP inhibitor olaparib. METHODS: Human TNBC cells were co-treated with olaparib and either SAHA or belinostat, and their effects on survival, proliferation, cell cycle, apoptosis and DNA repair pathways were evaluated. Subcutaneous xenografts were used to determine the effect of the combination treatment in vivo. RESULTS: HDACi and olaparib synergistically inhibited proliferation of a panel of 8 TNBC cell lines in vitro and in nude mice harboring TNBC xenografts in vivo. We noted a weaker synergism in PTEN-deficient TNBC cells and a stronger synergism in BRCA1-mutated TNBC cells. In the BRCA1-mutated cell line HCC-1937, we observed a drastic decrease in the expression of proteins involved in homologous recombination (HR), leading to a large imbalance of the ratio P-H2AX/RAD51. In BRCA1 wild type (wt) cell lines, effect of the combination treatment relied on DNA damage-induced cell cycle arrest followed by induction of apoptosis. CONCLUSION: In summary, these results provide a preclinical rationale to combine a HDACi with a PARP inhibitor to reduce HR efficiency in TNBC and sensitize these aggressive tumors to PARP inhibition.

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1-Dependent IGF-1 Signaling.

Ewing sarcoma (EWS) is an aggressive bone malignancy that mainly affects children and young adults. The mechanisms by which EWS (EWSR1) fusion genes drive the disease are not fully understood. CRM1 (XPO1) traffics proteins from the nucleus, including tumor suppressors and growth factors, and is overexpressed in many cancers. A small-molecule inhibitor of CRM1, KPT-330, has shown therapeutic promise, but has yet to be investigated in the context of EWS. In this study, we demonstrate that CRM1 is also highly expressed in EWS. shRNA-mediated or pharmacologic inhibition of CRM1 in EWS cells dramatically decreased cell growth while inducing apoptosis, cell-cycle arrest, and protein expression alterations to several cancer-related factors. Interestingly, silencing of CRM1 markedly reduced EWS-FLI1 fusion protein expression at the posttranscriptional level and upregulated the expression of the well-established EWS-FLI1 target gene, insulin-like growth factor binding protein 3 (IGFBP3), which inhibits IGF-1. Accordingly, KPT-330 treatment attenuated IGF-1-induced activation of the IGF-1R/AKT pathway. Furthermore, knockdown of IGFBP3 increased cell growth and rescued the inhibitory effects on IGF-1 signaling triggered by CRM1 inhibition. Finally, treatment of EWS cells with a combination of KPT-330 and the IGF-1R inhibitor, linsitinib, synergistically decreased cell proliferation both in vitro and in vivo Taken together, these findings provide a strong rationale for investigating the efficacy of combinatorial inhibition of CRM1 and IGF-1R for the treatment of EWS. Cancer Res; 76(9); 2687-97. ©2016 AACR.

[Her2 a paradigm for targeted therapy]. / Her2 : un modèle de cible thérapeutique.

Fifteen percent of breast cancers overexpress Her2, a tyrosin-kinase receptor. Because of its prognosis and its incidence, several efforts have been done in the last years to better understand mechanisms of Her2 action. This led to the development of targeted therapies such as trastuzumab, monoclonal antibody directed against the Her2 extra-cellular domain. Trastuzumab provides significant clinical benefit in women with Her2-positive breast cancers. However, many women will either not respond or progress despite this treatment. The aim of this article is to summarize mechanisms of action of Her2 and of trastuzumab, and to better understand pathways activated in resistant tumors in order to identify ways to overcome them.

Epithelial-to-mesenchymal transition and acquired resistance to sunitinib in a patient with hepatocellular carcinoma.

BACKGROUND & AIMS: Based on the success of sorafenib, several anti-angiogenic therapies are currently evaluated in advanced hepatocellular carcinomas. Few biological data are currently available from patients that may help understanding mechanisms of acquired resistance to these drugs. Herein, we report translational data from a post-treatment surgical specimen in a patient who experienced acquired resistance to sunitinib. METHODS: Clinical, radiological, and pathological data were collected before treatment, under treatment, and at the time of tumor progression. In addition, a biomolecular analysis was performed at the time of progression. RESULTS: In this patient with non-alcoholic steatohepatitis, initial response to sunitinib was followed by tumor progression within 6 months of treatment, requesting salvage surgical resection. Surprisingly, pathological examination on post-treatment specimens revealed the presence of two juxtaposed tissue components containing either sarcomatoid-like mesenchymal cells or well- to moderately-differentiated hepatocellular carcinoma cells. Cancer cells retain a high α-fetoprotein expression in both components. However, while cells from carcinoma expressed E-cadherin but no vimentin, cancer cells from the mesenchymal component highly expressed vimentin and lost E-cadherin protein expression as measured by immunostaining. HMGA2 and Ki67 mRNA were also expressed at higher levels in mesenchymal than in carcinoma cells. CONCLUSION: This case report suggests the occurrence of an epithelial-to-mesenchymal transition in discrete areas of hepatocellular carcinomas developing resistance to sunitinib.

[Targeted therapies in hepatocellular carcinoma]. / Thérapies ciblées dans le carcinome hépatocellulaire.

Hepatocellular carcinoma (HCC) stands as a major health problem worldwide. The management of advanced HCC, limited for a longtime by the disappointing results of conventional cytotoxic chemotherapies, has recently changed with the publication of the results of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, which demonstrated an overall survival benefit over placebo in patients with advanced HCC. This study was further confirmed by the Asian-Pacific trial using sorafenib in Eastern patients. Those trials demonstrated that therapeutic benefits may derive from improving our knowledge of deregulated signaling pathways involved in HCC carcinogenesis. This review summarizes the results of clinical trials in which targeted therapies are currently evaluated aiming to enlarge the therapeutic armamentarium for HCC in a near future.

Central neurological complications in critically ill patients with malignancies.

OBJECTIVE: To determine outcomes in critically ill patients hospitalized in the ICU for central neurological complications of cancer. DESIGN AND SETTING: A 7-year retrospective study. SUBJECT AND INTERVENTION: Observational study in 100 critically ill cancer patients with central neurological complications managed using standardized diagnostic and therapeutic strategies. MEASUREMENTS AND RESULTS: There were 52 men and 48 women, aged 55 years (IQR, 40-65). Presenting manifestations were coma (56%), epilepsy (48%), focal signs (35%), encephalopathy (31%), and meningitis (7%). Cerebral imaging was abnormal in 61 patients, lumbar puncture in 17, and electroencephalography in 6. Neurosurgical biopsy was performed on four patients. The main etiologies included drug toxicity in 28, malignant brain infiltration in 21 patients, and cerebrovascular disease in 20. Mechanical ventilation was needed for 60 patients. Anticancer chemotherapy was administered during the ICU stay in 15 patients. ICU and hospital mortalities were 28 and 45%, respectively. By multivariate analysis, independent positive predictors of hospital mortality were poor performance status [odds ratio (OR) 2.94, 95% CI, 1.01-8.55, P = 0.047), focal signs at presentation (OR 3.52, 95% CI, 1.14-10.88, P = 0.029), abnormal lumbar puncture (OR 5.49, 95% CI 1.09-27.66, P = 0.038), and need for vasoactive drugs (OR 6.47, 95% CI 1.32-31.66, P = 0.021), whereas remission of the malignancy (OR 0.20, 95% CI 0.04-0.88, P = 0.033) and GCS score at admission (OR 0.81/point, 95% CI, 0.70-0.95, P = 0.009) were negative predictors of hospital mortality. CONCLUSION: In cancer patients, central neurological events are mainly related to malignant brain infiltration and drug-related toxicity. Despite advanced severity, a standardized intensive management strategy yields a 55% hospital survival rate.

[Cancer and spirituality: the young oncologists' point of view]. / Spiritualité et cancer : le point de vue des jeunes oncologues.

Because of its pronostic, occurrence of cancer leads patients to questioning about death, life, and illness. Medical and paramedical staffs are often confronted to such questions, which can embarrassed them because not enough prepared and educated about them. How to help patients spiritually ? How to face a situation ethically ? Young french oncologists expose us their own experience and different trains of thought.