Targeted Therapy In Patients Research Articles

Abstract 4784: Combination of sorafenib with liver cancer-targeted gene therapy exerts synergistic efficacy against hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Sorafenib, a multikinase inhibitor, is the first-line target therapy for patients with advanced HCC, but the response rate is low. Thus, development of more effective therapeutics for HCC is needed. Previously we have established a HCC-targeted BikDD gene therapy vector driven by a liver cancer-specific α-fetoprotein promoter/enhancer and transcriptional amplification module. Systemic administration of liposome-loaded HCC-targeted BikDD gene therapy vector effectively suppressed tumor growth and prolonged survival in multiple orthotopic HCC mouse models with no toxicity. Here, we further investigated whether combination of sorafenib with gene therapy could enhance anti-HCC activity. The results showed that combination of BikDD gene therapy with HCC targeted therapeutic agent sorafenib synergistically killed a panel of liver cancer cells but not normal cells in vitro by WST-1 assays and analysis of combination index according to the Chou and Talalay method. Moreover, a low dose of sorafenib combined with BikDD gene therapy augmented tumor inhibition and better mice survival compared with separate treatment alone in xenograft and syngeneic orthotopic HCC mouse models. These results suggest that sorafenib combined with HCC-targeted gene therapy may improve the therapeutic efficacy and may be a potential alternative therapeutics for HCC. Citation Format: Huei-Yue Dai, Long-Yuan Li. Combination of sorafenib with liver cancer-targeted gene therapy exerts synergistic efficacy against hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4784.

SAT-353 The Synthetic Vitamin D Analog EB1089 Restricts Adrenocortical Tumor Proliferation in NCI-H295 Xenograft Model

The vitamin D (VD) receptor (VDR) is underexpressed in adult and pediatric adrenocortical tumors (ACT), especially in carcinomas (ACC). VDR activation by VD represses B-catenin signaling in different types of tumors that like ACT, present aberrant B-catenin expression. EB1089 is a potent synthetic VD analog that presents lower calcemic effects and is well tolerated at therapeutic doses. Since there is no effective adjuvant target-therapy for patients with ACT, we evaluated the effects of EB1089 in adrenocortical tumor proliferation. Methods:In vitro, we treated NCI-H295 (B-catenin mutant/activated) and Y1 (normal B-catenin) ACC cells with EB1089 (10-7M) and evaluated VDR and B-catenin signaling (qPCR) and cell proliferation (MTS). In vivo, we bilaterally inoculated subcutaneously 10 female NGS mice (8 week-old) with NCI-H295 cells (2.5x106 / 100 mcL). We assessed body weight (BW) and tumor volume (TuV; d2D/2) weekly. Once the TuV reached 100 mm3, we randomized the animals for EB1089 (n=5; 0.8mcg/kg BW) or vehicle [Control group (CG) n=5; 80% propylene glycol-20% PBS] treatment (sc injection; 5 days/week during 5 weeks). At the end of the protocol, mice were sacrificed and each tumor excised, weighted and fixed for pathological evaluation (H&E). Blood samples were taken for serum calcium (colorimetry), cortisol and testosterone (RIA) assessment. Data were presented as percentage or mean ± SEM. Results: In NCI-H295 cells the treatment with EB1089 (48h) increased VDR mRNA expression (47%; p=0.01) and activated its target gene CYP24A1 (p<0.0001). B-catenin expression and signaling decreased, as shown by reduced CTNNB1 (-24%; p=0.001), MYC (-40%; p=0.0001), CCND1 (-38%; p=0.02), and DKK3 (-40%; p=0.02) mRNA expression. Cell proliferation reduced after 96h (-15%; p=0.001). None of these observations were present in Y1 cells. In vivo, EB1089 significantly restricted tumor growth starting after 2 weeks of treatment (TuV: 284 ± 52 vs. 156 ± 20 mm3; p=0.05). At the end of the experiment TuV was ~50% lower in EB1089 xenografts (683 ± 345 vs. 368 ± 211 mm3; p=0.03). TuV and tumor weight correlated positively (r=0.88; p<0.0001). Both, EB1089 and CG tumors presented highly proliferative areas (pleomorphism, mitosis and few apoptotic bodies). However, EB1089 xenografts presented large necrotic areas. BW (p=0.98) and calcium levels (9.96 ± 0.4 vs. 11.3 ± 0.3 mg/dL; p=0.06) did not differ between groups. EB1089 mice presented reduced serum testosterone (76.7 ± 11.6 vs. 39 ± 5.6 ng/dL; p=0.02) and undetectable cortisol levels (CG: 2 ± 1.2 mcg/dL). Conclusion: The activation of VDR signaling by EB1089 inhibited B-catenin activated ACT proliferation. Furthermore, in vivo, EB1089 reduced tumor steroid secretion and did not result in important VD side effects like significant hypercalcemia and weight loss. VD analogs have antitumor activity and may emerge as an adjuvant therapy for patients with ACT.

The role of carbapenem-resistant pathogens in cSSTI and how to manage them.

Skin and soft tissue infections (SSTIs) with a wide spectrum of disease severity ranging from uncomplicated to potentially lethal are still a leading cause of morbidity and mortality. The burden of carbapenem-resistant gram-negative bacteria (CR-GNB) in SSTIs is increasing. Luckily, the armamentarium of drugs available is recently expanding as well. The present review looks at data on the role CR-GNB in SSTIs and on the old and new drugs available for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas, and Acinetobacter. The most recent information concern the availability of new antibiotics that, even if no specific clinical trials on complicated SSTIs (cSSTIs) have been performed, may play a role in clinical practice also for the treatment of cSSTIs caused by CR-GNB. Ceftolozane-tazobactam has been found to be a good option for CR Pseudomonas infections including SSTIs. Ceftazidime-avibactam is approved for several indications, including aerobic GNB infections with limited treatment options. Meropenem-vaborbactam therapy has been associated with decreased mortality in infections caused by CRE. Eravacycline has the potential to become useful for the treatment of CR Acinetobacter for which the treatment options are limited. In the carbapenem resistance era, the physicians goal should be to stratify patients according to risk factors for CR-GNB causing SSTIs in order to minimize inappropriate initial therapies. Some recently approved drugs seem destined to become the backbone of target therapy in patients with severe infections caused by susceptible CR-GNB strains. Prompt diagnosis of cSSTIs is crucial and, when feasible, surgical debridement as source control is essential as well.

IGF and mTOR pathway expression and in vitro effects of linsitinib and mTOR inhibitors in adrenocortical cancer

PurposeThe IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC.MethodsThe protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated.ResultsA high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect.ConclusionsIn addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.

Efficacy of targeted therapy (TT) after checkpoint inhibitors (CPI) in metastatic renal cell carcinoma (mRCC): Results from the Canadian Kidney Cancer Information System (CKCis).

568 Background: While the use of CPI has demonstrated clinical benefit in patients with mRCC, data showing the efficacy of subsequent TT is limited. This real-world analysis evaluated the efficacy of TT post CPI in mRCC patients. Methods: Data was collected and analyzed from CKCis. Patients with mRCC who received TT after CPI were identified and analyzed based on line of therapy. Time to treatment failure (TTF – time from starting first subsequent TT to stopping TT) and overall survival (OS) were calculated. Hazard Ratio (HR) calculations were adjusted for IMDC group and age. Results: 102 patients were treated with TT post CPI (table). Those who received first-line ipilimumab + nivolumab (I/N) versus a vascular endothelial growth factor inhibitor (VEGFi) + CPI combination prior to second-line TT had a median TTF of 8.0 vs 5.2 months (m) (HR=0.43, 95% CI: 0.13-1.44) and median OS of 16.5 m vs not reached (HR=0.76, 95% CI: 0.11-5.24). Patients who received a VEGFi versus a mammalian target of rapamycin inhibitor (mTORi) as third-line TT had a median TTF of 7.6 vs 4.4 m (HR=0.52, 95% CI: 0.24-1.10) and median OS of 21.7 vs 16.2 m (HR=0.41, 95% CI: 0.16-1.08). All third-line TT patients received first-line VEGFi and second-line nivolumab. Of the third-line VEGFi TT patients, 24 received axitinib (TTF 7.1 m, OS 21.7 m) and 22 received cabozantinib (data immature). Conclusions: Activity of TT in mRCC patients after CPI is demonstrated in multiple lines. In second-line, VEGFi TT had numerically better outcomes after I/N than after VEGFi+CPI combination. Efficacy of third-line TT was seen with a trend favoring VEGFi over mTORi. Axitinib in the third-line has notable activity after CPI, while data on cabozantinib and fourth-line TT are maturing. These results support the use of VEGFi after CPI in mRCC patients. [Table: see text]

Targeted agents or immuno-oncology therapies as first-line therapy for BRAF-mutated metastatic melanoma: a real-world study.

Aim: Targeted therapy (TT) and immuno-oncology (IO) drugs are approved for patients with BRAF mutant metastatic melanoma (MM). We compared real-world outcomes for first-line (1L) TT versus 1L IO to evaluate optimal sequencing. Materials & methods: Physicians-identified BRAF mutant MM patients initiating 1L TT or IO therapies and extracted treatment, disease and clinical outcomes including disease response which were compared between TT and IO and individual regimens. Results: 440MM patients (TT=283, IO=157) were identified. A higher proportion of TT patients had liver metastases (46.3 vs 35.0%) and abnormal lactate dehydrogenase (61.1 vs 42.7%). IO-treated had a RECIST-determined response rate of 45.9 versus 60.1% for TT and time on treatment of 7.2 versus 11.4 months, respectively. There was no survival difference between cohorts. Conclusion: Despite higher risk patients, 1L TT resulted in higher response rate and longer treatment duration suggesting a preferred 1L sequence.

Metatranscriptomic Evaluation of Pulmonary Complications after Pediatric Hematopoietic Cell Transplantation Reveals Pathogenic Microbes Linked to Dysregulated Human Immunologic Gene Expression

Introduction Pulmonary complications (PCs) after pediatric hematopoietic cell transplant (HCT) are heterogeneous in nature and are strongly associated with transplant-related mortality. Microbial pathogens play a role in the evolution of many post-HCT PCs and may contribute to or develop in the setting of an altered inflammatory microenvironment in the lungs. Objectives To improve characterization of the pulmonary microbiome and transcriptome in pediatric HCT patients with PCs. Methods Bronchoalveolar lavage (BAL) was performed at the University Medical Center in Utrecht between April 2004 and November 2016 for all children Results Relative to pre-HCT patients, post-HCT patients were more likely to have abnormal quantities of RNA aligning to pathogenic microbes (59.6% vs. 40.5%, p=0.017), including RNA aligning to pathogenic bacteria (23.4% vs. 11.0%, p=0.023) and pathogenic viruses (48.9% vs 29.0%, p=0.009), but not pathogenic fungi (6.4% vs 7.1%, p=0.854). In addition, post-HCT patients were also more likely to have depressed bacterial diversity (23.4% vs. 10.0%, p=0.012) and to harbor non-pathogenic viruses (27.7% vs. 7.1%, p Conclusions As detection of pathogenic pulmonary microbes is exceedingly common pre-HCT and increases after HCT, incorporation of host gene expression profiles along with standard diagnostic criteria for pulmonary complications may improve classification accuracy and facilitate patient-targeted therapies. Further investigation into the microbiologic and human transcriptional heterogeneity within these high-risk patients is required.

276P - Overexpression of HER3 and the survival of ovarian cancer

Background: Human epidermal growth factor receptor-2 (HER2) and 3 (HER3) belongs to epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases which is responsible for cell survival and proliferation, but their role in ovarian cancer is not yet established. In this study, their status in specimens of epithelial ovarian cancer was determined with immunohistochemistry (IHC) and in situ hybridization (ISH) and was analyzed to find out the correlation with clinical features of ovarian cancer. Methods: Tissue microarrays (TMAs) were prepared from paraffin blocks of 105 ovarian tumor samples. The immunohistochemical expression of HER2, HER3, PI3K, Akt, p-Akt, mTOR, p-mTOR, S6 and p-S6 were investigated. HER2 and HER3 gene amplifications were evaluated by ISH. The correlation between status of materials and disease outcome of the patients were analyzed. Results: HER2 positivity was 3.8% on IHC and 5.7% on ISH, otherwise HER3 showed 12.4% and 8.6% expression respectively. The concordances of IHC and ISH were 98.1% (103/105) in HER2, and 82.9% (87/105) in HER3. HER2 status was not related with disease outcome of ovarian cancer. However, the HER3 status on FISH was associated with rapid disease progression, and this was a significant risk factor even after adjusting other possible risk factors in multivariate analysis. Conclusions: HER3 could be an independent marker for poor prognosis in ovarian cancer, because HER3 signaling pathway might be distinguished from that of HER2. The possibility of target therapy in patients with HER3 gene alteration should be evaluated in the field of ovarian cancer. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Evidence of aldosterone synthesis in human myocardium in acute myocarditis

BackgroundMyocarditis may be self-limited but has been identified as an important contributor to downstream cardiomyopathy. Aldosterone mediates myocardial damage in various conditions, but has not been considered specifically as a therapeutic target for inflammatory damage in acute myocarditis. We sought to demonstrate local aldosterone synthesis in human myocardium affected by acute myocarditis. MethodsWe evaluated myocardial samples obtained via endomyocardial biopsy (EMB) for expression of CYP11B2, the final and key enzyme for aldosterone synthesis, from patients with acute myocarditis and from stable heart transplant recipients with no evidence of rejection as negative controls. Excised adrenal glands from patients with aldosterone-secreting adenomas were used as positive controls. An experienced cardiovascular pathologist blinded to clinical information rated CYP11B2 stains as negative, positive, or borderline, also recording location of any CYP11B2-positivity. ResultsSixteen patients' EMB samples showing definite acute myocarditis were identified (50% female). CYP11B2 was positive in 13/16 cases (81%), typically showing diffuse intracardiomyocyte cytoplasmic staining, vs. 2/16 borderline stains in transplant controls (p < 0.001 myocarditis vs. negative controls). All 3 adrenalectomy samples stained positive for CYP11B2 (diffuse intracellular staining). Importantly, no myocarditis or transplant patients were on aldosterone antagonist therapy at the time of biopsy. ConclusionsIn this proof-of-concept study, myocardium from patients with acute myocarditis demonstrates evidence and high prevalence of local aldosterone synthesis by immunohistochemistry that showed high accuracy, specificity, and sensitivity. Aldosterone warrants consideration as a specific target for therapy in patients with myocardial damage due to inflammation towards strategies that reduce downstream complications.

1230P - Anti-PD-1 therapy combined with chemotherapy or target therapy in patients with advanced biliary tract cancer in real-world clinical setting

1230P - Anti-PD-1 therapy combined with chemotherapy or target therapy in patients with advanced biliary tract cancer in real-world clinical setting

Third line scenario in advanced non-small cell lung cancer: is the anti-angiogenetic strategy the only actor up to now?

Lung cancer is the leading cause of cancer-related deaths worldwide. Among all the different types, non-small cell lung cancer (NSCLC) accounts for 80–85% and most patients (70%) are diagnosed at advanced disease (1). In the last decade, targeted therapies for patients with epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) or ROS1 rearrangements, together with immunotherapy have modified therapeutic landscape in metastatic NSCLC (2).

Review: What Is the Current Evidence for Disease Subsets in Giant Cell Arteritis?

Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium‐sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long‐term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.

BMPR2 inhibits activin and BMP signaling via wild-type ALK2.

TGF-β/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand-dependent downstream signaling. Activin A, a TGF-β superfamily member, inhibits growth of multiple myeloma cells, but the mechanism for this is unknown. We therefore aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2 (also known as ACVR1). We demonstrate that activin A and B activate SMAD1/5/8 in myeloma cells through endogenous wild-type ALK2. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and activin B-induced activation of SMAD1/5/8 and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which may also signal via ALK2, was potentiated by knockdown of BMPR2. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, which are necessary for activation of ALK2 by activins and several BMPs. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.This article has an associated First Person interview with the first author of the paper.

Comparative study of the efficacy and safety between mono-chemotherapy and targeted therapy for patients over 80 years old with advanced non-small cell lung cancer

Objective To compare the efficacy and safety between mono-chemotherapy and targeted therapy as first-line regimen for patients over 80 years old with advanced non-small cell lung cancer (NSCLC). Methods 108 NSCLC patients aged ≥80 years in our hospital were divided into two groups according to the therapeutic program, of which group A was mono-chemotherapy group (n=60) and group B was targeted therapy group (n=48). The primary endpoint was overall survival (OS) and progression free survival (PFS), while secondary endpoint was objective response rate (RR), disease control rate (DCR) and safety. Results The median PFS, and median OS in group B were significantly longer than those in group A (P=0.013, 0.025). The 1-year survival rate of group B was significantly higher than that of group A (P=0.001), and there was no significant difference between the two groups (P=0.605). There was also no statistically significant difference in RR between the two groups (P=0.408). DCR in Group B was significantly higher than that in group A (P=0.043). The incidence of skin rash in group B was significantly higher than that in group A, and the incidence of adverse reactions and hematological toxicity in group A was significantly higher than that in group B. Conclusions Compared with single-agent chemotherapy, epithelial growth factor receptor-tyrosinekinase (EGFR-TKI) targeted therapy has longer PFS and OS benefits for patients≥ 80 years with advanced NSCLC, and was well tolerated by patients. Key words: Carcinoma, non-small-cell lung/DT; Molecular targeted therapy; Aged, 80 and over

Transcriptome based individualized therapy of refractory pediatric sarcomas: feasibility, tolerability and efficacy.

Survival rates of pediatric sarcoma patients stagnated during the last two decades, especially in adolescents and young adults (AYAs). Targeted therapies offer new options in refractory cases. Gene expression profiling provides a robust method to characterize the transcriptome of each patient’s tumor and guide the choice of therapy.Twenty patients with refractory pediatric sarcomas (age 8-35 years) were assessed with array profiling: ten had Ewing sarcoma, five osteosarcoma, and five soft tissue sarcoma. Overexpressed genes and deregulated pathways were identified as actionable targets and an individualized combination of targeted therapies was recommended. Disease status, survival, adverse events (AEs), and quality of life (QOL) were assessed in patients receiving targeted therapy (TT) and compared to patients without targeted therapy (non TT).Actionable targets were identified in all analyzed biopsies. Targeted therapy was administered in nine patients, while eleven received no targeted therapy. No significant difference in risk factors between these two groups was detected. Overall survival (OS) and progression free survival (PFS) were significantly higher in the TT group (OS: P=0.0014, PFS: P=0.0011). Median OS was 8.83 versus 4.93 months and median PFS was 6.17 versus 1.6 months in TT versus non TT group, respectively. QOL did not differ at baseline as well as at four week intervals between the two groups. TT patients had less grade 1 AEs (P=0.009). The frequency of grade 2-4 AEs did not differ.Overall, expression based targeted therapy is a feasible and likely beneficial approach in patients with refractory pediatric sarcomas that warrants further study.

Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in hepatocellular carcinoma cell lines.

325 Background: Despite enhancing overall survival, sorafenib resistance usually occurs and is a significant limiting factor of improved prognosis in hepatocellular carcinoma (HCC) patients. Therefore, it is important to identify the mechanism of sorafenib resistance. This study is designed to identify that causative factor for sorafenib resistance and to suggest way for overcoming sorafenib resistance. Methods: The sensitivity of sorafenib was compared in human HCC lines and patient-derived HCC primary cells. Based on its cytotoxicity, analysis was performed to examine the altered signaling pathway by sorafenib and its causative factor. It was further investigated that how sorafenib modify the sorafenib resistant inducer through gene or protein expression or stability. We also design the treatment option to overcome sorafenib resistance. Results: Sorafenib activates the Raf/MEK/ERK pathway, causing sorafenib resistance in HCC cell lines and patient-derived HCC primary cells. Reactivation of the MAPK pathway by sorafenib occurs via down-regulation of RKIP at a post-translational level. Knockdown of RKIP increased phosphorylated ERK and consequently suppressed sorafenib-mediated cell death. We also found that sorafenib-reactivated ERK maybe an attractive target for second-line therapy in patients with sorafenib resistance. Sequential combination of sorafenib and PD98059 significantly reduced cell viability and proliferation, while increasing apoptosis efficacy in sorafenib-resistant cells. Conclusions: Our findings suggest that reactivation of the Raf/MEK/ERK pathway through aberrant expression of RKIP is one of the mechanisms for sorafenib resistance in HCC. Sequential combination treatment of sorafenib and PD98059 could provide a new strategy to overcome sorafenib resistance in future clinical studies.

MiR-128 regulation of glucose metabolism and cell proliferation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is prone to metastasis and has a poor prognosis, with lower survival rates than other breast cancer subtypes. MicroRNAs have recently emerged as powerful regulators of cancer processes and become a promising target in cancer therapy. Expression of miR-128 was examined in invasive ductal breast cancer, and its relationship with clinicopathological features analysed. A series of in vitro and in vivo experiments were performed to investigate the function and mechanism of miR-128 in the development of invasive ductal breast cancer. A cohort of 110 women with TNBC and 117 with non-TNBC were included in the study. In multivariable Cox regression analysis, overall and disease-free survival were significantly associated with lymph node metastasis, histological grade and molecular subtype. Subgroup analysis showed that low expression of miR-128 correlated with shorter overall and disease-free survival in TNBC (P < 0·001), and shorter overall but not disease-free survival in non-TNBC. In addition, miR-128 was able to inhibit glucose metabolism, mitochondrial respiration and proliferation of TNBC cells. These effects were consistent with miR-128 targeting inhibition of the insulin receptor and insulin receptor substrate 1. MiR-128 might be a prognostic marker and possible molecular target for therapy in patients with TNBC.

Myasthenia gravis: new developments in research and treatment.

Myasthenia gravis, a rare disorder of the neuromuscular transmission, is increasingly acknowledged as a syndrome more than as a single disease. This review summarizes recent advances in pathophysiology which confirm the disease heterogeneity, and may help find disease-targeted and patient-targeted therapies. Antibodies to the acetylcholine receptor, the muscle-specific tyrosine kinase and the lipoprotein receptor protein 4, characterize disease subtypes with distinct clinical traits and immune-pathogenic mechanisms. Genome-wide approaches have identified susceptibility loci within genes that participate in the immune response. Regulatory T and B cells appear to be defective in myasthenia gravis. In patients with acetylcholine receptor antibodies, thymectomy associated with prednisone proved more effective than prednisone alone in a multicenter randomized trial. New therapeutic options target B cells, B-cell growth factors and complement inhibition, and are currently reserved for patients with refractory disease. In the recent past, there has been an active search for new antigens in myasthenia gravis, whereas clinical and experimental studies have provided new insights of crucial pathways in immune regulation, which might become the targets of future therapeutic interventions.

Oncogenic role and therapeutic targeting of ABL-class and JAK-STAT activating kinase alterations in Ph-like ALL.

New therapies for Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) patients are urgently needed. The genetic landscape of Ph-like ALL is characterized by a diverse array of kinase-activating alterations (including rearrangements, sequence mutations, and copy number alterations), suggesting that patients with Ph-like ALL are candidates for targeted therapy, similar to BCR-ABL1 ALL. We sought to investigate the functional role and targetability of the spectrum of kinase-activating alterations identified in Ph-like ALL. We demonstrate cytokine-independent growth and activation of JAK-STAT signaling pathways in Ba/F3 cells by all alterations tested. The development of murine Arf-/- pre-B ALL expressing RCSD1-ABL2 or SSBP2-CSF1R was accelerated with the presence of IK6, a dominant negative isoform of Ikaros common in Ph-like ALL, providing evidence that these fusions are leukemogenic. In vitro screening using a panel of tyrosine kinase inhibitors against 14 different kinase alterations identified the ABL1-inhibitor, dasatinib, as a potent inhibitor of ABL-class fusions (ABL1, ABL2, CSF1R, PDGFRB), whereas the JAK1/JAK2 inhibitor ruxolitinib, was most effective against JAK-STAT-activating alterations (JAK1, JAK2, JAK3, IL7R, IL2RB), but not TYK2. Evaluation of dasatinib or ruxolitinib against patient-derived xenograft models demonstrated superior antileukemic efficacy when combined with dexamethasone compared with either agent alone. These data provide the foundation for rationally designed clinical trials that assess the efficacy of targeted therapy in patients with Ph-like ALL.

CURRENT STUDIES OF THE EFFICACY OF CITRATE THERAPY FOR URIC ACID NEPHROLITHIASIS IN RUSSIA

Urolithiasis is a common urological disease the prevalence of which tends to increase. The main targets of therapy for patients with uric acid nephrolithiasis include normalization of purine metabolism, dissolution of stones, and prevention of stone formation. Oral administration of a citrate mixture or sodium bicarbonate results in urine alkalinization and dissolution of the uric acid stone. The article demonstrates the results of the recent Russian studies of the efficacy and safety of litholytic therapy for uric acid nephrolithiasis both as monotherapy and in combination with remote lithotripsy. The studies show that citrate therapy is a highly effective, non-invasive method for the treatment and metaphylaxis of uric acid nephrolithiasis.