Amino acid conjugated chitosan nanoparticles for the brain targeting of a model dipeptidyl peptidase-4 inhibitor.

Int J Pharm. 2018 Aug 25;547(1-2):563-571

Authors: Fernandes J, Ghate MV, Basu Mallik S, Lewis SA

Abstract
Saxagliptin (SAX) is a dipeptidyl peptidase-4 enzyme inhibitor molecule now explored for its activity in the therapy of Alzheimer's disease. Being extremely hydrophilic, it is unable to permeate the blood-brain barrier by the conventional therapy modalities. Further repurposing the drug, SAX is associated with a reduction in the blood sugar level in the periphery. In the present study, the chitosan-l-valine conjugate was synthesized by carbodiimide chemistry. The conjugate was then used to prepare nanoparticles encapsulating SAX. The nanoparticles were characterized by particle size, surface morphology, and entrapment efficiency. The stability of the formulations was determined by incubation with rat plasma and brain homogenate. The blood brain barrier permeability of the nanoparticles was successfully demonstrated by the incorporation of fluorescent dye, Rhodamine B in the nanoparticles. In vivo studies were conducted in rats and the results showed that the nanoparticles were highly stable in the plasma releasing only a minute amount of SAX (2.5 ng/mL) which was less than the Cmax of the pure SAX (51 ng/mL). The brain uptake studies showed an accumulation of 53 ng/mL SAX from the nanoparticles whereas the pure SAX showed no detectable amount of the drug after 24 h. The pharmacokinetic studies demonstrated that nanoparticles had an (AUC0-t) of 3.42 times lower than the pure SAX, indicating the stability of the prepared formulation in the plasma.

PMID: 29906562 [PubMed - indexed for MEDLINE]

Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species.

Sci Rep. 2017 02 03;7:41755

Authors: González-Lizárraga F, Socías SB, Ávila CL, Torres-Bugeau CM, Barbosa LR, Binolfi A, Sepúlveda-Díaz JE, Del-Bel E, Fernandez CO, Papy-Garcia D, Itri R, Raisman-Vozari R, Chehín RN

Abstract
Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation. However, anti-inflammatory therapy per se is insufficient to account for neuroprotection. Herein we characterise novel targets of doxycycline describing the structural background supporting its effectiveness as a neuroprotector at subantibiotic doses. Our results show that doxycycline reshapes α-synuclein oligomers into off-pathway, high-molecular-weight species that do not evolve into fibrils. Off-pathway species present less hydrophobic surface than on-pathway oligomers and display different β-sheet structural arrangement. These structural changes affect the α-synuclein ability to destabilize biological membranes, cell viability, and formation of additional toxic species. Altogether, these mechanisms could act synergically giving novel targets for repurposing this drug.

PMID: 28155912 [PubMed - indexed for MEDLINE]

Can drug repurposing stop "chase and run" between aldehydes and reactive sulfur species in anti-cancer therapy?

Oncotarget. 2018 Oct 02;9(77):34453-34454

Authors: Suematsu M

PMID: 30349638 [PubMed]

Repurposing of Bromocriptine for Cancer Therapy.

Front Pharmacol. 2018;9:1030

Authors: Seo EJ, Sugimoto Y, Greten HJ, Efferth T

Abstract
Bromocriptine is an ergot alkaloid and dopamine D2 receptor agonist used to treat Parkinson's disease, acromegaly, hyperprolactinemia, and galactorrhea, and more recently diabetes mellitus. The drug is also active against pituitary hormone-dependent tumors (prolactinomas and growth-hormone producing adenomas). We investigated, whether bromocriptine also inhibits hormone-independent and multidrug-resistant (MDR) tumors. We found that bromocriptine was cytotoxic towards drug-sensitive CCRF-CEM, multidrug-resistant CEM/ADR5000 leukemic cells as well as wild-type or multidrug-resistant ABCB5-transfected HEK293 cell lines, but not sensitive or BCRP-transfected multidrug-resistant MDA-MB-231 breast cancer cells. Bromocriptine strongly bound to NF-κB pathway proteins as shown by molecular docking and interacted more strongly with DNA-bound NF-κB than free NF-κB, indicating that bromocriptine may inhibit NF-κB binding to DNA. Furthermore, bromocriptine decreased NF-κB activity by a SEAP-driven NF-κB reporter cell assay. The expression of MDR-conferring ABC-transporters (ABCB1, ABCB5, ABCC1, and ABCG2) and other resistance-mediating factors (EGFR, mutated TP53, and IκB) did not correlate with cellular response to bromocriptine in a panel of 60 NCI cell lines. There was no correlation between cellular response to bromocriptine and anticancer drugs usually involved in MDR (e.g., anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and others). COMPARE analysis of microarray-based mRNA expression in these cell lines revealed that genes from various functional groups such as ribosomal proteins, transcription, translation, DNA repair, DNA damage, protein folding, mitochondrial respiratory chain, and chemokines correlated with cellular response to bromocriptine. Our results indicate that bromocriptine inhibited drug-resistant tumor cells with different resistance mechanisms in a hormone-independent manner. As refractory and otherwise drug-resistant tumors represent a major challenge to successful cancer chemotherapy, bromocriptine may be considered for repurposing in cancer therapy.

PMID: 30349477 [PubMed]

Evaluation of isoprinosine to be repurposed as an adjunct anti-tuberculosis chemotherapy.

Med Hypotheses. 2018 Jun;115:77-80

Authors: Mishra AK, Yabaji SM, Dubey RK

Abstract
Isoprinosine (Inos) or immunovir is a synthetic purine derivative with immune-modulatory and antiviral properties. The drug shows apparent in vivo enhancement of host immune responses by inducing pro-inflammatory cytokines and rapid proliferation of T-cell subsets. Strikingly, the cytokines induced by Inos also play crucial roles in providing immune resistance against Mycobacterium tuberculosis (Mtb). Inos has been licensed for several antiviral diseases; however, its efficacy against Mtb has not been tested yet. Since Mtb subverts the host immune system to survive within the host. Therefore, we hypothesized that the immune-stimulatory properties of Inos can be explored as an adjunct therapy for the management of tuberculosis. We have also outlined a systematic direction of study to evaluate if Inos could be repurposed for tuberculosis. The in vivo studies for therapeutic evaluation of Inos alone or in combination with the first line anti-TB drugs in a suitable TB disease model would provide a clearer picture of its utility as a host-directed anti-TB drug and may endow us with a new application of an existing drug to combat tuberculosis.

PMID: 29685203 [PubMed - indexed for MEDLINE]

Antifungal drugs: New insights in research & development.

Pharmacol Ther. 2018 Oct 19;:

Authors: Nicola AM, Albuquerque P, Paes HC, Fernandes L, Costa FF, Kioshima ES, Abadio AKR, Bocca AL, Felipe MS

Abstract
The need for better antifungal therapy is commonly accepted in view of the high mortality rates associated with systemic infections, the low number of available antifungal classes, their associated toxicity and the increasing number of infections caused by strains with natural or acquired resistance. The urgency to expand the range of therapeutic options for the treatment of fungal infections has led researchers in recent decades to seek alternative antifungal targets when compared to the conventional ones currently used. Although new potential targets are reported, translating the discoveries from bench to bedside is a long process and most of these drugs fail to reach the patients. In this review, we discuss the development of antifungal drugs focusing on the approach of drug repurposing and the search for novel drugs for classical targets, the most recently described gene targets for drug development, the possibilities of immunotherapy using antibodies, cytokines, therapeutic vaccines and antimicrobial peptides.

PMID: 30347212 [PubMed - as supplied by publisher]

Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents.

PLoS Comput Biol. 2018 Oct 22;14(10):e1006515

Authors: Giuliani S, Silva AC, Borba JVVB, Ramos PIP, Paveley RA, Muratov EN, Andrade CH, Furnham N

Abstract
The development of novel therapeutics is urgently required for diseases where existing treatments are failing due to the emergence of resistance. This is particularly pertinent for parasitic infections of the tropics and sub-tropics, referred to collectively as neglected tropical diseases, where the commercial incentives to develop new drugs are weak. One such disease is schistosomiasis, a highly prevalent acute and chronic condition caused by a parasitic helminth infection, with three species of the genus Schistosoma infecting humans. Currently, a single 40-year old drug, praziquantel, is available to treat all infective species, but its use in mass drug administration is leading to signs of drug-resistance emerging. To meet the challenge of developing new therapeutics against this disease, we developed an innovative computational drug repurposing pipeline supported by phenotypic screening. The approach highlighted several protein kinases as interesting new biological targets for schistosomiasis as they play an essential role in many parasite's biological processes. Focusing on this target class, we also report the first elucidation of the kinome of Schistosoma japonicum, as well as updated kinomes of S. mansoni and S. haematobium. In comparison with the human kinome, we explored these kinomes to identify potential targets of existing inhibitors which are unique to Schistosoma species, allowing us to identify novel targets and suggest approved drugs that might inhibit them. These include previously suggested schistosomicidal agents such as bosutinib, dasatinib, and imatinib as well as new inhibitors such as vandetanib, saracatinib, tideglusib, alvocidib, dinaciclib, and 22 newly identified targets such as CHK1, CDC2, WEE, PAKA, MEK1. Additionally, the primary and secondary targets in Schistosoma of those approved drugs are also suggested, allowing for the development of novel therapeutics against this important yet neglected disease.

PMID: 30346968 [PubMed - as supplied by publisher]

Anti-Candida activity of antidepressants sertraline and fluoxetine: effect upon pre-formed biofilms.

Med Microbiol Immunol. 2018 Aug;207(3-4):195-200

Authors: Oliveira AS, Martinez-de-Oliveira J, Donders GGG, Palmeira-de-Oliveira R, Palmeira-de-Oliveira A

Abstract
As an opportunistic fungal pathogen Candida spp. has the ability to form biofilms. The most prescribed drugs for Candida infections, azoles, have shown to be less effective when biofilms are present. In addition, increasing treatment costs and the fact that most prescribed antifungal drugs have only fungistatic activity justify the search for new treatment strategies. One promising approach is third generation antidepressants, selective serotonin re-uptake inhibitors (SSRIs), because of their proven antifungal activity against several Candida spp. Thus, the aim of this work was to determine the ability of two commonly used SSRIs, fluoxetine and sertraline, to impair both biofilm metabolic viability and biofilm biomass. The in vitro effect of fluoxetine and sertraline was individually tested against biofilm metabolic viability and biofilm biomass using the MTT assay and the Crystal Violet assay, respectively. For both drugs, a dose-dependent reduction on both biofilm metabolism and biomass was present. At high concentrations, fluoxetine was able to reduce biofilm metabolism by 96% (C. krusei) and biofilm biomass by 82% (C. glabrata), when compared to the control. At similar conditions, sertraline achieved a reduction of 88% on biofilm biomass (C. glabrata) and 90% on biofilm metabolism (C. parapsilosis). Moreover, fluoxetine showed interesting anti-biofilm activity at previously reported planktonic MIC values and even at sub-MIC values. These results reinforce the potential interest of SSRIs as anti-biofilm agents to be study to counteract resistance phenomena on candidosis.

PMID: 29556778 [PubMed - indexed for MEDLINE]

Repurposing: Der schnellere Weg vom Target zur klinisch anwendbaren Substanz.

Drug Res (Stuttg). 2017 Nov;67(S 01):S16

Authors: Rossner M

PMID: 29069679 [PubMed - indexed for MEDLINE]

Clotrimazole inhibits the Wnt/β-catenin pathway by activating two eIF2α kinases: The heme-regulated translational inhibitor and the double-stranded RNA-induced protein kinase.

Biochem Biophys Res Commun. 2018 Oct 17;:

Authors: Yonezawa H, Ogawa M, Katayama S, Shimizu Y, Omori N, Oku Y, Sakyo T, Uehara Y, Nishiya N

Abstract
The Wnt/β-catenin signaling pathway controls cell proliferation and differentiation, and therefore, when this pathway is excessively activated, it causes tumorigenesis. Our chemical suppressor screening in zebrafish embryos identified antifungal azoles including clotrimazole, miconazole, and itraconazole, as Wnt/β-catenin signaling inhibitors. Here we show the mechanism underlying the Wnt/β-catenin pathway inhibition by antifungal azoles. Clotrimazole reduced β-catenin revels in a proteasome-independent fashion. By gene knockdown of two translational regulators, heme-regulated translational inhibitor and double-stranded RNA-induced protein kinase, we show that they mediate the clotrimazole-induced inhibition of the Wnt/β-catenin pathway. Thus, clotrimazole inhibits the Wnt/β-catenin pathway by decreasing β-catenin protein levels through translational regulation. Antifungal azoles represent genuine candidate compounds for anticancer drugs or chemopreventive agents that reduce adenomatous polyps.

PMID: 30342850 [PubMed - as supplied by publisher]

Drug repurposing prediction for immune-mediated cutaneous diseases using a word-embedding based machine learning approach.

J Invest Dermatol. 2018 Oct 17;:

Authors: Patrick MT, Raja K, Miller K, Sotzen J, Gudjonsson JE, Elder JT, Tsoi LC

Abstract
Immune-mediated diseases affect >20% of the population and many autoimmune diseases affect the skin. Drug repurposing (aka repositioning) is a cost-effective approach for revealing drugs that can be used to treat diseases for which they are currently not prescribed. We implemented an efficient bioinformatics approach using "word embedding" to summarize drug information from >20 million articles, and applied machine learning to model the drug-disease relationship. We trained our drug repurposing approach separately on 9 cutaneous diseases (including psoriasis, atopic dermatitis and alopecia areata), as well as 8 other immune-mediated diseases, and obtained a mean AUROC of 0.93 in cross-validation. Focusing in particular on psoriasis, a chronic inflammatory condition of skin that affects >100 million people worldwide, we were able to confirm drugs that are known to be effective for psoriasis, and identify potential candidates used to treat other diseases. Furthermore, the targets of drug candidates predicted by our approach were significantly enriched among genes differentially expressed in psoriatic lesional skin from a large-scale RNA-seq cohort. While our algorithm cannot be used to determine clinical efficacy, our work provides an approach for suggesting drugs for repurposing to immune-mediated cutaneous diseases.

PMID: 30342048 [PubMed - as supplied by publisher]

Mutational interactions define novel cancer subgroups.

Nat Commun. 2018 Oct 19;9(1):4353

Authors: Kuipers J, Thurnherr T, Moffa G, Suter P, Behr J, Goosen R, Christofori G, Beerenwinkel N

Abstract
Large-scale genomic data highlight the complexity and diversity of the molecular changes that drive cancer progression. Statistical analysis of cancer data from different tissues can guide drug repositioning as well as the design of targeted treatments. Here, we develop an improved Bayesian network model for tumour mutational profiles and apply it to 8198 patient samples across 22 cancer types from TCGA. For each cancer type, we identify the interactions between mutated genes, capturing signatures beyond mere mutational frequencies. When comparing mutation networks, we find genes which interact both within and across cancer types. To detach cancer classification from the tissue type we perform de novo clustering of the pancancer mutational profiles based on the Bayesian network models. We find 22 novel clusters which significantly improve survival prediction beyond clinical information. The models highlight key gene interactions for each cluster potentially allowing genomic stratification for clinical trials and identifying drug targets.

PMID: 30341300 [PubMed - in process]

Drug Repurposing Patent Applications April-June 2018.

Assay Drug Dev Technol. 2018 Oct;16(7):420-426

Authors: Mucke HAM

PMID: 30339089 [PubMed - in process]

BE-DTI': Ensemble framework for drug target interaction prediction using dimensionality reduction and active learning.

Comput Methods Programs Biomed. 2018 Oct;165:151-162

Authors: Sharma A, Rani R

Abstract
BACKGROUND AND OBJECTIVE: Drug-target interaction prediction plays an intrinsic role in the drug discovery process. Prediction of novel drugs and targets helps in identifying optimal drug therapies for various stringent diseases. Computational prediction of drug-target interactions can help to identify potential drug-target pairs and speed-up the process of drug repositioning. In our present, work we have focused on machine learning algorithms for predicting drug-target interactions from the pool of existing drug-target data. The key idea is to train the classifier using existing DTI so as to predict new or unknown DTI. However, there are various challenges such as class imbalance and high dimensional nature of data that need to be addressed before developing optimal drug-target interaction model.
METHODS: In this paper, we propose a bagging based ensemble framework named BE-DTI' for drug-target interaction prediction using dimensionality reduction and active learning to deal with class-imbalanced data. Active learning helps to improve under-sampling bagging based ensembles. Dimensionality reduction is used to deal with high dimensional data.
RESULTS: Results show that the proposed technique outperforms the other five competing methods in 10-fold cross-validation experiments in terms of AUC=0.927, Sensitivity=0.886, Specificity=0.864, and G-mean=0.874.
CONCLUSION: Missing interactions and new interactions are predicted using the proposed framework. Some of the known interactions are removed from the original dataset and their interactions are recalculated to check the accuracy of the proposed framework. Moreover, validation of the proposed approach is performed using the external dataset. All these results show that structurally similar drugs tend to interact with similar targets.

PMID: 30337070 [PubMed - in process]

Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells.

Oncotarget. 2018 Sep 18;9(73):33832-33843

Authors: Okazaki S, Shintani S, Hirata Y, Suina K, Semba T, Yamasaki J, Umene K, Ishikawa M, Saya H, Nagano O

Abstract
The cystine-glutamate antiporter subunit xCT suppresses iron-dependent oxidative cell death (ferroptosis) and is therefore a promising target for cancer treatment. Given that cancer cells often show resistance to xCT inhibition resulting in glutathione (GSH) deficiency, however, we here performed a synthetic lethal screen of a drug library to identify agents that sensitize the GSH deficiency-resistant cancer cells to the xCT inhibitor sulfasalazine. This screen identified the oral anesthetic dyclonine which has been recently reported to act as a covalent inhibitor for aldehyde dehydrogenases (ALDHs). Treatment with dyclonine induced intracellular accumulation of the toxic aldehyde 4-hydroxynonenal in a cooperative manner with sulfasalazine. Sulfasalazine-resistant head and neck squamous cell carcinoma (HNSCC) cells were found to highly express ALDH3A1 and knockdown of ALDH3A1 rendered these cells sensitive to sulfasalazine. The combination of dyclonine and sulfasalazine cooperatively suppressed the growth of highly ALDH3A1-expressing HNSCC or gastric tumors that were resistant to sulfasalazine monotherapy. Our findings establish a rationale for application of dyclonine as a sensitizer to xCT-targeted cancer therapy.

PMID: 30333913 [PubMed]

Itraconazole as a Noncastrating Treatment for Biochemically Recurrent Prostate Cancer: A Phase 2 Study.

Clin Genitourin Cancer. 2018 Sep 24;:

Authors: Lee M, Hong H, Kim W, Zhang L, Friedlander TW, Fong L, Lin AM, Small EJ, Wei XX, Rodvelt TJ, Miralda B, Stocksdale B, Ryan CJ, Aggarwal R

Abstract
BACKGROUND: Patients with biochemically recurrent prostate cancer and short prostate-specific antigen doubling time (PSADT) are at risk for metastasis yet may wish to avoid androgen deprivation therapy. Itraconazole may have antitumor activity without affecting circulating androgen levels. We therefore evaluated itraconazole as a potentially noncastrating treatment approach in biochemically recurrent prostate cancer.
PATIENTS AND METHODS: Patients with biochemically recurrent prostate cancer and PSADT ≤ 15 months, with serum testosterone > 150 ng/dL, were prospectively enrolled. The primary end point was the proportion of patients who experienced ≥ 50% decline from baseline in serum prostate-specific antigen (PSA) by week 12.
RESULTS: Twenty-one patients were enrolled. The median (range) age, baseline PSA, and PSADT at study entry was 72 (49-76) years, 7.6 (1.5-45.5) ng/mL, and 5.7 (1.2-13.0) months, respectively. Among 19 patients with evaluable data, 1 patient (5%) had a > 50% PSA decline. Nine patients (47%) experienced any PSA decline (mean decline 25.0%, range 2%-60%) by week 12. Among 10 patients without a PSA decline, the on-treatment versus pretreatment PSADT was not significantly longer (median 6.8 vs. 4.3 months, P = .17). There was no significant change from baseline to week 12 in serum testosterone (median change = 32.4%, P = .21) or androstenedione (median change = -8.3%, P = .85). The most common adverse events were edema (52%), fatigue (38%), hypertension (24%), and hypokalemia (24%).
CONCLUSION: Itraconazole modulates serum PSA levels without lowering serum testosterone. However, the magnitude of effect is modest, and treatment carries risk of toxicities associated with mineralocorticoid excess.

PMID: 30327180 [PubMed - as supplied by publisher]

Drugs for hyperlipidaemia may slow the progression of hearing loss in the elderly: A drug repurposing study.

Basic Clin Pharmacol Toxicol. 2018 Oct 16;:

Authors: Choo OS, Yoon D, Choi Y, Jo S, Jung HM, An JY, Choung YH

Abstract
Hearing loss in the elderly causes communication difficulties, decreased quality of life, isolation, loneliness and frustration. The aim of this study was to identify the modifiable variables that may affect the progression of hearing loss in the elderly. A case-control study was conducted using two datasets. Data were extracted from the health examination survey of Ajou University Hospital (2010-2014) and the Korea National Health and Nutrition Examination Survey (2009-2012) datasets. Audiometry data were evaluated according to variables such as age, sex and drug use for underlying diseases. Logistic regression analysis was performed on the entire study population, and middle-aged and elderly groups using odds ratios (ORs). Factors including older age, female gender and diabetes mellitus were significantly associated with hearing levels in all age groups (OR [95% confidence interval, 95% CI], 0.375 [0.388-0.415], 1.202 [1.195-1.208], and 1.427 [1.183-1.721], respectively). However, when the results from the middle-aged and elderly groups were compared, medication for hyperlipidaemia had a significantly positive effect on the preservation of hearing in the elderly group (OR [95%CI], 0.713 [0.567-0.897]), but not in the middle-aged group (OR [95%CI], 0.967 [0.791-1.183]). People, especially those in the elderly group, exposed to medication for hyperlipidaemia are likely to have better hearing than those not exposed to such drugs. Thus, drugs prescribed for hyperlipidaemia may maintain hearing in the elderly. However, to overcome potential confounding-by unmeasured variables-that is present in this study, further studies must be performed with more elaborate research design and methodology. This article is protected by copyright. All rights reserved.

PMID: 30325579 [PubMed - as supplied by publisher]

The emerging field of senotherapeutic drugs.

Future Med Chem. 2018 Oct 16;:

Authors: Myrianthopoulos V

PMID: 30325213 [PubMed - as supplied by publisher]

Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial.

Front Pharmacol. 2018;9:00950

Authors: Verschuur A, Heng-Maillard MA, Dory-Lautrec P, Truillet R, Jouve E, Chastagner P, Leblond P, Aerts I, Honoré S, Entz-Werle N, Sirvent N, Gentet JC, Corradini N, André N

Abstract
Background: Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC has shown its efficacy in adult tumor types such as breast and ovarian cancer and has to some extent been studied in pediatrics. Objective: To assess the anti-tumor activity and toxicity of a four-drug metronomic regimen in relapsing/refractory pediatric brain tumors (BT) with progression-free survival (PFS) after two cycles as primary endpoint. Methods: Patients ≥4 to 25 years of age were included with progressing BT. Treatment consisted of an 8-week cycle of celecoxib, vinblastine, and cyclophosphamide alternating with methotrexate. Kepner and Chang two-steps model was used with 10 patients in the first stage. If stabilization was observed in ≥2 patients, 8 additional patients were recruited. Assessment was according WHO criteria with central radiology review. Results: Twenty-nine patients (27 evaluable) were included in two groups: ependymoma (group 1, N = 8), and miscellaneous BT (group 2): 3 medulloblastoma (MB), 5 high grade glioma (HGG), 11 low grade glioma (LGG), 2 other BT. After first stage, recruitment for ependymoma was closed [one patient had stable disease (SD) for 4 months]. Cohort 2 was opened for second stage since 1 HGG and 3 LGG patients had SD after two cycles. Recruitment was limited to LGG for the second stage and 2 partial responses (PR), 6 SD and 2 progressive disease (PD) were observed after two cycles. Of these patients with LGG, median age was 10 years, nine patients received vinblastine previously. Median number of cycles was 6.8 (range: 1-12). Treatment was interrupted in five patients for grade 3/4 toxicity. Conclusion: This regimen is active in patients with LGG, even if patients had previously received vinblastine. Toxicity is acceptable. Trial Registration: This study was registered under clinicaltrials.gov - NCT01285817; EUDRACT nr: 2010-021792-81.

PMID: 30319400 [PubMed]

p53 modeling as a route to mesothelioma patients stratification and novel therapeutic identification.

J Transl Med. 2018 Oct 13;16(1):282

Authors: Tian K, Bakker E, Hussain M, Guazzelli A, Alhebshi H, Meysami P, Demonacos C, Schwartz JM, Mutti L, Krstic-Demonacos M

Abstract
BACKGROUND: Malignant pleural mesothelioma (MPM) is an orphan disease that is difficult to treat using traditional chemotherapy, an approach which has been effective in other types of cancer. Most chemotherapeutics cause DNA damage leading to cell death. Recent discoveries have highlighted a potential role for the p53 tumor suppressor in this disease. Given the pivotal role of p53 in the DNA damage response, here we investigated the predictive power of the p53 interactome model for MPM patients' stratification.
METHODS: We used bioinformatics approaches including omics type analysis of data from MPM cells and from MPM patients in order to predict which pathways are crucial for patients' survival. Analysis of the PKT206 model of the p53 network was validated by microarrays from the Mero-14 MPM cell line and RNA-seq data from 71 MPM patients, whilst statistical analysis was used to identify the deregulated pathways and predict therapeutic schemes by linking the affected pathway with the patients' clinical state.
RESULTS: In silico simulations demonstrated successful predictions ranging from 52 to 85% depending on the drug, algorithm or sample used for validation. Clinical outcomes of individual patients stratified in three groups and simulation comparisons identified 30 genes that correlated with survival. In patients carrying wild-type p53 either treated or not treated with chemotherapy, FEN1 and MMP2 exhibited the highest inverse correlation, whereas in untreated patients bearing mutated p53, SIAH1 negatively correlated with survival. Numerous repositioned and experimental drugs targeting FEN1 and MMP2 were identified and selected drugs tested. Epinephrine and myricetin, which target FEN1, have shown cytotoxic effect on Mero-14 cells whereas marimastat and batimastat, which target MMP2 demonstrated a modest but significant inhibitory effect on MPM cell migration. Finally, 8 genes displayed correlation with disease stage, which may have diagnostic implications.
CONCLUSIONS: Clinical decisions related to MPM personalized therapy based on individual patients' genetic profile and previous chemotherapeutic treatment could be reached using computational tools and the predictions reported in this study upon further testing in animal models.

PMID: 30316293 [PubMed - in process]