Drug Repositioning in Oncology.

Am J Ther. 2018 Dec 28;:

Authors: Serafin MB, Bottega A, da Rosa TF, Machado CS, Foletto VS, Coelho SS, da Mota AD, Hörner R

Abstract
BACKGROUND: The worldwide increase in the occurrence of cancer associated with the limitations of immunotherapy and the emergence of resistance have impaired the prognosis of cancer patients, which leads to the search for alternative treatment methods. Drug repositioning, a well-established process approved by regulatory agencies, is considered an alternative strategy for the fast identification of drugs, because it is relatively less costly and represents lower risks for patients.
AREAS OF UNCERTAINTY: We report the most relevant studies about drug repositioning in oncology, emphasizing that its implementation faces financial and regulatory obstacles, making the creation of incentives necessary to stimulate the involvement of the pharmaceutical industry.
DATA SOURCES: We present 63 studies in which 52 non-anticancer drugs with anticancer activity against a number of malignancies are described.
THERAPEUTIC INNOVATIONS: Some have already been the target of phase III studies, such as the Add-Aspirin trial for nonmetastatic solid tumors, as well as 9 other drugs (aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, and sertraline) in the CUSP9* clinical trial for the treatment of recurrent glioblastoma. Others have already been successful in repositioning such as thalidomide, zoledronic acid, celecoxib, methotrexate, and gemcitabine.
CONCLUSIONS: Therefore, drug repositioning represents a promising alternative for the treatment of oncological disorders; however, the support from funding agencies and from the government is still needed, the latter regarding regulatory issues.

PMID: 31033488 [PubMed - as supplied by publisher]

Computational Drug Discovery in Chemotherapy-induced Alopecia via Text Mining and Biomedical Databases.

Clin Ther. 2019 Apr 25;:

Authors: Zhang N, Xu W, Wang S, Qiao Y, Zhang X

Abstract
PURPOSE: Chemotherapy-induced alopecia (CIA) is a common and often stressful adverse effect associated with chemotherapy. CIA can cause more psychosocial pressure in patients, including effects on sexuality, self-esteem, and social relationships. We analyzed publicly available data to identify drugs formulated for topical use targeting the relevant CIA molecular pathways by using computational tools.
METHODS: The genes associated with CIA were determined by text mining, and the gene ontology of the gene set was studied using the Functional Enrichment analysis tool. Protein-protein interaction network analysis was performed using the String database. Enriched gene sets belonging to the identified pathways were queried against the Drug-Gene Interaction database to find drug candidates for topical use in CIA.
FINDINGS: Our analysis identified 427 genes common to CIA text-mining concepts. Gene enrichment analysis and protein-protein interaction analysis yielded 19 genes potentially targetable by a total of 29 drugs that could possibly be formulated for topical application.
IMPLICATIONS: The findings from the present analysis would give a new thought to help discover more effective agents, and present tremendous opportunities to study novel target pharmacology and facilitate drug repositioning efforts in the pharmaceutical industry.

PMID: 31030996 [PubMed - as supplied by publisher]

Screening of antibacterial drugs for antimicrobial activity against Pythium insidiosum.

Med Mycol. 2019 Jun 01;57(4):523-525

Authors: Loreto ES, Tondolo JSM, Santurio JM, Alves SH

Abstract
We tested 25 isolates of Pythium insidiosum to investigate their susceptibility to antibacterial drugs that act through inhibition of protein synthesis or other mechanisms of action. We observed that tetracycline, erythromycin, linezolid, nitrofurantoin, Synercid (quinupristin and dalfopristin), chloramphenicol, clindamycin, cetrimide, and crystal violet had inhibitory activity against P. insidiosum. Those in vitro results suggest that antibacterials that inhibit protein synthesis should be the primary antimicrobials investigated for the treatment of pythiosis in animals and humans.

PMID: 30929019 [PubMed - indexed for MEDLINE]

Chemoproteomic Discovery of a Ritanserin-Targeted Kinase Network Mediating Apoptotic Cell Death of Lung Tumor Cells.

Mol Pharmacol. 2018 11;94(5):1246-1255

Authors: Campbell ST, Franks CE, Borne AL, Shin M, Zhang L, Hsu KL

Abstract
Ritanserin was tested in the clinic as a serotonin receptor inverse agonist but recently emerged as a novel kinase inhibitor with potential applications in cancer. Here, we discovered that ritanserin induced apoptotic cell death of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells via a serotonin-independent mechanism. We used quantitative chemical proteomics to reveal a ritanserin-dependent kinase network that includes key mediators of lipid [diacylglycerol kinase α, phosphatidylinositol 4-kinase β] and protein [feline encephalitis virus-related kinase, rapidly accelerated fibrosarcoma (RAF)] signaling, metabolism [eukaryotic elongation factor 2 kinase, eukaryotic translation initiation factor 2-α kinase 4], and DNA damage response [tousled-like kinase 2] to broadly kill lung tumor cell types. Whereas ritanserin exhibited polypharmacology in NSCLC proteomes, this compound showed unexpected specificity for c-RAF in the SCLC subtype, with negligible activity against other kinases mediating mitogen-activated protein kinase signaling. Here we show that ritanserin blocks c-RAF but not B-RAF activation of established oncogenic signaling pathways in live cells, providing evidence in support of c-RAF as a key target mediating its anticancer activity. Given the role of c-RAF activation in RAS-mutated cancers resistant to clinical B-RAF inhibitors, our findings may have implications in overcoming resistance mechanisms associated with c-RAF biology. The unique target landscape combined with acceptable safety profiles in humans provides new opportunities for repositioning ritanserin in cancer.

PMID: 30158316 [PubMed - indexed for MEDLINE]

Disulfiram, an alcohol dependence therapy, can inhibit the in vitro growth of Francisella tularensis.

Int J Antimicrob Agents. 2019 Apr 25;:

Authors: Hamblin KA, Flick-Smith H, Barnes KB, Pereira-Leal JB, Surkont J, Hampson R, Atkins HS, Harding SV

Abstract
Disulfiram can help treat alcohol dependency by inhibiting aldehyde dehydrogenase. Genomic analysis revealed that Francisella tularensis, the causative agent of tularemia, has lost all but one aldehyde dehydrogenase (ALDH)-Like domain and that this domain retains the target of disulfiram. Minimum inhibitory concentration (MIC) assays demonstrated that both disulfiram and its primary metabolite diethyldithiocarbamate (DDC) have strong antimicrobial activity against F. tularensis strain SCHU S4 with the MIC of disulfiram determined as 2 µg/ml in comparison to DDC with an MIC of 8 µg/ml. The activity of disulfiram was further confirmed using in vitro human macrophage infection assays. F. tularensis bacteria in disulfiram treated cells were reduced in comparison to untreated and DDC treated cells comparable to that observed in doxycycline treated cells. This suggests disulfiram may be suitable for further investigation as an in vivo therapy for tularemia.

PMID: 31029736 [PubMed - as supplied by publisher]

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis.

EBioMedicine. 2019 Apr 23;:

Authors: Lago EM, Silva MP, Queiroz TG, Mazloum SF, Rodrigues VC, Carnaúba PU, Pinto PL, Rocha JA, Ferreira LLG, Andricopulo AD, de Moraes J

Abstract
BACKGROUND: Treatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases, depend almost entirely on a single drug, praziquantel. Since the funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in medical and veterinary fields were evaluated for their anti-schistosomal properties.
METHODS: The efficacy of NSAIDs was first tested against adult Schistosoma mansoni ex vivo using phenotypic screening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease parameters measured were worm and egg burden, hepato- and splenomegaly.
FINDINGS: From 73 NSAIDs, five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac) were identified to effectively kill schistosomes. These results were further supported by scanning electron microscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, revealed to be a critical property for the ex vivo activity profile. Compounds were then tested in vivo using both patent and a prepatent S. mansoni infection in a mouse model. The most effective NSAID was mefenamic acid, which highly reduced worm burden, egg production, and hepato- and splenomegaly.
INTERPRETATION: The treatment regimen used in this study is within the range for which mefenamic acid has been used in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent anti-schistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis.

PMID: 31027918 [PubMed - as supplied by publisher]

Screening of an FDA-Approved Drug Library with a Two-Tier System Identifies an Entry Inhibitor of Severe Fever with Thrombocytopenia Syndrome Virus.

Viruses. 2019 Apr 25;11(4):

Authors: Yuan S, Chan JF, Ye ZW, Wen L, Tsang TG, Cao J, Huang J, Chan CC, Chik KK, Choi GK, Cai JP, Yin F, Chu H, Liang M, Jin DY, Yuen KY

Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case-fatality rates of up to 30%. There are currently very limited treatment options for SFTSV infection. We conducted a drug repurposing program by establishing a two-tier test system to rapidly screen a Food and Drug Administration- (FDA)-approved drug library for drug compounds with anti-SFTSV activity in vitro. We identified five drug compounds that inhibited SFTSV replication at low micromolar concentrations, including hexachlorophene, triclosan, regorafenib, eltrombopag, and broxyquinoline. Among them, hexachlorophene was the most potent with an IC50 of 1.3 ± 0.3 µM and a selectivity index of 18.7. Mechanistic studies suggested that hexachlorophene was a virus entry inhibitor, which impaired SFTSV entry into host cells by interfering with cell membrane fusion. Molecular docking analysis predicted that the binding of hexachlorophene with the hydrophobic pocket between domain I and domain III of the SFTSV Gc glycoprotein was highly stable. The novel antiviral activity and mechanism of hexachlorophene in this study would facilitate the use of hexachlorophene as a lead compound to develop more entry inhibitors with higher anti-SFTSV potency and lower toxicity.

PMID: 31027241 [PubMed - in process]

Mining Clinical Case Reports to Identify New Lines of Investigation in Alzheimer's Disease: The Curious Case of DNase I.

J Alzheimers Dis Rep. 2019 Mar 22;3(1):71-76

Authors: Smalheiser NR

Abstract
Mining the case report literature identified an intriguing, yet neglected finding: Deoxyribonuclease I (DNase I) as a possible treatment for Alzheimer's disease. This finding is speculative, both because it is based on one patient, and because the underlying mechanism(s) of action remain obscure. However, further literature review revealed that there are several plausible mechanisms by which DNase I might affect the course of Alzheimer's disease. Given that DNase I is an FDA-approved drug, with extensive studies in both animals and man in the context of other diseases, I suggest that investigation of DNAse I in Alzheimer's disease is worthwhile.

PMID: 31025031 [PubMed]

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

Front Pharmacol. 2019;10:339

Authors: Moreno E, Cavic M, Krivokuca A, Casadó V, Canela E

Abstract
The endocannabinoid system (ECS) has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumorigenesis and inhibition of tumor growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), and other members of the endocannabinoid-like system, into attractive new targets for the treatment of various cancer subtypes. Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing. As drug repurposing is significantly faster and more economical than de novo introduction of a new drug into the clinic, there is hope that the existing pharmacokinetic and safety data on the ECS ligands will contribute to their successful translation into oncological healthcare. CB1R and CB2R are members of a large family of membrane proteins called G protein-coupled receptors (GPCR). GPCRs can form homodimers, heterodimers and higher order oligomers with other GPCRs or non-GPCRs. Currently, several CB1R and CB2R-containing heteromers have been reported and, in cancer cells, CB2R form heteromers with the G protein-coupled chemokine receptor CXCR4, the G protein-coupled receptor 55 (GPR55) and the tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2). These protein complexes possess unique pharmacological and signaling properties, and their modulation might affect the antitumoral activity of the ECS. This review will explore the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it, and will develop on the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers.

PMID: 31024307 [PubMed]

Transcriptome-based identification of lovastatin as a breast cancer stem cell-targeting drug.

Pharmacol Rep. 2019 Feb 16;71(3):535-544

Authors: Vásquez-Bochm LX, Velázquez-Paniagua M, Castro-Vázquez SS, Guerrero-Rodríguez SL, Mondragon-Peralta A, De La Fuente-Granada M, Pérez-Tapia SM, González-Arenas A, Velasco-Velázquez MA

Abstract
BACKGROUND: Breast cancer is a neoplastic disease with high morbidity and mortality in women worldwide. Breast cancer stem cells (CSCs) have a significant function in tumor growth, recurrence, and therapeutic resistance. Thus, CSCs have been pointed as targets of new therapies for breast cancer. Herein, we aimed to repurpose certain drugs as breast CSC-targeting agents.
METHODS: We compared a consensus breast CSC signature with the transcriptomic changes that were induced by over 1300 bioactive compounds using Connectivity Map. The effects of the selected drugs on SOX2 promoter transactivation, SOX2 expression, viability, clonogenicity, and ALDH activity in breast cancer cells were analyzed by luciferase assay, western blot, MTT assay, mammosphere formation assay, and ALDEFLUOR® test, respectively. Gene Set Enrichment Analysis (GSEA) was performed using the gene expression data from mammary tumors of mice that were treated with lovastatin.
RESULTS: Five drugs (fasudil, pivmecillinam, ursolic acid, 16,16-dimethylprostaglandin E2, and lovastatin) induced signatures that correlated negatively with the query CSC signature. In vitro, lovastatin inhibited SOX2 promoter transactivation, and reduced the efficiency of mammosphere formation and the percentage of ALDH+ cells. Mevalonate mitigated the effects of lovastatin, suggesting that the targeting of CSCs by lovastatin was mediated by the inhibition of its reported target, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). By GSEA, lovastatin downregulated genes that are involved in stemness and invasiveness in mammary tumors, corroborating our in vitro findings.
CONCLUSION: Lovastatin is a breast CSC-targeting drug. The inhibition of HMGCR might develop new adjuvant therapeutic strategies for breast tumors.

PMID: 31026757 [PubMed - as supplied by publisher]

An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer.

Mol Metab. 2019 Apr 10;:

Authors: Longo J, Mullen PJ, Yu R, van Leeuwen JE, Masoomian M, Woon DTS, Wang Y, Chen EX, Hamilton RJ, Sweet JM, van der Kwast TH, Fleshner NE, Penn LZ

Abstract
OBJECTIVE: The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death.
METHODS: Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography-mass spectrometry.
RESULTS: High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells.
CONCLUSION: Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.

PMID: 31023626 [PubMed - as supplied by publisher]

Advancing the repurposing of ivermectin for malaria.

Lancet. 2019 04 13;393(10180):1480-1481

Authors: Chaccour C, Rabinovich NR

PMID: 30878223 [PubMed - indexed for MEDLINE]

Development of a Cx46 Targeting Strategy for Cancer Stem Cells.

Cell Rep. 2019 Apr 23;27(4):1062-1072.e5

Authors: Mulkearns-Hubert EE, Torre-Healy LA, Silver DJ, Eurich JT, Bayik D, Serbinowski E, Hitomi M, Zhou J, Przychodzen B, Zhang R, Sprowls SA, Hale JS, Alban TJ, Berezovsky A, Bell BA, Lockman PR, Jha BK, Lathia JD

Abstract
Gap-junction-mediated cell-cell communication enables tumor cells to synchronize complex processes. We previously found that glioblastoma cancer stem cells (CSCs) express higher levels of the gap junction protein Cx46 compared to non-stem tumor cells (non-CSCs) and that this was necessary and sufficient for CSC maintenance. To understand the mechanism underlying this requirement, we use point mutants to disrupt specific functions of Cx46 and find that Cx46-mediated gap-junction coupling is critical for CSCs. To develop a Cx46 targeting strategy, we screen a clinically relevant small molecule library and identify clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuates proliferation, self-renewal, and tumor growth and synergizes with temozolomide to induce apoptosis. Although clofazimine does not cross the blood-brain barrier, the combination of clofazimine derivatives optimized for brain penetrance with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.

PMID: 31018124 [PubMed - in process]

The retinoic acid receptor (RAR) α-specific agonist Am80 (tamibarotene) and other RAR agonists potently inhibit hepatitis B virus transcription from cccDNA.

Antiviral Res. 2019 Apr 21;:

Authors: Nkongolo S, Nußbaum L, Lempp FA, Wodrich H, Urban S, Ni Y

Abstract
Chronic infection with the human Hepatitis B virus (HBV) is a major global health problem. Hepatitis D virus (HDV) is a satellite of HBV that uses HBV envelope proteins for cell egress and entry. Using infection systems encoding the HBV/HDV receptor human sodium taurocholate co-transporting polypeptide (NTCP), we screened 1181 FDA-approved drugs applying markers for interference for HBV and HDV infection. As one primary hit we identified Acitretin, a retinoid, as an inhibitor of HBV replication and HDV release. Based on this, other retinoic acid receptor (RAR) agonists with different specificities were found to interfere with HBV replication, verifying that the retinoic acid receptor pathway regulates replication. Of the eight agonists investigated, RARα-specific agonist Am80 (tamibarotene) was most active. Am80 reduced secretion of HBeAg and HBsAg with IC50s < 10 nM in differentiated HepaRG-NTCP cells. Similar effects were observed in primary human hepatocytes. In HepG2-NTCP cells, profound Am80-mediated inhibition required prolonged treatment of up to 35 days. Am80 treatment of cells with an established HBV cccDNA pool resulted in a reduction of secreted HBsAg and HBeAg, which correlated with reduced intracellular viral RNA levels, but not cccDNA copy numbers. The effect lasted for >12 days after removal of the drug. HBV genotypes B, D, and E were equally inhibited. By contrast, Am80 did not affect HBV replication in transfected cells or HepG2.2.15 cells, which carry an integrated HBV genome. In conclusion, our results indicate a persistent inhibition of HBV transcription by Am80, which might be used for drug repositioning.

PMID: 31018112 [PubMed - as supplied by publisher]

Rescue therapy for acute idiopathic thrombocytopenic purpura unresponsive to conventional treatment.

BMJ Case Rep. 2019 Jan 14;12(1):

Authors: Reynolds SB, Hashmi H, Ngo P, Kloecker G

Abstract
A 61-year-old woman with chronic lymphocytic leukaemia, with Richter's transformation to a diffuse, large, B-cell lymphoma, treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone and in complete remission, presented to the hospital after her platelets were found to be 2×10³/µL in outpatient laboratory studies. She initially underwent a platelet transfusion without improvement. This was followed by 4 days of high-dose dexamethasone and intravenous immunoglobulin, which again yielded no meaningful effect. Even a single-dose rituximab failed to achieve a platelet increase after 5 days of monitoring. The patient was then given 2 mg of intravenous vincristine along with a high-dose of dexamethasone and IVIG and demonstrated substantial recovery in platelets to >50×10³/µL within 48 hours. This case study provides an overview of the current management strategies for idiopathic thrombocytopenic purpura that is unresponsive to conventional medical therapy and particularly sheds light on their therapeutic benefits and potential adverse effects.

PMID: 30642865 [PubMed - indexed for MEDLINE]

In silico repositioning of approved drugs against Schistosoma mansoni energy metabolism targets.

PLoS One. 2018;13(12):e0203340

Authors: Calixto NM, Dos Santos DB, Bezerra JCB, Silva LA

Abstract
Schistosomiasis is a neglected parasitosis caused by Schistosoma spp. Praziquantel is used for the chemoprophylaxis and treatment of this disease. Although this monotherapy is effective, the risk of resistance and its low efficiency against immature worms compromises its effectiveness. Therefore, it is necessary to develop new schistosomicide drugs. However, the development of new drugs is a long and expensive process. The repositioning of approved drugs has been proposed as a quick, cheap, and effective alternative to solve this problem. This study employs chemogenomic analysis with use of bioinformatics tools to search, identify, and analyze data on approved drugs with the potential to inhibit Schistosoma mansoni energy metabolism enzymes. The TDR Targets Database, Gene DB, Protein, DrugBank, Therapeutic Targets Database (TTD), Promiscuous, and PubMed databases were used. Fifty-nine target proteins were identified, of which 18 had one or more approved drugs. The results identified 20 potential drugs for schistosomiasis treatment; all approved for use in humans.

PMID: 30596650 [PubMed - indexed for MEDLINE]

Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

J Med Chem. 2018 04 26;61(8):3350-3369

Authors: Giroud M, Dietzel U, Anselm L, Banner D, Kuglstatter A, Benz J, Blanc JB, Gaufreteau D, Liu H, Lin X, Stich A, Kuhn B, Schuler F, Kaiser M, Brun R, Schirmeister T, Kisker C, Diederich F, Haap W

Abstract
Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.

PMID: 29590750 [PubMed - indexed for MEDLINE]

AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer.

Oncotarget. 2019 Mar 12;10(21):2055-2067

Authors: Goyette MA, Cusseddu R, Elkholi I, Abu-Thuraia A, El-Hachem N, Haibe-Kains B, Gratton JP, Côté JF

Abstract
Triple-Negative Breast Cancer (TNBC) is an aggressive cancer subtype that is associated with a poor prognosis due to its propensity to form metastases. The receptor tyrosine kinase AXL plays a role in tumor cell dissemination and its expression in breast cancers correlates with poor patient survival. Here, we explored whether already used drugs might elicit a gene signature similar to that seen with AXL knockdown in TNBC cells and which could, therefore, offer an opportunity for drug repurposing. To this end, we queried the Connectivity Map with an AXL gene signature which revealed a class of dopamine receptors antagonists named phenothiazines (Thioridazine, Fluphenazine and Trifluoperazine) typically used as anti-psychotics. We next tested if these drugs, similarly to AXL depletion, were able to limit growth and metastatic progression of TNBC cells and found that phenothiazines are able to reduce cell invasion, proliferation, viability and increase apoptosis of TNBC cells in vitro. Mechanistically, these drugs did not affect AXL activity but instead reduced PI3K/AKT/mTOR and ERK signaling. When administered to mice bearing TNBC xenografts, phenothiazines were able to reduce tumor growth and metastatic burden. Collectively, these results suggest that these antipsychotics display anti-tumor and anti-metastatic activity and that they could potentially be repurposed, in combination with standard chemotherapy, for the treatment of TNBC.

PMID: 31007848 [PubMed]

Chemotherapy-induced peripheral neuropathy: where are we now?

Pain. 2019 May;160 Suppl 1:S1-S10

Authors: Colvin LA

Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge, with increasing impact as oncological treatments, using potentially neurotoxic chemotherapy, improve cancer cure and survival. Acute CIPN occurs during chemotherapy, sometimes requiring dose reduction or cessation, impacting on survival. Around 30% of patients will still have CIPN a year, or more, after finishing chemotherapy. Accurate assessment is essential to improve knowledge around prevalence and incidence of CIPN. Consensus is needed to standardize assessment and diagnosis, with use of well-validated tools, such as the EORTC-CIPN 20. Detailed phenotyping of the clinical syndrome moves toward a precision medicine approach, to individualize treatment. Understanding significant risk factors and pre-existing vulnerability may be used to improve strategies for CIPN prevention, or to use targeted treatment for established CIPN. No preventive therapies have shown significant clinical efficacy, although there are promising novel agents such as histone deacetylase 6 (HDAC6) inhibitors, currently in early phase clinical trials for cancer treatment. Drug repurposing, eg, metformin, may offer an alternative therapeutic avenue. Established treatment for painful CIPN is limited. Following recommendations for general neuropathic pain is logical, but evidence for agents such as gabapentinoids and amitriptyline is weak. The only agent currently recommended by the American Society of Clinical Oncology is duloxetine. Mechanisms are complex with changes in ion channels (sodium, potassium, and calcium), transient receptor potential channels, mitochondrial dysfunction, and immune cell interactions. Improved understanding is essential to advance CIPN management. On a positive note, there are many potential sites for modulation, with novel analgesic approaches.

PMID: 31008843 [PubMed - in process]

Assessment of concomitant non-oncologic medication in patients with surgically treated renal cell carcinoma: impact on prognosis, cell-cycle progression and proliferation.

J Cancer Res Clin Oncol. 2019 Apr 22;:

Authors: Neumann E, Klaiber P, Freitag K, Schwab M, Schaeffeler E, Hennenlotter J, Fend F, Kruck S, Scharpf M, Stenzl A, Bedke J, Rausch S

Abstract
INTRODUCTION: Based on the observation of beneficial effects on cancer metabolism, microenvironment, or VEGF-signaling, several non-anticancer drugs have been discussed as useful in renal cell carcinoma (RCC). In the present study, we investigated the prognostic impact of concomitant medication in RCC and correlated comedication with cell-cycle and proliferation activity in corresponding surgical specimen.
METHODS: A total of 388 patients who underwent surgery for localized RCC were included. The individual medication was evaluated according to substance classes. Tissue microarrays from corresponding tumor specimen were immunohistochemically (IHC) stained for Cyclin D1 and Ki67 and semi-quantitatively evaluated. Uni- and multivariate analyses were used to compare survival outcomes. For the comparison of IHC expression according to medication subgroups, Kruskal-Wallis analysis was performed.
RESULTS: Median follow-up was 57.93 months (95% CI 53.27-69.43) and median OS accounted for 181.12 months (129.72-237.17). Univariate analysis identified pathological standard variables (T-stage > T2, Grading > G2, L1, N1, M1, sarcomatoid subtype, necrosis) as significant determinants of OS. Moreover, statin use (p = 0.009) and sartan use (p = 0.032) were significantly associated with improved OS. Multivariate analysis identified M1-stage (p < 0.001), statin and sartan use (p = 0.003 and p = 0.033, respectively) as independent prognosticators of survival. Expression of Ki67 was significantly reduced in patients with statin use (p = 0.013), while Cyclin D1 expression showed no correlation with comedication.
CONCLUSIONS: Concomitant intake of statins and sartans identifies as an independent predictor of OS in RCC, and reduced Ki67 expression was significantly associated with statin use. Further evaluation of drug repurposing approaches with these substances in RCC appear warranted.

PMID: 31006846 [PubMed - as supplied by publisher]