We previously reported that inhibition of autophagy significantly augmented the anticancer activity histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. thus conducted first-in-human study to investigate safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) combination hydroxychloroquine (HCQ) VOR in patients with advanced solid tumors. Of 27 treated study, 24 were considered fully evaluable for assessments toxicity....

Cellular stress induced by nutrient deprivation, hypoxia, and exposure to many chemotherapeutic agents activates an evolutionarily conserved cell survival pathway termed autophagy. This enables cancer cells undergo self-digestion generate ATP other essential biosynthetic molecules temporarily avoid death. Therefore, disruption of autophagy may sensitize death augment chemotherapy-induced apoptosis. Chloroquine its analog hydroxychloroquine are the only clinically relevant inhibitors. Because...

Ovarian cancer has the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause treatment failure and novel therapeutic strategies are urgently needed. MLN4924 NEDDylation inhibitor currently under investigation in multiple phase I studies. We investigated its anticancer activity cisplatin-sensitive -resistant ovarian models.Cellular sensitivity to MLN4924/cisplatin was determined by measuring viability, clonogenic survival, apoptosis. The effects drug...

Abstract Purpose: The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has exhibited promising anticancer activity for the treatment renal cell cancers (RCC). Survivin expression been implicated in drug resistance and reducing its levels with histone deacetylase (HDAC) vorinostat may enhance temsirolimus. Experimental Design: sensitivity RCC lines to combination was determined by measuring viability, clonogenic survival, apoptosis. effects this on survivin were vitro vivo....

Purpose: Although autophagy plays important roles in malignant pathogenesis and drug resistance, there are few clinical agents that disrupt this pathway, the potential therapeutic benefit of inhibition remains undetermined. We used medicinal chemistry approaches to generate a series novel inhibit autophagic degradation.Experimental Design: ROC-325 was selected as lead compound for further evaluation. Comprehensive vitro vivo studies were conducted evaluate selectivity, tolerability, efficacy...

Activating mutation of KRas is a genetic alteration that occurs in the majority pancreatic tumors and therefore an ideal therapeutic target. The ability reoviruses to preferentially replicate induce cell death transformed cells express activated Ras prompted development reovirus-based formulation for cancer therapy called Reolysin. We hypothesized Reolysin exposure would trigger heavy production viral products leading endoplasmic reticular (ER) stress-mediated apoptosis. Here, we report...

Repurposing FDA approved drugs with off-target autophagy inhibition such as chloroquine/hydroxychloroquine (CQ, HCQ) has produced modest anticancer activity in clinical trials, due part, to a failure define predictive biomarkers that enable the selection of patients best respond this treatment strategy. We identified new role for REDD1 determinant sensitivity renal cell carcinoma (RCC). RNA sequencing, qRT-PCR, immunoblotting, gene silencing, knockout and overexpression studies revealed...

Abstract Background The Syrian hamster, Mesocricetus auratus , has distinct immunological features and is uniquely susceptible to intracellular pathogens. Studies in hamsters are limited by the relative unavailability of tools conduct studies. To address this limitation we developed duplex real-time reverse transcriptase (RT) PCR assays for quantification mRNAs hamster cytokines, chemokines, related immune response molecules. Results Real-time RT-PCR primers probes were synthesized analysis...

Abstract Novel therapies are urgently needed to improve clinical outcomes for patients with acute myeloid leukemia (AML). The investigational drug alisertib (MLN8237) is a novel Aurora A kinase inhibitor being studied in multiple Phase I and II studies. We investigated the preclinical efficacy pharmacodynamics of AML cell lines, primary cells mouse models AML. Here, we report that disrupted viability, diminished clonogenic survival, induced expression FOXO3a targets p27 BIM triggered...

The clinicopathological features of the hamster model visceral leishmaniasis (VL) closely mimic active human disease. Studies in humans and hamsters indicate that inability to control parasite replication VL could be related ineffective classical macrophage activation. Therefore, we hypothesized pathogenesis might driven by a program alternative Indeed, infected spleen showed low NOS2 but high arg1 enzyme activity protein mRNA expression (p<0.001) increased polyamine synthesis (p<0.05)....

// Kevin R. Kelly 1 , Claudia M. Espitia 2 Weiguo Zhao Erik Wendlandt 3 Guido Tricot Fenghuang Zhan Jennifer S. Carew 4 Steffan T. Nawrocki Anne Nohl Division of Hematology and Center for the Study Blood Diseases, University Southern California Keck School Medicine, Los Angeles, CA, USA Department Medicine The Institute Drug Development, Cancer Therapy Research at Texas Health Science Center, San Antonio, TX, Hematology, Oncology, Marrow Transplantation, Internal Iowa, Iowa City, IA,...

The tumor-selective viral replication capacity and pro-apoptotic effects of oncolytic reovirus have been reported to be dependent on the presence an activated RAS pathway in several solid tumor types. However, mechanisms selective anticancer efficacy reovirus-based formulation for cancer therapy (Reolysin, pelareorep) not rigorously studied soft tissue sarcomas (STS). Here we report that Reolysin triggered a striking induction anti-angiogenic chemokine interferon-γ-inducible protein 10...

Upregulation of PIM kinase expression has been reported in many malignancies, suggesting that inhibition activity may be an attractive therapeutic strategy. We hypothesised with SGI-1776, a novel small molecule inhibitor activity, would reduce the viability renal cell carcinoma (RCC) cells and enhance sunitinib. Immunoblotting, qRT–PCR, gene arrays were carried out to identify genes modulated by SGI-1776 treatment. The anticancer sunitinib was determined apoptosis assays tumour xenografts...

Abstract Inhibition of bromodomain and extra terminal (BET) protein family members, including BRD4, decreases the expression c-MYC other key oncogenic factors also significantly induces histone deacetylase 6 (HDAC6) expression. On basis role HDAC6 in malignant pathogenesis, we hypothesized that rational cotargeting BET proteins may represent a novel approach yields synergistic antimyeloma activity. We used genetic pharmacologic approaches to selectively impair function evaluated...

Patients with late-stage and human papillomavirus (HPV)-negative head neck squamous cell carcinoma (HNSCC) continue to have a very poor prognosis. The development of more effective novel therapies that improve overall survival overcome drug resistance is an urgent priority. Here we report HNSCC tumors significantly overexpress NEDD8 exhibit high sensitivity the first-in-class NEDD8-activating enzyme (NAE) inhibitor pevonedistat. Additional studies established disruption NEDD8-mediated...

Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal carcinoma (RCC) pathogenesis is not well defined. We investigated roles RCC tumor progression, resistance mTOR inhibitors, evaluated therapeutic activity suppressant YM155 models. Here, we report that levels were significantly higher lines compared with normal cells. Stable targeted knockdown completely abrogated ability...

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis that may be promising agent in cancer therapy due to its selectivity toward tumor cells. However, many cells are resistant TRAIL defects signaling or activation survival pathways. We hypothesized disruption pro-survival cascades with the multi-tyrosine kinase inhibitor sunitinib would an effective strategy enhance TRAIL-mediated apoptosis. Here we demonstrate significantly augments anticancer...

Background Hypoxia-inducible factor (HIF) is an attractive therapeutic target for renal cell carcinoma (RCC) as its high expression due to the loss of von Hippel-Lindau (VHL) promotes RCC progression. Considering this, we hypothesized that ELR510444, a novel orally available small molecule inhibitor HIF activity, would reduce angiogenesis and possess significant activity in RCC. The mechanism action efficacy ELR510444 were investigated vitro vivo models Principal Findings decreased HIF-1α...