Mining the adenovirus virome for oncolytics against multiple solid tumor types

Although there are 55 serotypes of adenovirus (Ad) that infect humans, Ad serotype 5 (Ad5) is the most widely studied because of the availability of commercial kits for its genetic manipulation. In fact, engineered Ad 5 is currently being used in all of the 87 global clinical trials utilizing Ad for the treatment of cancer. Unfortunately, Ad5 is one of the most seroprevalent serotypes, meaning that this virus has to confront additional immunological barriers to be effective in Ad5-immune patients. In this work, we compare Ad5 to 13 other adenoviral serotypes from species B, C, D and E for oncolytic potential in both immunodeficient mouse and immunocompetent hamster models. Our results indicate that species D Ads are not effective oncolytics against most solid tumors. Conversely, lower seroprevalent Ad6 and Ad11 had anti-cancer activity comparable to Ad5. This work strongly supports the consideration of Ad6-based oncolytic therapies for the treatment of breast, ovarian, kidney and liver tumors.     

Evaluation of 30 DNA damage response and 6 mismatch repair gene mutations as biomarkers for immunotherapy outcomes across multiple solid tumor types

Objective:DNA damage response (DDR) genes have low mutation rates, which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor (ICI) treatment. Thus, a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database. A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center (FUSCC). A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis. A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute (DFCI) cohort were obtained from a published dataset. The Cancer Genome Atlas (TCGA) level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study. Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI, and most of them predicted the therapeutic efficacy of ICI, in a manner dependent on TMB, except for 4 combined DDR gene mutations, which were associated with the therapeutic efficacy of ICI independently of the TMB. Single MMR/DDR genes showed low mutation rates; however, the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high, reaching 10%–30% in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.     

HOX D13 expression across 79 tumor tissue types

HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas‐tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis. © 2009 UICC     

Antibiotics that target mitochondria effectively eradicate cancer stem cells,across multiple tumor types: Treating cancer like an infectious disease

Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.     

Pharmacokinetics of liquid calcitriol formulation in advanced solid tumor patients: comparison with caplet formulation

The non linear relationship between calcitriol (1,25-D₃) dose and AUC in cancer patients suggests that the commercially available caplet 1,25-D₃ formulation (Rocaltrol) cannot achieve the high systemic exposure associated with antitumor activity in animal models. The primary objective of this analysis was to determine whether a liquid 1,25-D₃ formulation had a more favorable pharmacokinetic profile. This analysis was based on the results obtained in 2 phase I clinical studies seeking to determine the maximum tolerated dose of 1,25-D₃ administered in combination with either dexamethasone or paclitaxel daily for three consecutive days weekly. Data were available for 12 patients treated with the caplet formulation at doses ranging from 12 g to 21 g, and for 16 patients treated with the liquid formulation at doses ranging from 13 g to 36 g; data for 19 patients were available at doses for which both formulations were used. There were no differences in C_max and AUC_0–24h between the two formulations (P>0.17) As was noted with the caplet formulation, dose-related proportional increases in C_max and AUC_0–24h were not observed with liquid 1,25-D₃ at doses 13 g (P>0.83). We conclude that the commercially available liquid 1,25-D₃ formulation offers no PK advantage over caplet formulation.     

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 and DR5), and 2 potentially antiapoptotic receptors lacking death domains (DcR1 and DcR2). Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types. Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. We examined the methylation and expression status of TRAIL receptor genes in cancers of breast, lung, mesothelioma, prostate, bladder, cervix, ovary, brain and in hematopoietic malignancies. Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. Methylation of DR4 and DR5 was rare in all the tumor types examined. Methylation of all the 4 receptors was rare in non malignant tissues. In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. The concordance between loss of gene expression and aberrant methylation ranged from 70-100%. Treatment with 5-aza-2'-deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcR1 and DcR2 expression. Our results demonstrate that DcR1 and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re-evaluated.     

Graphene oxide selectively targets cancer stem cells,across multiple tumor types: Implications for non-toxic cancer treatment,via “differentiation-based nano-therapy”

Tumor-initiating cells (TICs), a.k.a. cancer stem cells (CSCs), are difficult to eradicate with conventional approaches to cancer treatment, such as chemo-therapy and radiation. As a consequence, the survival of residual CSCs is thought to drive the onset of tumor recurrence, distant metastasis, and drug-resistance, which is a significant clinical problem for the effective treatment of cancer. Thus, novel approaches to cancer therapy are needed urgently, to address this clinical need. Towards this end, here we have investigated the therapeutic potential of graphene oxide to target cancer stem cells. Graphene and its derivatives are well-known, relatively inert and potentially non-toxic nano-materials that form stable dispersions in a variety of solvents. Here, we show that graphene oxide (of both big and small flake sizes) can be used to selectively inhibit the proliferative expansion of cancer stem cells, across multiple tumor types. For this purpose, we employed the tumor-sphere assay, which functionally measures the clonal expansion of single cancer stem cells under anchorage-independent conditions. More specifically, we show that graphene oxide effectively inhibits tumor-sphere formation in multiple cell lines, across 6 different cancer types, including breast, ovarian, prostate, lung and pancreatic cancers, as well as glioblastoma (brain). In striking contrast, graphene oxide is non-toxic for “bulk” cancer cells (non-stem) and normal fibroblasts. Mechanistically, we present evidence that GO exerts its striking effects on CSCs by inhibiting several key signal transduction pathways (WNT, Notch and STAT-signaling) and thereby inducing CSC differentiation. Thus, graphene oxide may be an effective non-toxic therapeutic strategy for the eradication of cancer stem cells, via differentiation-based nano-therapy.     

Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types

BackgroundWe hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types.Patients and methodsRNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy.ResultsIn pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%–84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80^th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response.ConclusionsOur study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.     

Pharmacokinetics of mitoxantrone in humans following single-agent infusion or intra-arterial injection therapy or combined-agent infusion therapy

Summary This study describes the pharmacokinetics of mitoxantrone determined by a sensitive and specific HPLC-method.The time-concentration curves of i.v.-treated patients (15 mg/m² over 30 min) correspond to a three-compartment model with a T1/2 of 12 min, a T1/2 of 93 min, and a slow elimination phase of 36 h.The central compartment volume was 26.22 and the distribution volume, 1381.9. The mean urinary excretion was 4.9% of the total dose.The pharmacokinetic parameters were also defined in five patients who were treated with combination chemotherapy (mitoxantrone 12 mg/m², methotrexate 30 mg/m² and vincristine 2 mg). These results were not different from those with the single-drug treatment, except for the volume of the central compartment, which was significantly decreased. The peak levels after hepatic arterial infusion of mitoxantrone were three times lower than those after the identical dose given i.v. to the same patient. Pleural fluid sampling showed a six-fold increase compared with the plasma level (12 ng/ml versus 2 ng/ml).A multiple linear regression analysis of the data revealed correlations between the pharmacokinetic results and some of the baseline parameters. It is possible to predict changes in the kinetic behaviour of mitoxantrone on the basis of these relations but on the other hand toxicity is less predictable from the baseline parameters or from the pharmacokinetic results.     

实体瘤的放射免疫治疗

放射免疫治疗是众多免疫靶向治疗的一种,在恶性肿瘤的治疗中具有独到的优势,目前主要应用于淋巴瘤以及部分实体瘤的治疗.关于前者的综述较多,而鲜见有关实体瘤的放射免疫治疗综述.现就实体瘤的基础研究及临床应用作一全面综述.     

实体瘤的放射免疫治疗

放射免疫治疗是众多免疫靶向治疗的一种,在恶性肿瘤的治疗中具有独到的优势,目前主要应用于淋巴瘤以及部分实体瘤的治疗.关于前者的综述较多,而鲜见有关实体瘤的放射免疫治疗综述.现就实体瘤的基础研究及临床应用作一全面综述.     

实体瘤的放射免疫治疗

放射免疫治疗是众多免疫靶向治疗的一种,在恶性肿瘤的治疗中具有独到的优势,目前主要应用于淋巴瘤以及部分实体瘤的治疗.关于前者的综述较多,而鲜见有关实体瘤的放射免疫治疗综述.现就实体瘤的基础研究及临床应用作一全面综述.     

实体瘤的放射免疫治疗

放射免疫治疗是众多免疫靶向治疗的一种,在恶性肿瘤的治疗中具有独到的优势,目前主要应用于淋巴瘤以及部分实体瘤的治疗.关于前者的综述较多,而鲜见有关实体瘤的放射免疫治疗综述.现就实体瘤的基础研究及临床应用作一全面综述.     

实体瘤的放射免疫治疗

放射免疫治疗是众多免疫靶向治疗的一种,在恶性肿瘤的治疗中具有独到的优势,目前主要应用于淋巴瘤以及部分实体瘤的治疗.关于前者的综述较多,而鲜见有关实体瘤的放射免疫治疗综述.现就实体瘤的基础研究及临床应用作一全面综述.     

实体瘤的放射免疫治疗

放射免疫治疗是众多免疫靶向治疗的一种,在恶性肿瘤的治疗中具有独到的优势,目前主要应用于淋巴瘤以及部分实体瘤的治疗.关于前者的综述较多,而鲜见有关实体瘤的放射免疫治疗综述.现就实体瘤的基础研究及临床应用作一全面综述.