Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.Herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

Prognostic factors of primary gastrointestinal stromal tumors： a cohort study based on high-volume centers

Objective： We aimed to evaluate the clinicopathologic characteristics, immunohistochemical expression and prognostic factors of patients with primary gastrointestinal stromal tumors（GISTs）.Methods： Data from 2,570 consecutive GIST patients from four medical centers in China（January2001–December 2015） were reviewed. Survival curves were constructed by the Kaplan-Meier method, and Cox regression models were used to identify independent prognostic factors.Results： Of the included patients, 1,375（53.5%） were male, and the patient age range was 18 to 95（median, 58）years. The tumors were mostly found in the stomach（64.5%）, small intestine（25.1%） and colorectal region（5.1%）.At the time of diagnosis, the median tumor size was 4.0（range： 0.1–55.0） cm, and the median mitotic index per 50 high power fields（HPFs） was 3（range： 0–254）. Of the 2,168 resected patients, 2,009（92.7%） received curative resection. According to the modified National Institutes of Health（NIH） classification, 21.9%, 28.9%, 14.1% and35.1% were very low-, low-, intermediate-and high-risk tumors, respectively. The rate of positivity was 96.4% for c-Kit, 87.1% for CD34, 96.9% for delay of germination 1（DOG-1）, 8.0% for S-100, 31.0% for smooth muscle actin（SMA） and 5.1% for desmin. However, the prognostic value of each was limited. Multivariate analysis showed that age, tumor size, mitotic index, tumor site, occurrence of curative resection and postoperative imatinib were independent prognostic factors. Furthermore, we found that high-risk patients benefited significantly from postoperative imatinib（P〈0.001）, whereas intermediate-risk patients did not（P=0.954）.Conclusions： Age, tumor size, mitotic index, tumor site, occurrence of curative resection and postoperative imatinib were independent prognostic factors in patients with GISTs. Moreover, determining whether intermediate-risk patients can benefit from adjuvant imatinib would be of considerable interest in future studies.

Targeted and imaging-guided in vivo photodynamic therapy for tumors using dual-function, aggregation- induced emission nanoparticles

Imaging-guided photodynamic therapy （PDT） has been regarded as a promising strategy for precise cancer treatment. Because of their excellent modifiability and drug-loading capacity, nanoparticles have played an important role in PDT. Nonetheless, when traditional photosensitizers are made into nanoparticles, both their fluorescence and reactive oxygen species generation efficacy decrease due to a phenomenon known as aggregation-caused quenching. Fortunately, in recent years, several kinds of organic dyes with ＂abnormal＂ properties （termed aggregation-induced emission, AIE） were developed. With enhanced fluorescence emission in the nanoaggregation state, the traditional obstacles mentioned above may be overcome by AIE luminogens. Herein, we provide a better combination of photosensitizers and nanoparticles, namely, dual-function AIE nanopartides capable of producing reactive oxygen species, to implement targeted and imaging-guided in vivo PDT. Good contrast of in vivo imaging and obvious therapeutic efficacy were observed at a low dose of AIE nanoparticles and low irradiance of light, thus resulting in negligible side effects. Our work shows that AIE nanopartides may play a promising role in imaging-guided clinical PDT for cancer in the near future.

Phenylboronic acid-modified hollow silica nanoparticles for dual-responsive delivery of doxorubicin for targeted tumor therapy

This work reports a multifunctional nanocarrier based on hollow mesoporous silica nanoparticles(HMSNs)for targeting tumor therapy.Doxorubicin(DOX)was loaded into HMSNs and blocked with cytochrome C conjugated lactobionic acid(CytC–LA)via redox-cleavable disulfide bonds and pH-disassociation boronate ester bonds as intermediate linkers.The CytC–LA was used both as sealing agent and targeting motif.A series of characterizations demonstrated the successful construction of the drug delivery system.The system demonstrated pH and redox dual-responsive drug release behavior in vitro.The DOX loading HMSNs system displayed a good biocompatibility,which could be specifically endocytosed by HepG2 cells and led to high cytotoxicity against tumor cells by inducing cell apoptosis.In vivo data(tumor volume,tumor weight,terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining)proved that the system could deliver DOX to tumor site with high efficiency and inhibit tumor growth with minimal toxic side effect.

Interleukin-6: a villain in the drama of pancreatic cancer development and progression

BACKGROUND： Pancreatic ductal adenocarcinoma（PDAC）is a devastating malignancy with a poor prognosis and little treatment options. The development and progression of the disease is fostered by inflammatory cells and cytokines. One of these cytokines is interleukin-6（IL-6）, which plays an important role in a wide range of biologic activities.DATA SOURCES： A systematic search of PubMed was performed to identify relevant studies using key words such as interleukin-6,inflammatory cytokines, inflammation and pancreatic cancer or PDAC. Articles related to IL-6 and pancreatic cancer were systematically reviewed.RESULTS： IL-6 is elevated in the serum of pancreatic cancer patients and correlates with cachexia, advanced tumor stage and poor survival. Its expression is enhanced by hypoxia and proteins involved in pancreatic cancer development like Kras,mesothelin or ZIP4. IL-6 in turn contributes to the generation of a pro-tumorigenic microenvironment and is probably involved in angiogenesis and metastasis. In experimental mouse models of PDAC, IL-6 was important for the development and progression of precursor lesions.CONCLUSION： IL-6 emerges as a key player in pancreatic cancer development and progression, and hence should be considered as a new therapeutic target.

Strategies for efficient photothermal therapy at mild temperatures:Progresses and challenges

Photothermal therapy(PTT), typically ablates tumors via hyperthermia generated from photothermal agents(PTAs) under laser irradiation, has attracted great attentions in the past decades. Unfortunately,longstanding, frequent and high-power density laser irradiations are needed to maintain the hyperthermal status(>50 ℃) for efficient therapy, which will damage the skin and nearby healthy tissues. Suppressing cancer cells with a mild temperature elevation is more attractive and feasible for PTT. Recently,low-temperature photothermal therapy(LTPTT), which could inhibit tumor under mild hyperthermia, has been widely investigated by researchers. Herein, we systematically summarized the strategies to achieve LTPTT. Diverse PTAs including organic and inorganic materials reported for LTPTT were introduced. The established strategies for LTPTT were intensively described. Finally, the challenges as well as future perspectives in this field were discussed.

The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies

Transient receptor potential(TRP)channels are one primary type of calcium(Ca^(2+))permeable channels,and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems.Nowadays,however,accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression,inducing tumor invasion and metastasis.However,the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive.Therefore,in this review,we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance(MDR),metastasis,apoptosis,proliferation,immune surveillance evasion,and the alterations of relevant tumor micro-environment.Moreover,we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors’efficacy.The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented.Furthermore,it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.

Selected Secondary Plant Metabolites for Cancer Therapy

Secondary plant metabolites reveal numerous biological activities making them attractive as resource for drug development of human diseases.As the majority of cancer drugs clinically established during the past half century is derived from nature, cancer researchers worldwide try to identify novel natural products as lead compounds for cancer therapy. Natural products are considered as promising cancer therapeutics,either as single agents or in combination protocols, to enhance the antitumor activity of additional therapeutic modalities. Most natural compounds exert pleotrophic effects and modulate various signal transduction pathways. A better understanding of the complex mechanisms of action of natural products is expected to open new perspectives in coming years for their use alone or in combination therapies in oncology.Two major strategies to identify novel drug candidates from nature are the bioactivity-guided fractionation of medicinal plant extracts to isolate cytotoxic chemicals and the identification of small molecules inhibiting specific targets in cancer cells. In the present review, we report on our own efforts to unravel the molecular modes of action of phytochemicals in cancer cells and focus on resveratrol, betulinic acid,artesunate, dicentrine and camptothecin derivatives.