Personalized immunotherapy in cancer precision medicine

With the significant advances in cancer genomics using next-generation sequencing technologies,genomic and molecular profilingbased precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments for individual cancer patients.Although many molecular-targeted therapies for a number of actionable genomic alterations have been developed,the clinical application of such information is still limited to a small proportion of cancer patients.In this review,we summarize the current status of personalized drug selection based on genomic and molecular profiling and highlight the challenges how we can further utilize the individual genomic information.Cancer immunotherapies,including immune checkpoint inhibitors,would be one of the potential approaches to apply the results of genomic sequencing most effectively.Highly cancer-specific antigens derived from somatic mutations,the so-called neoantigens,occurring in individual cancers have been in focus recently.Cancer immunotherapies,which target neoantigens,could lead to a precise treatment for cancer patients,despite the challenge in accurately predicting neoantigens that can induce cytotoxic T cells in individual patients.Precise prediction of neoantigens should accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for a broader range of cancer patients.

Insight into the evolution of breast cancer driven by genetic alterations

Breast cancer originates primarily from the epithelial cells of the mammary gland.Repeated mammary gland expansion and degeneration are accompanied by an increased risk of genetic alterations in the breast1.These mutations in breast epithelial cells dynamically occur in response to pregnancy,labor and delivery,breastfeeding,and the menstrual cycle,with a decline in mutation rates after menopause,which may be related to a decrease in estrogen levels.The breast epithelial cell mutations are also consistent with epidemiologic observations2.

Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells

Objective:Pancreatic ductal adenocarcinoma(PDAC)is a deadly malignancy,due in large part to its resistance to conventional therapies,including radiotherapy(RT).Despite RT exerting a modest antitumor response,it has also been shown to promote an immunosuppressive tumor microenvironment.Previous studies demonstrated that focal adhesion kinase inhibitors(FAKi)in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory(T regs)cells,and subsequently enhance effector T cell infiltration.FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies.Thus,we investigated the impact of FAK inhibition on RT,its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.Methods:We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.Results:In this study we showed that IN10018,a small molecular FAKi,enhanced antitumor response to RT.Antitumor activity of the combination of FAKi and RT is T cell dependent.FAKi in combination with RT enhanced CD8+T cell infiltration significantly in comparison to the radiation or FAKi treatment alone(P<0.05).FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone(P<0.01).Conclusions:These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.

KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2

Excessive fructose diet is closely associated with colorectal cancer(CRC)progression.Nevertheless,fructose’s specific function and precise mechanism in colorectal cancer liver metastasis(CRLM)is rarely known.Here,this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM,and the expression of KHK-A,not KHK-C,in liver metastasis was higher than in paired primary tumors.Furthermore,KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37.PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2.EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells’migration ability and anoikis resistance during CRLM progression.TEPP-46 treatment,targeting the phosphorylation of PKM2,inhibited the pro-metastatic effect of KHK-A.Besides,c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A,forming a positive feedback loop.

Immunohistochemical prognostic markers of esophageal squamous cell carcinoma:a systematic review

Background: Esophageal squamous cell carcinoma(ESCC) is an aggressive malignancy, with a high incidence and poor prognosis. In the past several decades, hundreds of proteins have been reported to be associated with the prognosis of ESCC, but none has been widely accepted to guide clinical care. This study aimed to identify proteins with great potential for predicting prognosis of ESCC.Methods: We conducted a systematic review on immunohistochemical(IHC) prognostic markers of ESCC according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) Guidelines. Literature related to IHC prognostic markers of ESCC were searched from PubMed, Embase, Web of Science, and Cochrane Library until January 30 th, 2017. The risk of bias of these original studies was evaluated using the Quality in Prognosis Studies(QUIPS) tool.Results: We identified 11 emerging IHC markers with reproducible results, including eight markers [epidermal growth factor receptor(EGFR), Cyclin D1, vascular endothelial growth factor(VEGF), Survivin, Podoplanin, Fascin,phosphorylated mammalian target of rapamycin(p-mTOR), and pyruvate kinase M2(PKM2)] indicating unfavorable prognosis and 3 markers(P27, P16, and E-cadherin) indicating favorable prognosis of ESCC.Conclusion: Strong evidence supports that these 11 emerging IHC markers or their combinations may be useful in predicting prognosis and aiding personalized therapy decision-making for ESCC patients.

Research advances of secretory proteins in malignant tumors

Secretory proteins in tumor tissues are important components of the tumor microenvironment.Secretory proteins act on tumor cells or stromal cells or mediate interactions between tumor cells and stromal cells,thereby affecting tumor progression and clinical treatment efficacy.In this paper,recent research advances in secretory proteins in malignant tumors are reviewed.

Insights into the transition of ductal carcinoma in situ to invasive ductal carcinoma:morphology,molecular portraits,and the tumor microenvironment

Breast cancer is posing an increasing burden and has become the cancer with the highest incidence among in women in China.The most common histological subtype of breast cancer is invasive ductal carcinoma(IDC)1,2.Ductal carcinoma in situ(DCIS)is a pre-cancerous lesion that may give rise to IDC.DCIS is a highly heterogeneous group of lesions consisting of 5 main types,which differ in clinical presentation,histologic features,biomarker profiles,genetic abnormalities,progression potential,and clinical outcomes.When cancer cells invade through the basal membrane,they acquire the ability to metastasize.This process is usually accompanied by many genetic and epigenetic changes in tumor suppressors and oncogenes.

Clinicopathological parameters predicting recurrence of pT1N0 esophageal squamous cell carcinoma

AIM To identify the clinicopathological characteristics of pT1 N0 esophageal squamous cell carcinoma(ESCC) that are associated with tumor recurrence. METHODS We reviewed 216 pT1 N0 thoracic ESCC cases who underwent esophagectomy and thoracoabdominal two-field lymphadenectomy without preoperative chemoradiotherapy. After excluding those cases with clinical follow-up recorded fewer than 3 mo and those who died within 3 mo of surgery, we included 199 cases in the current analysis. Overall survival and recurrencefree survival were assessed by the Kaplan-Meier method, and clinicopathological characteristics associated with any recurrence or distant recurrence were evaluated using univariate and multivariate Cox proportional hazards models. Early recurrence(≤ 24 mo) and correlated parameters were assessed using univariate and multivariate logistic regression models.RESULTS Forty-seven(24%) patients had a recurrence at 3 to 178(median, 33) mo. The 5-year recurrence-free survival rate was 80.7%. None of 13 asymptomatic cases had a recurrence. Preoperative clinical symptoms, upper thoracic location, ulcerative or intraluminal mass macroscopic tumor type, tumor invasion depth level, basaloid histology, angiolymphatic invasion, tumor thickness, submucosal invasion thickness, diameter of the largest single tongue of invasion, and complete negative aberrant p53 expression were significantly related to tumor recurrence and/or recurrence-free survival. Upper thoracic tumor location, angiolymphatic invasion, and submucosal invasion thickness were independent predictors of tumor recurrence(Hazard ratios = 3.26, 3.42, and 2.06, P < 0.001, P < 0.001, and P = 0.002, respectively), and a nomogram for predicting recurrence-free survival with these three predictors was constructed. Upper thoracic tumor location and angiolymphatic invasion were independent predictors of distant recurrence. Upper thoracic tumor location, angiolymphatic invasion, submucosal invasion thickness, and diameter of the largest single tongue of invasion were independent predictors of early recurrence.CONCLUSION These results should be useful for designing optimal individual follow-up and therapy for patients with T1 N0 ESCC.

Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is frequently diagnosed and treated in advanced tumor stages with poor prognosis.More effective screening programs and novel therapeutic means are urgently needed.Recent studies have regarded tight junction protein claudin 18.2(CLDN18.2)as a candidate target for cancer treatment,and zolbetuximab(formerly known as IMAB362)has been developed against CLDN18.2.However,there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AIM To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.METHODS The Cancer Genome Atlas,Genotype-Tissue Expression,Gene Expression Omnibus,and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue.Second,we analyzed the expression of CLDN18.2 in 93 primary PDACs,86 para-cancer tissues,and 13 normal pancreatic tissues by immunohistochemistry.Immunostained tissues were assessed applying the histoscore.subsequently,they fell into two groups according to the expression state of CLDN18.2.Furthermore,the correlations between CLDN18.2 expression and diverse clinicopathological characteristics,including survival,were investigated.RESULTS The gene expression of CLDN18 was statistically higher(P<0.01)in pancreatic tumors than in normal tissues.However,there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients.CLDN18.2 was expressed in 88(94.6%)of the reported PDACs.Among these tumors,50(56.8%)cases showed strong immunostaining.The para-cancer tissues were positive in 81(94.2%)cases,among which 32(39.5%)of cases were characterized for strong staining intensities.Normal pancreatic tissue was identified solely via weak immunostaining.Finally,CLDN18.2 expression significantly correlated with lymph node metastasis,distant metastasis,nerve invasion,stage,and survival of PDAC patients,while there was no correlation between CLDN18.2 expression and localization,tumor size,patient age and sex,nor any other clinicopathological characteristic.CONCLUSION CLDN18.2 expression is frequently increased in PDAC patients.Thus,it may act as a potential therapeutic target for zolbetuximab in PDAC.

Molecular and functional imaging in cancer-targeted therapy:current applications and future directions

Targeted anticancer drugs block cancer cell growth by interfering with specific signaling pathways vital to carcinogenesis and tumor growth rather than harming all rapidly dividing cells as in cytotoxic chemotherapy.The Response Evaluation Criteria in Solid Tumor(RECIST)system has been used to assess tumor response to therapy via changes in the size of target lesions as measured by calipers,conventional anatomically based imaging modalities such as computed tomography(CT),and magnetic resonance imaging(MRI),and other imaging methods.However,RECIST is sometimes inaccurate in assessing the efficacy of targeted therapy drugs because of the poor correlation between tumor size and treatment-induced tumor necrosis or shrinkage.This approach might also result in delayed identification of response when the therapy does confer a reduction in tumor size.Innovative molecular imaging techniques have rapidly gained importance in the dawning era of targeted therapy as they can visualize,characterize,and quantify biological processes at the cellular,subcellular,or even molecular level rather than at the anatomical level.This review summarizes different targeted cell signaling pathways,various molecular imaging techniques,and developed probes.Moreover,the application of molecular imaging for evaluating treatment response and related clinical outcome is also systematically outlined.In the future,more attention should be paid to promoting the clinical translation of molecular imaging in evaluating the sensitivity to targeted therapy with biocompatible probes.In particular,multimodal imaging technologies incorporating advanced artificial intelligence should be developed to comprehensively and accurately assess cancer-targeted therapy,in addition to RECIST-based methods.

A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer(CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment(TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death(ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3(Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin(QTN) that elicited reactive oxygen species(ROS). To amelioratein vivo delivery barriers associated with chemotherapeutic drugs, a folate(FA)-targeted polyethylene glycol(PEG)-modified amphiphilic cyclodextrin nanoparticle(NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation(CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.

Pancreatic cancer cells render tumor-associated macrophages metabolically reprogrammed by a GARP and DNA methylation-mediated mechanism

How tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We thus conducted a study by employing a PDA-macrophage co-culture system, an “orthotopic” PDA syngeneic mouse model, and human PDA specimens, together with macrophages derived from GARP knockout mice and multiple analytic tools including whole-genome RNA sequencing, DNA methylation arrays, multiplex immunohistochemistry, metabolism measurement, and invasion/metastasis assessment. Our study showed that PDA tumor cells, through direct cell–cell contact, induce DNA methylation and downregulation of a panel of glucose metabolism and OXPHOS genes selectively in M1-like macrophages, leading to a suppressed glucose metabolic status in M1-like but not in M2-like macrophages. Following the interaction with PDA tumor cells, M1-like macrophages are reprogrammed phenotypically to M2-like macrophages. The interaction between M1-like macrophages and PDA cells is mediated by GARP and integrin αV/β8, respectively. Blocking either GARP or integrin would suppress tumor-induced DNA methylation in Nqo-1 gene and the reprogramming of M1-like macrophages. Glucose-response genes such as Il-10 are subsequently activated in tumor-educated M1-like macrophages. Partly through Il-10 and its receptor Il-10R on tumor cells, M1-like macrophages functionally acquire a pro-cancerous capability. Both exogenous M1-like and M2-like macrophages promote metastasis in a mouse model of PDA while such a role of M1-like macrophages is dependent on DNA methylation. Our results suggest that PDA cells are able to reprogram M1-like macrophages metabolically and functionally through a GARP-dependent and DNA methylation-mediated mechanism to adopt a pro-cancerous fate.

Cancer-associated fibroblasts as accomplices to confer therapeutic resistance in cancer

The “seed and soil” concept has reformed paradigms for cancer treatment in the past decade. Accumulatingevidence indicates that the intimate crosstalk between cancer cells and stromal cells plays a tremendous role intumor progression. Cancer-associated fibroblasts (CAFs), the largest population of stroma cells, influencetherapeutic effects through diverse mechanisms. Herein, we summarize the recent advances in the versatilefunctions of CAFs regarding their heterogeneity, and we mainly discuss the pro-tumorigenic functions of CAFswhich promote tumorigenesis and confer therapeutic resistance to tumors. Targeting CAFs is emerging as one ofthe most appealing strategies in anticancer therapies. The endeavors to target or reprogram the specific subtypesof CAFs provide great cancer treatment opportunities, which may provide a better clinical benefit to cancerpatients.

Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant

The single-nucleotide polymorphism(SNP)of p53,in particular the codon 72 variants,has recently been implicated as a critical regulator in tumor progression.However,the underlying mechanism remains elusive.Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation.Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant(but not p5372R)with phosphoserine aminotransferase 1(PSAT1).Interestingly,p53^(72P)-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)that otherwise bound to p53^(72P),leading to subsequent nuclear translocation of PGC-1αand activation of oxidative phosphorylation(OXPHOS)and tricarboxylic acid(TCA)cycle.Depletion of PSAT1 restored p53^(72P)-PGC-1αinteraction and impeded the OXPHOS and TCA function,resulting in mitochondrial dysfunction and metastasis suppression.Notably,pharmacological targeting the PSAT1-p53^(72P)interaction by aminooxyacetic acid(AOA)crippled the growth of liver cancer cells carrying the p53^(72P)variant in both in vitro and patient-derived xenograft models.Moreover,AOA plus regorafenib,an FDA-proved drug for hepatocellular carcinoma and colorectal cancer,achieved a better anti-tumor effect on tumors carrying the p53^(72P)variant.Therefore,our findings identified a gain of function of the p53^(72P)variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p53^(72P)-PSAT1 perturbation.

Managing cardiotoxicity associated with immune checkpoint inhibitors

Immuno-oncology is a fast evolving field of cancer therapy and immune checkpoint inhibitors (ICIs) are clearly a breakthrough in this field. Cardiotoxicity with conventional anti-cancer therapies has been well studied in the past and clear guidelines for management of these side effects are available in the literature. However, cardiotoxicity with novel agents such as ICIs has been fairly under-reported and/or underestimated and we are yet to formulate clear guidelines for management of these rare side effects. In the last few years, there has been an overall increase in the number of cases of cardiotoxicity related to ICIs. In this literature review, we describe the mechanism of action of the most widely used ICIs and their related cardiotoxicities. The increase in number of case reports about the potential of cardiotoxicities with these novel agents clearly indicates the need for a new insight into the field of cardio-immuno-oncology.

Sphingosine kinase 1 promotes growth of glioblastoma by increasing inflammation mediated by the NF-κB/IL-6/STAT3 and JNK/PTX3 pathways

Glioblastoma(GBM)is the most challenging malignant tumor of the central nervous system because of its high morbidity,mortality,and recurrence rate.Currently,mechanisms of GBM are still unclear and there is no effective drug for GBM in the clinic.Therefore,it is urgent to identify new drug targets and corresponding drugs for GBM.In this study,in silico analyses and experimental data show that sphingosine kinase 1(SPHK1)is up-regulated in GBM patients,and is strongly correlated with poor prognosis and reduced overall survival.Overexpression of SPHK1 promoted the proliferation,invasion,metastasis,and clonogenicity of GBM cells,while silencing SPHK1 had the opposite effect.SPHK1 promoted inflammation through the NF-κB/IL-6/STAT3 signaling pathway and led to the phosphorylation of JNK,activating the JNK-JUN and JNK-ATF3 pathways and promoting inflammation and proliferation of GBM cells by transcriptional activation of PTX3.SPHK1 interacted with PTX3 and formed a positive feedback loop to reciprocally increase expression,promote inflammation and GBM growth.Inhibition of SPHK1 by the inhibitor,PF543,also decreased tumorigenesis in the U87-MG and U251-MG SPHK1 orthotopic mouse models.In summary,we have characterized the role and molecular mechanisms by which SPHK1 promotes GBM,which may provide opportunities for SPHK1-targeted therapy.

Cell cycle regulation and hematologic malignancies

A complex network precisely regulates the cell cycle through the G1,S,G2,and M phases and is the basis for cell division under physiological and pathological conditions.On the one hand,the transition from one phase to another as well as the progression within each phase is driven by the specific cyclin-dependent kinases(CDKs;e.g.,CDK1,CDK2,CDK4,CDK6,and CDK7),together with their exclusive partner cyclins(e.g.,cyclin A1,B1,D1–3,and E1).On the other hand,these phases are negatively regulated by endogenous CDK inhibitors such as p16^(ink4a),p18^(ink4c),p19^(ink4d),p21^(cip1),and p27^(kip1).In addition,several checkpoints control the commitment of cells to replicate DNA and undergo mitosis,thereby avoiding the passage of genomic errors to daughter cells.CDKs are often constitutively activated in cancer,which is characterized by the uncontrolled proliferation of transformed cells,due to genetic and epigenetic abnormalities in the genes involved in the cell cycle.Moreover,several oncogenes and defective tumor suppressors promote malignant changes by stimulating cell cycle entry and progression or disrupting DNA damage responses,including the cell cycle checkpoints,DNA repair mechanisms,and apoptosis.Thus,genes or proteins related to cell cycle regulation remain the main targets of interest in the treatment of various cancer types,including hematologic malignancies.In this context,advances in the understanding of the cell cycle regulatory machinery provide a basis for the development of novel therapeutic approaches.The present article summarizes the pathways as well as their genetic and epigenetic alterations that regulate the cell cycle;moreover,it discusses the various approved or potential therapeutic targets associated with the cell cycle,focusing on hematologic malignancies.

A contemporary evidence basis for neoadjuvant chemotherapy in upfront resectable pancreatic adenocarcinoma:a systematic review of the literature

Pancreatic ductal adenocarcinoma(PDAC)is an aggressive cancer with poor survival.Local control through surgical resection paired with radiotherapy and chemotherapy comprise the primary tenets of treatment.Debate exists regarding the timing of treatment and ordering of systemic therapy and resection in the management of early stage disease.The goal of this study was to review the literature and describe the contemporary evidence basis for the role of neoadjuvant therapy(NAT)in the setting of upfront resectable(UP-R)PDAC.Five databases were searched in parallel to identify relevant original articles investigating neoadjuvant therapy where at least 1 study arm contained UP-R PDAC;studies with only borderline resectable or locally advanced disease were excluded.Due to the diversity in NAT regimens and study design between trials,qualitative analyses were performed to investigate patient selection,impact on perioperative and survival outcomes,safety,and cost effectiveness.Thirty-five studies met inclusion criteria,of which 24 unique trials are discussed here in detail.These studies included those trials using single agents as well as more recent trials comparing modern multiagent therapies,and several large database analyses.Overall the data suggest that NAT is safe,may confer survival benefit for appropriately selected patients,is cost effective,and is an appropriate approach for UP-R PDAC.Nevertheless,the risk for disease progression during upfront medical therapy,requires appropriate patient identification and close monitoring,and emphasizes the need for further discovery of more effective chemotherapeutics,useful biomarkers or molecular profiles,and additional prospective comparative studies.