Personalized pancreatic cancer therapy:from the perspective of mRNA vaccine

Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and microenvironment.Conventional therapeutic strategies for pancreatic cancer usually suffer resistance,highlighting the necessity for personalized precise treatment.Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting,minimal nonspecific effects,broad therapeutic window,low toxicity,and induction of persistent immunological memory.Multiple conventional vaccines based on the cells,microorganisms,exosomes,proteins,peptides,or DNA against pancreatic cancer have been developed;however,their overall efficacy remains unsatisfactory.Compared with these vaccine modalities,messager RNA(mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment,and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer.This review summarizes the current progress on pancreatic cancer vaccines,highlights the superiority of mRNA vaccines over other conventional vaccines,and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.

Advances in precision treatment of ovarian cancer

Ovarian cancer is one of the most common malignant tumors in female reproductive organs.Due to the lack of effective screening and early diagnosis methods,the vast majority of patients with ovarian cancer are in advanced stages once diagnosed.Precision therapy mainly includes immunotherapy,targeted therapy,biological therapy,and gene therapy.At present,precision therapy is increasingly used in the clinical treatment of ovarian cancer due to its advantages,such as fewer side effects and a high degree of killing.This article summarizes the recent advances in the precise treatment of ovarian cancer.

Long noncoding RNA PPP1R14B-AS1 imitates microRNA-134-3p to facilitate breast cancer progression by upregulating LIM and SH3 protein 1

Long noncoding RNA PPP1R14B antisense RNA 1(PPP1R14B-AS1)has emerged as a critical modulator of liver cancer and lung adenocarcinoma progression.However,the functional importance and biological relevance of PPP1R14B-AS1 in breast cancer remain unclear.Therefore,this study was designed to detect PPP1R14B-AS1 levels in breast cancer cells using qRT–PCR and elucidate the influence of PPP1R14B-AS1 on aggressive phenotypes.Furthermore,molecular events mediating the action of PPP1R14B-AS1 were characterized in detail.Functional experiments addressed the impacts of PPP1R14B-AS1 knockdown on breast cancer cells.In this study,PPP1R14B-AS1 was found to be overexpressed in breast cancer,exhibiting a close correlation with poor patient prognosis.Results also showed that breast cancer cell proliferation and motility were suppressed when PPP1R14B-AS1 was silenced.Mechanistically,PPP1R14B-AS1 acted as a competing endogenous RNA for microRNA-134-3p(miR-134-3p)in breast cancer cells.PPP1R14B-AS1 also increased LIM and SH3 protein 1(LASP1)levels by imitating miR-134-3p in breast cancer cells.Rescue experiments further corroborated that the knockdown of miR-134-3p or an increase in LASP1 restored the aggressive malignant characteristics of breast cancer cells that were weakened by PPP1R14B-AS1 depletion.In summary,PPP1R14B-AS1 facilitated the oncogenicity of breast cancer cells by controlling the miR-134-3p/LASP1 axis.We believe that ourfindings may contribute to the development of precision therapy techniques in thefield of breast cancer treatment.

Dual stimuli-activatable versatile nanoplatform for photodynamic therapy and chemotherapy of triple-negative breast cancer

Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal invasiveness.However,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to their"always-on"photoactivity in blood circulation.To address this concern,we herein report a series of acid-activatable PSs for ultrasensitive PDT of triple-negative breast tumors.These set of novel PSs are synthesized by covalently modifying tetrakis(4-carboxyphenyl)porphyrin(TCPP)with a variety of tertiary amines for acidity-activatable fluorescence imaging and reactive oxygen species(RoS)generation.The resultant TCPP derivatives are grafted with a poly(ethylene glycol)(PEG)chain via a matrix metalloproteinase-2(MMP-2)-liable peptide spacer and chelated with Mn^(2+)for magnetic resonance imaging(MRI)capability.The PEGylated TCPP derivatives are amphiphilic and self-assemble into micellar nanoparticles to elongate blood circulation and for tumor-specific PDT.We further demonstrate that the PEGylated TCPP nanoparticles could serve as a nanoplatform to deliver the anticancer drug doxorubicin(DOX)and perform fluorescence image-guided combinatorial PDT and chemotherapy,which efficiently suppress the growth of 4T1 breast tumors and lung metastases in a mouse model.These acid-activatable PS-incorporated nanoparticles might provide a versatile platform for precise PDT and combinatorial breast cancer therapy.

Immune precision medicine for cancer:a novel insight based on the efficiency of immune effector cells

Cancer cell growth is associated with immune surveillance failure.Nowadays,restoring the desired immune response against cancer cells remains a major therapeutic strategy.Due to the recent advances in biological knowledge,efficient therapeutic tools have been developed to support the best bio-clinical approaches for immune precision therapy.One of the most important successes in immune therapy is represented by the applicational use of monoclonal antibodies,particularly the use of rituximab for B-cell lymphoproliferative disorders.More recently,other monoclonal antibodies have been developed,to inhibit immune checkpoints within the tumor microenvironment that limit immune suppression,or to enhance some immune functions with immune adjuvants through different targets such as Toll-receptor agonists.The aim is to inhibit cancer proliferation by the diminishing/elimination of cancer residual cells and clinically improving the response duration with no or few adverse effects.This effect is supported by enhancing the number,functions,and activity of the immune effector cells,including the natural killer(NK)lymphocytes,NKT-lymphocytes,γδT-lymphocytes,cytotoxic T-lymphocytes,directly or indirectly through vaccines particularly with neoantigens,and by lowering the functions of the immune suppressive cells.Beyond these new therapeutics and their personalized usage,new considerations have to be taken into account,such as epigenetic regulation particularly from microbiota,evaluation of transversal functions,particularly cellular metabolism,and consideration to the clinical consequences at the body level.The aim of this review is to discuss some practical aspects of immune therapy,giving to clinicians the concept of immune effector cells balancing between control and tolerance.Immunological precision medicine is a combination of modern biological knowledge and clinical therapeutic decisions in a global vision of the patient.

Development of a novel RNAi therapy:Engineered miR-31 exosomes promoted the healing of diabetic wounds

Rationale:Chronic wounds associated with diabetes exact a heavy burden on individuals and society and do not have a specific treatment.Exosome therapy is an extension of stem cell therapy,and RNA interference(RNAi)-based therapy is a type of advanced precision therapy.Based on the discovery of chronic wound-related genes in diabetes,we combined exosome therapy and RNAi therapy through an engineering approach for the treatment of diabetic chronic wounds.Methods:We combined exosome therapy and RNAi therapy to establish a precision therapy for diabetes-associated wounds via an engineered exosome approach.Results:First,chronic diabetic wounds express low levels of miR-31-5p compared with nondiabetic wounds,and an miR-31-5p mimic was shown to be effective in promoting the proliferation and migration of three wound-related cell types in vitro.Second,bioinformatics analysis,luciferase reporter assays and western blotting suggested that miR-31-5p promoted angiogenesis,fibrogenesis and reepithelization by inhibiting factor-inhibiting HIF-1(HIF1AN,also named FIH)and epithelial membrane protein-1(EMP-1).Third,engineered miR-31 exosomes were generated as a miR-31-5p RNAi therapeutic agent.In vivo,the engineered miR-31 exosomes promoted diabetic wound healing by enhancing angiogenesis,fibrogenesis and reepithelization.Conclusion:Engineered miR-31 exosomes are an ideal disease pathophysiology-initiated RNAi therapeutic agent for diabetic wounds.

Smart drug delivery systems for precise cancer therapy

Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.

Novel directions of precision oncology:circulating microbial DNA emerging in cancer-microbiome areas

Microbiome research has extended into the cancer area in the past decades.Microbes can affect oncogenesis,progression,and treatment response through various mechanisms,including direct regulation and indirect impacts.Microbiota-associated detectionmethods and agents have been developed to facilitate cancer diagnosis and therapy.Additionally,the cancermicrobiome has recently been redefined.The identification of intra-tumoral microbes and cancer-related circulating microbial DNA(cmDNA)has promoted novel research in the cancer–microbiome area.In this review,we define the human system of commensal microbes and the cancer microbiome from a brand-new perspective and emphasize the potential value of cmDNA as a promising biomarker in cancer liquid biopsy.We outline all existing studies on the relationship between cmDNA and cancer and the outlook for potential preclinical and clinical applications of cmDNA in cancer precision medicine,as well as critical problems to be overcome in this burgeoning field.

Lipoprotein-biomimetic nanostructure enables tumor-targeted penetration delivery for enhanced photo-gene therapy towards glioma

Glioma is one of the most malignant primary tumors affecting the brain.The efficacy of therapeutics for glioma is seriously compromised by the restriction of blood-brain barrier(BBB),interstitial tumor pressure of resistance to chemotherapy/radiation,and the inevitable damage to normal brain tissues.Inspired by the natural structure and properties of high-density lipoprotein(HDL),a tumor-penetrating lipoprotein was prepared by the fusion tLyP-1 to apolipoprotein A-I-mimicking peptides(D4F),together with indocyanine green(ICG)incorporation and lipophilic small interfering RNA targeted HIF-1α(siHIF)surface anchor for site-specific photo-gene therapy.tLyP-1 peptide is fused to HDL-surface to facilitate BBB permeability,tumor-homing capacity and-site accumulation of photosensitizer and siRNA.Upon NIR light irradiation,ICG not only served as real-time targeted imaging agent,but also provided toxic reactive oxygen species and local hyperthermia for glioma phototherapy.The HIF-1αsiRNA in this nanoplatform downregulated the hypoxia-induced HIF-1αlevel in tumor microenvironment and enhanced the photodynamic therapy against glioma.These studies demonstrated that the nanoparticles could not only efficiently across BBB and carry the payloads to orthotopic glioma,but also modulate tumor microenvironment,thereby inhibiting tumor growth with biosafety.Overall,this study develops a new multifunctional drug delivery system for glioma theranostic,providing deeper insights into orthotopic brain tumor imaging and treatment.

Precise cell therapy for liver fibrosis: Endothelial cell and macrophage therapy

Liver fibrosis is typically caused by chronic viral hepatitis and,more recently,fatty liver disease associated with obesity.There are currently no approved drugs for liver cirrhosis,and liver transplantation is limited by donor scarcity,thus driving the investigation of novel therapeutic strategies.The development of liver fibrosis presents with stage-and zone-dependent characteristics that manifest as distinct dynamic changes during vascularization and extracellular matrix(ECM)deposition.However,current cellular therapies do not consider the spatiotem-poral variations of liver fibrosis without identifying the precise location and stage to administer the intervention to achieve optimal therapeutic effects.Herein,we focus on endothelial cell(EC)and macrophage therapy for liver fibrosis because of their important roles in regulating the spatiotemporal changes of vascularization and ECM deposition during liver fibrosis progression.Overall,this review summarizes the stage-dependent EC and macrophage therapy for liver fibrosis,elucidates their respective mechanisms,and exemplifies potential strategies to realize precise cell therapy by targeting specific liver zones.

Intrinsically bioactive and biomimetic nanoparticle-derived therapies alleviate asthma by regulating multiple pathological cells

Asthma is a serious global public health concern. Airway neutrophilic inflammation is closely related to severe asthma, for which effective and safe therapies remain to be developed. Here we report nanotherapies capable of simultaneously regulating multiple target cells relevant to the pathogenesis of neutrophilic asthma. A nanotherapy LaCD NP based on a cyclic oligosaccharide-derived bioactive material was engineered. LaCD NP effectively accumulated in the injured lungs of asthmatic mice and mainly distributed in neutrophils, macrophages, and airway epithelial cells after intravenous or inhalation delivery, thereby ameliorating asthmatic symptoms and attenuating pulmonary neutrophilic inflammation as well as reducing airway hyperresponsiveness, remodeling, and mucus production. Surface engineering via neutrophil cell membrane further enhanced targeting and therapeutic effects of LaCD NP. Mechanistically, LaCD NP can inhibit the recruitment and activation of neutrophils, especially reducing the neutrophil extracellular traps formation and NLRP3 inflammasome activation in neutrophils. Also, LaCD NP can suppress macrophage-mediated pro-inflammatory responses and prevent airway epithelial cell death and smooth muscle cell proliferation, by mitigating neutrophilic inflammation and its direct effects on relevant cells. Importantly, LaCD NP showed good safety performance. Consequently, LaCD-derived multi-bioactive nanotherapies are promising for effective treatment of neutrophilic asthma and other neutrophil-associated diseases.

Aptamer technology: a new approach to treat lymphoma?

Oligonucleotide aptamers are a class of small-molecule ligands.Functionally similar to protein antibodies,aptamers can specifically bind to their targets with high affinity.Biomedical studies have revealed the potential clinical value of aptamer technology for disease diagnosis and targeted therapy.Lymphoma is a group of cancers originating from the lymphatic system.Currently,chemotherapy is the primary treatment for lymphoma,although it may cause serious side effects in patients due to lack of target specificity.Here,we selectively discuss the recent development of potential applications of aptamer technology for precision lymphoma therapy,which are able to not only achieve high therapeutic efficacy but also do not cause off-target side effects.

Cancer stem cell-mediated therapeutic resistance in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy.In the clinic,therapeutic resistance is largely attributed to tumor heterogeneity.Growing evidence indicates that cancer stem cells(CSCs)are the major source of tumor heterogeneity.Hence,uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics.CSCs resemble embryonic stem cells.Embryonic developmentrelated genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC.Multiple strategies have been applied to identify oncofetal drivers.The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure.Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance.This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance.

Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer

Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype.It disproportionately affects BRCA mutation carriers and young women,especially African American(AA)women.Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies.With the approval of immune checkpoint blockade(ICB)for TNBC,the addition of pembrolizumab to systemic chemotherapy has become standard of care(SOC)in neoadjuvant systemic therapy(NST)for high-risk early-stage TNBC.Pembrolizumab plus chemotherapy significantly increased the pathologic complete response(pCR)and improved event-free survival in TNBC.However,clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes.Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse.Therefore,novel treatment strategies and innovative new research initiatives are needed.We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC.Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated(ON),indicating an ineffective response to treatment.These chemoresistant tumor clones persist in expressing SIAH(SIAH^(High/ON))and are linked to early tumor relapse and poorer prognosis.Conversely,the loss of SIAH expression(SIAH^(Low/OFF))in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation(OFF),indicating effective therapy and chemo-sensitive tumor cells.SIAH^(Low/OFF) signal is linked to tumor remission and better prognosis post-NACT/NST.Therefore,SIAH is well-positioned to become a novel tumor-specific,therapy-responsive,and prognostic biomarker.Potentially,this new biomarker(SIAH^(High/ON))could be used to quantify therapy response,predict chemo-resistance,and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.