Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Exploring Shaking for Cancer Treatment

1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional orientation.Vibration or shaking,such as precession caused by external torque,nutation stemming from off-axis angular momentum,and wobbling due to geometric misalignment,necessitate active and passive damping mechanisms.This principle extends beyond spacecraft to centrifugation techniques,pivotal not only in washing machines but also in a spectrum of biomedical apparatuses used for isolating cells and organelles and separating DNA and proteins.

Cancer-cell-intrinsic mechanisms shaping the immunosuppressive landscape of prostate cancer

Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy.This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer.Therefore,it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment.Here,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance.Based on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.

Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue

Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval.Protein arginine methyltransferase 5(PRMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CRC),and breast cancer(BC),making PRMT5 an important target for cancer therapy.Previously,we showed that PRMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in cancers.In this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PRMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in vitro.Furthermore,PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug treatment.Using in silico prediction,we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity.Finally,Clo and Can treatment have exhibited marked reduction in tumor growth in vivo.Overall,we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies.Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.

CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

Sperm hyaluronidase is critical to mammals'fertilization for its ability to disperse cumulus-oocyte complex layer

Glycosylphosphatidylinositol-anchored sperm hyaluronidases have long been believed to assist in sperm penetration through the cumulus-oocyte complex(COC);however,their role in mammalian fertilization remains unclear.Previously,we have shown that hyaluronidase 5(Hyal5)/Hyal7 double-knockout(dKO)mice produce significantly fewer offspring than their wild-type(WT)counterparts because of defective COC dispersal.Male infertility is mainly caused by a low sperm count.It can be further exacerbated by the deficiency of sperm hyaluronidase,which disperses the cumulus cells of the outer layer of the COC.In the current study,we evaluated the effects of a low count of Hyal-deficient sperm and conditions of ovulated oocytes on the fertilization rate using a mouse model.Our results demonstrated that a low sperm count further decreases the in vitro fertilization(IVF)rate of Hyal-deficient dKO spermatozoa.In addition,the dKO spermatozoa resulted in a fertilization rate of 12.5%upon fertilizing COCs with a thick cumulus layer,whereas the IVF rate was comparable to that of WT spermatozoa when oocytes with a thin or no cumulus layer were fertilized.Finally,we proved that the IVF rate of dKO spermatozoa could be recovered by adding rat spermatozoa as a source of sperm hyal.Our results suggest that a deficiency of proteins involved in fertilization,such as sperm hyal,has a vital role in fertilization.

Insights into the co-evolution of glioblastoma and associated macrophages

Glioblastoma(GBM)is one of the most immunosuppressive and heterogeneous tumors with limited treatment options.Most studies relied on treatment-experienced patient samples to elucidate the origins of tumor heterogeneity,introducing bias into the analysis.The analysis of samples from multifocal GBM patients,in which independent lesions arise from the same progenitor and undergo parallel evolution,enables the study of the natural evolution of GBM while removing the effect of therapy on the emergence of heterogeneity.This enables the identification of critical events in the evolution of GBM and the unbiased study of subtype progression,diversity,and invasive potential.The tumor microenvironment of GBM undergoes significant changes throughout tumor progression.Recent studies have highlighted the switch from an abundance of resident microglia-derived macrophages in earlier stages to the prevalence of blood-derived macrophages in later stages of GBM.There is conclusive evidence that these alterations cannot be viewed in isolation and that the tumor microenvironment co-evolves with tumor cells during cancer progression.Together with an increasingly hypoxic environment,this culminates in highly immunosuppressive conditions,resulting in a feedback loop further reinforcing evolutionary changes in the tumor.A new study now provides a unique look at the natural evolution of GBM,identifies critical events in its development,and has the potential to help improve the diagnosis and therapy of this deadly disease.

Suppression of osteosarcoma progression by engineered lymphocyte-derived proteomes

Cancer cells tend to develop resistance to chemotherapy and enhance aggressive-ness.A counterintuitive approach is to tame aggressiveness by an agent that acts opposite to chemotherapeutic agents.Based on this strategy,induced tumor-suppressing cells(iTSCs)have been generated from tumor cells and mesenchymal stem cells.Here,we examined the possi-bility of generating iTSCs from lymphocytes by activating PKA signaling for suppressing the pro-gression of osteosarcoma(OS).While lymphocyte-derived CM did not present anti-tumor capabilities,the activation of PKA converted them into iTSCs.Inhibiting PKA conversely gener-ated tumor-promotive secretomes.In a mouse model,PKA-activated CM suppressed tumorinduced bone destruction.Proteomics analysis revealed that moesin(MSN)and calreticulin(Calr),which are highly expressed intracellular proteins in many cancers,were enriched in PKA-activated CM,and they acted as extracellular tumor suppressors through CD44,CD47,and CD91.The study presented a unique option for cancer treatment by generating iTSCs that secret tumor-suppressive proteins such as MSN and Calr.We envision that identifying these tu-mor suppressors and predicting their binding partners such as CD44,which is an FDA-approved oncogenic target to be inhibited,may contribute to developing targeted protein therapy.