The Warburg effect drives dedifferentiation through epigenetic reprogramming

German biochemist and cell physiologist,Otto H.Warburg(Figure 1),made a groundbreaking discovery in 1923.Specifically,tumors were shown to consume large amounts of glucose and ferment glucose into lactate,even in the presence of oxygen—a phenomenon termed"aerobic glycolysis"1,2.This phenomenon,later named the Warburg effect by Efraim Racker in the 1970s,remains pivotal in cancer research3.

PET probes beyond ^(18)F-FDG

During the past several decades,positron emission tomography（PET） has been one of the rapidly growing areas of medical imaging;particularly,its applications in routine oncological practice have been widely recognized.At present,^18F-fluorodeoxyglucose（^18F-FDG） is the most broadly used PET probe.However,^18F-FDG also suffers many limitations.Thus,scientists and clinicians are greatly interested in exploring and developing new PET imaging probes with high affinity and specificity.In this review,we briefly summarize the representative PET probes beyond ^18F-FDG that are available for patients imaging in three major clinical areas（oncology,neurology and cardiology）,and we also discuss the feasibility and trends in developing new PET probes for personalized medicine.

Research advances and new challenges in overcoming triple-negative breast cancer

Triple-negative breast cancer(TNBC)is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification.TNBC includes a collection of multiple distinct disease entities based upon genomic,transcriptomic and phenotypic characterization.Despite improved clinical outcomes with the development of novel therapeutics,TNBC still yields the worst prognosis among all clinical subtypes of breast cancer.We will systematically review evidence of the genomic evolution of TNBC,as well as potential mechanisms of disease progression and treatment resistance,defined in part by advances in next-generation DNA sequencing technology(including single cell sequencing),providing a new perspective on treatment strategies,and promise to reveal new potential therapeutic targets.Moreover,we review novel therapies aimed at homologous recombination deficiency,PI3 kinase/AKT/PTEN pathway activation,androgen receptor blockade,immune checkpoint inhibition,as well as antibody-drug conjugates engaging novel cell surface targets,including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC.Despite major advances in treatment for TNBC,including FDA approval of 2 PARP inhibitors for metastatic TNBC,the crossing of the superiority boundary in a phase 3,placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer,the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC,and the FDA approval of the first antibody drug conjugate for TNBC,significant challenges remain.For example,despite the dawn of immunotherapy in metastatic TNBC,durable responses are limited to a small subset of patients,definitive biomarkers for patient selection are lacking,and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 checkpoint antibody high risk early-stage TNBC in the neoadjuvant setting.Also,despite early positive randomized phase 2 studies of AKT inhibition in metastatic TNBC,a recent phase 3 registration trial failed to validate earlier phase 2 data.Finally,we note that level one evidence for clinical efficacy of androgen receptor blockade in TNBC is still lacking.To meet these and other challenges,we will catalogue the ongoing exponential increase in interest in basic,translational,and clinical research to develop new treatment paradigms for TNBC.

Targeted protein degradation bypassing cereblon and von Hippel-Lindau

Targeted protein degradation(TPD)has emerged as a new drug discovery approach to wipe out disease-causing proteins by harnessing the ubiquitin-proteasome system(UPS).A major class of molecules in the field are called proteolysis-targeting chimeras(PROTACs),which are heterobifunctional molecules encompassing two ligands that bind to a protein of interest and the E3 ligase,respectively joint by a linker.1 Due to its catalytic mechanism that enables event-driven pharmacology,PROTACs technology can induce an efficient degradation and therefore achieve the pharmacology at a lower dose compared with traditional small molecule inhibitors that exert their inhibition through an occupancy-driven mechanism.Since the first PROTAC was reported as a proof-ofconcept 20 years ago,this technology has led to a paradigm shift that culminated in the clinic trials of new modalities such as ARV-110,ARV-471,etc.

Genomic stability at the coding regions of the multidrug transporter gene ABCB1: insights into the development of alternative drug resistance mechanisms in human leukemia cells

Aim:Despite considerable efforts to reverse clinical multidrug resistance(MDR),targeting the predominant multidrug transporter ABCB1/P-glycoprotein(P-gp)using small molecule inhibitors has been unsuccessful,possibly due to the emergence of alternative drug resistance mechanisms.However,the non-specific P-gp inhibitor cyclosporine(CsA)showed significant clinical benefits in patients with acute myeloid leukemia(AML),which likely represents the only proof-of-principle clinical trial using several generations of MDR inhibitors.Nevertheless,the mutational mechanisms that may underlie unsuccessful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular models.In this study,our aims were to establish CsA-resistant leukemia models and to examine the presence or absence of ABCB1 exonic mutations in these models as well as in diverse types of human cancer samples including AMLs.Methods:Drug-resistant lines were established by stepwise drug co-selection and characterized by drug sensitivity assay,rhodamine-123 accumulation,[3H]-labeled drug export,ABCB1 cDNA sequencing,and RNase protection assay.The genomic stability of the ABCB1 coding regions was evaluated by exome sequencing analysis of variant allele frequencies in human populations.Moreover,the mutational spectrum of ABCB1 was further assessed in diverse types of cancer samples including AMLs in the Cancer Genome Atlas(TCGA)at the National Cancer Institute.Results:We report the development of two erythroleukemia variants,RVC and RDC,which were derived by stepwise co-selection of K562/R7 drug-resistant leukemia cells with the etoposide-CsA and doxorubicin-CsA drug combinations,respectively.Interestingly,both RVC and RDC cell lines,which retained P-gp expression,showed altered multidrug-resistant phenotypes that were resistant to CsA modulation.Strikingly,no mutations were found in the ABCB1 coding regions in these variant cells even under long-term stringent drug selection.Genomically,ABCB1 displayed relatively low variant allele frequencies in human populations when compared with several ABC superfamily members.Moreover,ABCB1 also exhibited a very low mutational frequency in AMLs compared with all types of human cancer.In addition,we found that CsA played a role in undermining the selection of highly drug-resistant cells via induction of low-level and unstable drug resistance.Conclusion:Our data indicate that ABCB1 coding regions are genomically stable and relatively resistant to drug-induced mutations.Non-ABCB1 mutational mechanisms are responsible for the drug-resistant phenotypes in both RVC and RDC cell lines,which are also prevalent in clinical AML patients.Accordingly,we propose several relevant models that account for the development of alternative drug resistance mechanisms in the absence of ABCB1 mutations.