Cancer genome profiling has revealed important genetic alterations that serve as prognostic indicators and guides for treatment decisions, enabling precision medicine. The shift to molecular diagnosis of brain tumors, as reflected in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, is a crucial role for treatment decision-making. This review discusses the significance and role of cancer genome profiling in precision medicine for malignant brain tumors, particularly gliomas. Furthermore, we explore the progress in cancer genome analysis, focusing on cancer gene panel testing, integration of genomic information in brain tumor classification, and hereditary tumors. Additionally, we discuss the transformative effect of genomic medicine on early detection, risk assessment, and precision medicine strategies. The tumor mutational burden in brain tumors is considered low, but the application of molecular targeted drugs, such as isocitrate dehydrogenase inhibitors, v-raf murine sarcoma viral oncogene homolog B1 inhibitors, fibroblast growth factor receptor inhibitors, neurotrophic tyrosine receptor kinase, mechanistic target of rapamycin inhibitors, and anti-programmed death receptor-1 antibody drugs are promising for glioma treatment. We also discuss the future prospects of molecular targeted drugs.

Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.

Interstitial lung disease (ILD) is a serious adverse event common to many molecular targeted anticancer drugs. The development of ILD significantly reduces the QOL of patients and results in treatment discontinuation. Because the development of ILD is also associated with therapeutic efficacy, the establishment of prediction strategies for ILD is important. We have focused on signal transducer and activator of transcription 3 (STAT3) as an important mechanistic factor in ILD induced by molecular targeted drugs. Our study aimed to establish mechanism-based ILD prediction strategies; therefore, we investigated the hypothesis that a genetic polymorphism in STAT3 is a predictive factor of the incidence of ILD induced by mammalian target of rapamycin (mTOR) inhibitors, a class of molecular targeted drugs associated with a higher incidence of ILD. Our clinical study clearly demonstrated that the rate of ILD induced by mTOR inhibitors was significantly higher in patients with the G allele homozygous genotype of STAT3 -1697C>G compared with those with other genotypes. The cumulative incidence of ILD in patients with the G allele homozygous genotype was significantly higher compared with that in patients carrying other genotypes. Furthermore, our in vitro study indicated that the epithelial-to-mesenchymal transition (EMT), a pre-process of tissue fibrosis, was induced by an mTOR inhibitor in lung alveolar epithelial cell lines carrying the G allele homozygous genotype which was associated with a higher risk of ILD. Our study provided a novel predictive strategy for the development of ILD induced by molecular targeted drugs.

\"Undruggable\" targets such as KRAS are particularly challenging in the development of drugs. We devised a novel chemical knockdown strategy, CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics) technology, which promotes protein degradation using small molecules (CANDDY molecules) that are conjugated to a degradation tag (CANDDY tag) modified from proteasome inhibitors. We demonstrated that CANDDY tags allowed for direct proteasomal target degradation independent of ubiquitination. We synthesized a KRAS-degrading CANDDY molecule, TUS-007, which induced degradation in KRAS mutants (G12D and G12V) and wild-type KRAS. We confirmed the tumor suppression effect of TUS-007 in subcutaneous xenograft models of human colon cells (KRAS G12V) with intraperitoneal administrations and in orthotopic xenograft models of human pancreatic cells (KRAS G12D) with oral administrations. Thus, CANDDY technology has the potential to therapeutically target previously undruggable proteins, providing a simpler and more practical drug targeting approach and avoiding the difficulties in matchmaking between the E3 enzyme and the target.

Acute myeloid leukemia (AML) remains a most lethal hematological malignancy, partly because of its slow development of targeted therapies compared with other cancers. PLK1 inhibitor, volasertib (Vol), is among the few molecular targeted drugs granted breakthrough therapy status for AML; however, its fast clearance and dose-limiting toxicity greatly restrain its clinical benefits. Here, we report that transferrin-guided polymersomes (TPs) markedly augment the targetability, potency and safety of Vol to AML. Vol-loaded TPs (TPVol) with 4% transferrin exhibited best cellular uptake, effective down-regulation of p-PLK1, p-PTEN and p-AKT and superior apoptotic activity to free Vol in MV-4-11 leukemic cells. Intravenous injection of TPVol gave 6-fold higher AUC than free Vol and notable accumulation in AML-residing bone marrow. The efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood, bone marrow, liver and spleen, effectively enhanced mouse survival rate, and impeded bone loss. This transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.

Hepatocellular carcinoma (HCC) is a complex heterogeneous disease with high morbidity and mortality. Recent progress in molecular targeted drugs including multikinase inhibitors and immune checkpoint inhibitors has demonstrated substantial survival improvement in patients with advanced HCC, but it remains as a challenging issue to discover surrogate markers for precisely distinguishing responders and non-responders. Genome-based medicine has changed cancer treatment from empirical use of cytotoxic agents to theoretical use of molecular targeted drugs in various types of cancer, while not in HCC due to lack of druggable targets. Integrated genomic and transcriptomic analysis reveal that HCC is divided into three major subtypes, proliferative, CTNNB1-mutated and metabolic disease-associated, with distinctive molecular and immunological features, and an increasing number of studies provide evidence for the close correlation between the subtype and the response to molecular targeted drugs using both of clinical data and preclinical models. Dozens of immunocompetent mouse models, such as hydrodynamic tail vain injection models and implantable syngeneic models, reflect molecular characteristics and tumor immune microenvironment of the subtypes, and help us to evaluate the efficacy of single and combination therapies and understand the molecular mechanisms underlying vulnerability and resistance to them. Thus, the consensus classification and relevant preclinical models could accelerate the establishment of predictive biomarkers and the development of subtype-specific therapies.

PLK1 is a promising target for clinical treatment of diverse malignancies including ovarian cancer (OC), in which PLK1 over-expression is often correlated with poor prognosis and short survival. PLK1 can be blocked with small molecular inhibitors like volasertib (Vol) or silenced with PLK1-specific siRNA (siPLK1), hence effectively suppressing tumor growth. Surprisingly, despite intensive work on molecular inhibitor and siRNA therapeutics, there is no direct comparison between them reported for targeted tumor therapy. Herein, we employing folate as a ligand and polymersomes as a nanovehicle performed a comparative study on Vol and siPLK1 in inhibiting OC in vitro and in vivo. Folate-targeted polymersomal Vol and siPLK1 (termed as FA-Ps-Vol and FA-Ps-siPLK1, respectively) were both nano-sized and stable, and displayed an optimal FA density of 20% for SKOV-3 cells. Notably, FA-Ps-Vol and FA-Ps-siPLK1 exhibited an IC50 of 193 and 770 nM, respectively, to SKOV-3 cells, indicating a greater potency of Vol than siPLK1. The markedly increased uptake for FA-Ps-Vol and FA-Ps-siPLK1 compared with respective non-targeted controls by SKOV-3 tumor xenografts in mice confirmed that FA mediates strong OC-targeting in vivo. Intriguingly, FA-Ps-Vol while greatly lessening toxic effects of Vol potently repressed tumor growth with a remarkable tumor inhibition rate (TIR) of 97% at 20 mg (i.e. 32.4 µmol) Vol equiv./kg. FA-Ps-siPLK1 achieved effective tumor inhibition (TIR = ca. 87% or 90%) at 2 or 4 mg (i.e. 0.15 or 0.3 µmol) siPLK1 equiv./kg without causing adverse effects. This comparative study highlights that molecular inhibitor has the advantage of easy dose escalation and potent protein inhibition at the expense of certain adverse effects while siRNA therapeutics has low toxicity with moderate protein inhibition in vivo. STATEMENT OF SIGNIFICANCE: PLK1 is a promising target for the development of innovative and specific treatments against diverse malignancies. Interestingly, despite intensive work on molecular inhibitors and siRNA against PLK1, little work has been directed to compare their efficacy in targeted tumor therapy. Here, we employed folate as a ligand and polymersomes as a nanovehicle and have performed a comparative study on volasertib and siPLK1 in inhibiting ovarian cancer in vitro and in vivo. Our data show that the dose of volasertib can be easily escalated to induce prominent antitumor efficacy at the expense of certain adverse effects, while siPLK1 brings about moderate protein inhibition and antitumor therapy without causing toxicity at two-orders-of-magnitude lower dose.

Hepatocellular carcinoma (HCC) occurs in the chronic liver inflammation such as viral hepatitis, alcoholic and non-alcoholic steatohepatitis. While anti-viral treatment has been significantly improved, the prevalence of HCC remains high and treatment is still challenging. The continuation of hepatocyte death, inflammation, and fibrosis leads to the accumulation of gene alterations, which may trigger carcinogenesis. Hepatocytes are a unique cell type having more than one complete set of 23 chromosomes, termed polyploidy. Due to gene redundancy, hepatocytes may tolerate lethal mutations. Next generation sequencing technology has revealed gene alterations in HCC related to telomere maintenance, Wnt/β-catenin pathway, p53 cell-cycle pathway, epigenetic modifiers, oxidative stress pathway, PI3K/AKT/mTOR, and RAS/RAF/MAPK pathway with or without a chromosomal instability. Some type of driver gene mutations accumulates in hepatocytes and breaks the orchestration of excessive copies of chromosomes, which may lead to unfavorable gene expressions and fuel tumorigenesis. Recently, molecular targeted drugs, developed with the aim of interfering with these signaling pathways, are being used for HCC patients in the clinics. Therefore, a deeper understanding of hepatocyte ploidy and genetic or epigenetic alterations is indispensable for the establishment of novel therapeutic strategies against HCC.

In acute myeloid leukemia (AML), a number of chromosomal abnormalities and gene mutations associated with onset and recurrence were discovered by the recent progress of genome analysis technology. The founding did not only have clinical application as prognostic factors and minimal residual disease markers but also contributed to novel molecular targeted drug development. Many new drugs, such as first-generation FLT3 inhibitor, IDH1/2 inhibitor, and BCL2 inhibitor, have been developed in Europe and the United States. In addition, the second-generation FLT3 inhibitors, gilteritinib and quizartinib, were developed in Japan, which significantly improved the treatment outcome of AML. However, there is still a large disparity in drug availability between Europe and the United States and Japan. As a result, treatment guidelines in Europe and the United States cannot be applied to practical use in Japan. This paper presents an outline of the prognosis stratification and indication of allogenic hematopoietic cell transplantation for AML by gene diagnosis in Japan.

Rhabdomyosarcoma, the most common soft tissue sarcoma noted in childhood, requires multimodality treatment, including chemotherapy, surgical resection, and/or radiation therapy. The majority of the patients with localized rhabdomyosarcoma can be cured; however, the long-term outcomes in patients with metastatic rhabdomyosarcoma remain poor. The standard chemotherapy regimen for patients with rhabdomyosarcoma is the combination of vincristine, actinomycin, and cyclophosphamide/ifosfamide. In recent clinical trials, modifications of the standard chemotherapy protocol have shown improvements in the outcomes in patients with rhabdomyosarcoma. In various type of malignancies, new treatments, such as molecular targeted drugs and immunotherapies, have shown superior clinical outcomes compared to those of standard treatments. Therefore, it is necessary to assess the benefits of these treatments in patients with rhabdomyosarcoma. Moreover, recent basic and clinical studies on rhabdomyosarcoma have reported promising therapeutic targets and novel therapeutic approaches. This article reviews the recent challenges and advances in the management of rhabdomyosarcoma.