ATP-binding cassette (ABC) transporters, which comprise the largest gene-family in humans, are membrane proteins that transport various substrates, depending on ATP hydrolysis. Among these transporters, several include ABCB1 (P-glycoprotein), identified here for the first time in humans, which exports anti-cancer drugs from cancer cells, thus participating in multidrug resistance (MDR). ABC transporters also export drugs, in general, from the human body, therefore affecting overall pharmacokinetics. We have contributed, here, to a better understanding of the role of these exporter proteins in two aspects. First, we have cloned the human ABCC2 gene and identified mutations in hereditary hyperbilirubinemia patients, demonstrating the role of ABCC2 as a xenobiotic export pump. Second, we also found an unexpected role of ABCB1 in cancer, in that it promotes tumor initiation independently of the MDR phenomenon, which was further confirmed by a chemoprevention experiment using verapamil, an ABCB1 inhibitor. In this review, I discuss the role of ABC transporters, both in biodefense against xenobiotics and in cancer development and malignant alterations, based on our results as well as the studies of others.

Humans are continually exposed to various chemicals in the environment. Some of these environmental chemicals not only induce malignant transformation but also enhance the malignant potential of the cancer. In this review, the author summarizes the findings on the effects of environmental chemicals on cancer with a focus on inorganic cadmium (Cd) and organic bisphenol A (BPA). Cd, an established human carcinogen, enhances the invasive capacity of rat liver TRL 1215 cells during malignant transformation by downregulating apolipoprotein E (ApoE), a suppressor of cell invasion, via induction of DNA hypermethylation in its promoter region by the oxidative stress/ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-mediated machinery. BPA, which is recognized as an endocrine disruptor, raises the concern that very high concentrations (beyond environmental levels) of BPA are required for activation of estrogen receptors α/β (ERα/β) in vitro. We identified a BPA metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which exhibited more potent estrogenic activity than BPA. Thus, MBP may be a key candidate for explaining the endocrine-disrupting effects of BPA. In addition, the estrogenic action of MBP can be enhanced by repeated exposure of MCF-7 cells to the actualized ERβ subtype because of the downregulation of ERα in human breast cancer MCF-7 cells. MBP downregulates the expression of the tumor suppressor gene, G protein-coupled estrogen receptor 1 (GPER1), via ERβ signaling.

Pancreatic cancer has poor prognosis despite the various developed multimodal treatment strategies. Currently, neoadjuvant chemotherapy and immunotherapy have attracted substantial attention as effective treatment strategies. However, amplifying immune response with existing treatments is difficult. We developed telomerase-specific oncolytic adenoviruses (OAs), including OBP-301 that is currently tested in a clinical trial of combined anti-PD-1 antibody and p53-armed OBP- 301 variant(OBP-702). OAs have immune-modulation functions and induce CD8+ T cells into tumors by releasing immunogenic cell death markers, such as extracellular adenosine triphosphate. Here, we investigated the effectiveness of OBP- 702 in pancreatic cancer treatments, focusing on the influence on CD8+ memory T cells.

Prospective studies have demonstrated the efficacy of pembrolizumab in patients with previously treated unresectable or metastatic microsatellite instability-high(MSI-H)cancers. Pembrolizumab has been covered by the Japanese health insurance system since December 2018. The frequency of MSI-H in patients is as low as approximately 2%. In addition, some patients with MSI-H cancers are diagnosed with Lynch syndrome. In the present study, we retrospectively investigated patients who received MSI testing at Kitasato University Hospital from April 2019 to June 2020. We also investigated the therapeutic effect of pembrolizumab for MSI-H cancers and patients who received genetic counseling for Lynch syndrome. Results identified that 5 out of 263 patients who underwent MSI testing(1.9%)had MSI-H. The therapeutic outcomes of pembrolizumab in those patients were as follows: 1(20%)complete response, 3(60%)partial response, and 1(20%) progressive disease. The positive-outcome rate of MSI-H treatment in our institution was comparable to that in the previous reports. The high response rate of pembrolizumab was confirmed in the present study. Four out of 5 patients received genetic counseling at the genetic clinic, and 1 patient underwent genetic testing for Lynch syndrome. No deleterious variant of Lynch syndrome was detected in the genetic testing.

Neurotrophic tyrosine receptor kinase(NTRK)gene variants have been reported in a variety of cancer types. The prevalence of NTRK gene variants is less than 1% in many types of solid cancer. The highest NTRK gene fusions frequencies were found in secretary breast carcinoma and infantile fibrosarcoma. There are several methods to detect NTRK gene variants, including RT-PCR, and comprehensive genome profiling. Two NTRK inhibitors, entrectinib and larotrectinib, are approved for NTRK gene fusion positive solid cancers in Japan. NTRK inhibitors provide a durable response, but duration of response may be limited by acquired resistance. A next-generation TRK inhibitors are expected to overcome acquired resistance.

Therapeutic landscape of lung cancer has undergone a dramatic shift due to the better understandings of disease biology and the identification of oncogenic driver alterations. Consequently, the new classification paradigm of non-small-cell lung cancer is further characterized by molecularly defined subsets, and making the therapeutic landscape increasingly complex. Driver gene mutations have been found in approximately 75% of Japanese non-squamous, non-small-cell lung cancers. Among these, the gene mutations for which molecularly-targeted therapies are being developed include EGFR mutations, ALK fusion gene, ROS1 fusion gene, BRAF V600E mutation, MET exon 14 skipping mutation, KRAS G12C mutation, RET fusion gene, and NTRK fusion gene. When limited to fusion genes, as of June 2022, crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for the ALK fusion gene; crizotinib and entrectinib for the ROS1 fusion gene; selpercatinib for the RET fusion gene; entrectinib and larotrectinib for the NTRK fusion gene have been approved in Japan. This article summarizes the therapeutic development of each fusion gene mutation, as well as the therapeutic outcomes and adverse events of the approved drugs.

Gemcitabine plus cisplatin is the mainstay of first-line chemotherapy for unresectable biliary tract cancer, but the standard of care for second-line has not been established. In recent years, genetic abnormalities in biliary tract cancers have been identified, and therapeutic development targeting these genetic abnormalities has been promoted. In March 2021, based on the results of the FIGHT-202 trial, pemigatinib was approved for the treatment of FGFR2 fusion gene-positive biliary tract cancer. Pemigatinib is attracting attention as new treatment option for unresectable biliary tract cancer. Clinical trial data and other information on cancer therapies targeting the FGFR2 fusion gene will be presented.

Chronic myelogenous leukemia(CML)is a myeloproliferative neoplasm caused by a reciprocal translocation (t 9 ; 22) (q34 ; q11). The finding that the constitutive tyrosine kinase activity of the BCR-ABL1 fusion protein, which is produced by fusing the ABL1 and BCR genes, is involved in the pathogenesis of CML has led to the development of drugs targeting the BCR-ABL1 fusion protein. Imatinib, a first-generation tyrosine kinase inhibitor(TKI), was introduced in 2001 as a treatment for CML, dramatically changing CML therapy. With the advent of imatinib, disease progression is largely prevented and the prognosis of CML patients is markedly improved, allowing a substantial proportion of patients to remain in the chronic phase for an extended period of time. In the TKI-era, it is no longer the primary disease that defines the long-term prognosis of CML patients, but rather comorbidities other than CML and adverse events(AEs), including cardiovascular events, and management to avoid AEs associated with long-term TKI use has become increasingly important. In recent years, treatment-free remission(TFR)is becoming a new therapeutic goal, as many reports have shown that some patients who have achieved deep molecular response with TKIs can maintain long-term TFR without relapsing after TKI discontinuation.

In recent years, genetic testing using next-generation sequencers has become widespread in the field of cancer drug therapy, and treatments based on individual genetic disorders are now routinely used. Drug development is underway to target various fusion genes among the detected genetic disorders. However, the functional significance of most of the detected fusion genes is unknown, and it is necessary to understand their biological characteristics and elucidate their functions for the development of personalized medicine. We review the molecular biology, detection, and treatment of cancer fusion genes from a pan-cancer perspective.

Intratumoral HER2 heterogeneity is a well-described gastric cancer feature and may explain many false-negative results related to this oncogene. An 81-year-old man was diagnosed at our hospital with stage IV gastric cancer with multiple lymph node metastases. Immunohistochemistry (IHC) analysis indicated that the primary tumor was HER2-negative. After a chemotherapy course, we submitted a pretreatment biopsy specimen for comprehensive cancer genome profiling (CGP) to determine the last-line therapy. This revealed HER2 amplification. The specimen was reevaluated using fluorescence in situ hybridization and IHC with deeper-cut specimens, which confirmed that the tumor was indeed HER2-positive. Therefore, the patient was treated with chemotherapy plus trastuzumab, which elicited tumor shrinkage and conferred long-term survival. Our current data underscore the CGP importance, which can provide more accurate tumor profilings and inform subsequent treatment decisions.

Chimeric antigen receptor (CAR)-engineered T-cell therapy against B-cell malignancies and multiple myeloma was recently introduced for clinical use. However, the efficacy of CAR-T cell therapy is not durable in most patients, warranting the development of CAR-T cells with additional genetic modification or engineering of synthetic molecules to enhance their functions. This review will provide an overview of the molecular mechanisms underlying the functional alteration of T cells, especially transcriptional networks associated with memory formation and T cell exhaustion. In addition, methods to rationally improve CAR-T cell functions based on these mechanistic insights will be discussed.

Several types of nonhematopoietic cells, including mesenchymal stem or progenitor cells, mature mesenchymal cells, and endothelial cells, and mature hematopoietic cells such as monocytes, macrophages, NK cells, T cells, and B cells regulate the proliferation and survival of myeloma cells. The cell functions adjacent to myeloma cells is specialized by the location of these cells, called a niche. This review focuses on the role and interaction of cellular components of the myeloma-specific niche revealed by studies that utilized the recently developed experimental techniques of single-cell RNA sequencing and high-parameter cytometry. In the myeloma niche, immune cells and mesenchymal cells regulate tumor proliferation. Bone marrow inflammation induced by multiple myeloma, tumor cells, mesenchymal stromal cells, and immune cells interact, results in the dysregulation of anti-tumor immunity. This complex network could affect tumorigenesis, disease progression, and treatment resistance of multiple myeloma.

It is well documented that multiple myeloma (MM) originates in a single plasma cell transformed by chromosome 14q translocations or chromosomal hyperdiploidy and evolves with the accumulation of point mutations of driver genes and/or cytogenetic abnormalities. Furthermore, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at premalignant stages and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes, including drug sensitivities. Generally, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs although could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to the microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, ∼20% of MM evolve neutrally in the context of strong oncogenic drivers, including high-risk IgH translocations, and are relatively resistant to IMiDs. Treatment strategies considering the genomic landscape and the pattern of clonal evolution may further improve the treatment outcome of MM.

Malignant lymphomas are a group of diseases in which epigenomic abnormalities are fundamental to the pathogenesis and pathophysiology and are characterized by a high frequency of abnormalities in DNA methylation regulators and histone modifiers. These epigenomic abnormalities directly amplify malignant clones. They also originated from a cell lineage differentiated from hematopoietic stem cells through epigenomic changes. These characteristics are associated with their high affinity for epigenomic therapies. Hematology has been a leader in the basic, clinical, and drug discovery areas of disease epigenetics. However, the epigenomic regulation is generally recognized as a complex system, and gaps are observed between basic and clinical studies. To overview the status and importance of "epigenomic abnormalities in malignant lymphoma," this review first summarizes the concept and essential importance of the epigenome and then outlines the current status and future perspective of epigenomic abnormalities in malignant lymphomas.

Since the discovery of the JAK2V617F, MPL gene, and Calreticulin gene mutations, remarkable changes have occurred in the identification of the pathology of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnostic criteria of polycythemia vera, essential thrombocythemia, and primary myelofibrosis in the world health organization classification systems have also been amended to include these driver gene mutations. Additionally, treatment algorithms for each disease have been reviewed. Following these changes, real world data form several countries based on national surveys have been reported. In Japan, the Japanese Society of Hematology has conducted a prospective study, named the JSH-MPN-15 study, to investigate the overall survival and risk factors of patients with MPNs. Furthermore, the retrospective JSH-MPN-R18 study was conducted and the results have been coming out. In this lecture, the results of these studies will be discussed.

Malignant lymphomas are a group of heterogeneous lymphoid malignancies, consisting of over 70 subtypes, which are classified according to their cell of origin. Classically, disease classification has been based on cellular morphology and immunophenotype. Due to the advancement of next-generation sequencing (NGS) technology, many comprehensive genomic studies have clarified the landscape of somatic alterations in these lymphomas, which has drastically improved our understanding of their molecular pathogenesis. Consequently, a new framework has been proposed for disease classification based on such somatic alterations and/or gene expression characteristic of each lymphoma subtype. Additionally, the results from the genomic studies have also established an important basis for the development of new targeted therapies and prognostic biomarkers. In the future, NGS-based gene panels will be covered by health insurance, and cancer precision medicine is expected to become more prevalent in this field. This paper outlines the analytical methods used in genomic studies by primarily focusing on NGS technology, and describes the results of major genomic and single-cell studies for various subtypes of malignant lymphoma.

The landscape of acute myeloid leukemia treatment has changed dramatically over the past decade. In Japan, three novel molecularly targeted agents have been approved and rapidly changing the paradigm of AML therapy. However, as the clinical experience of these novel drugs accumulate, various resistance mechanisms have started to emerge. Here, we discuss the mechanism of action and resistance of the three recently approved drugs, FLT3 inhibitor, IDH inhibitor, and BCL2 inhibitor.

Acute myelogenous leukemia (AML) is a hematopoietic malignancy that is characterized by clonal autonomous proliferation of myeloid cells with impaired differentiation and maturation. Recent advances in next-generation sequencing technology have elucidated the pathogenesis of AML at the genetic level. Furthermore, the molecular targeted therapy to efficiently eradicate leukemic cells has been rapidly expanding since 2017. In Japan, gilteritinib and quizartinib, which target FMS-like tyrosine kinase 3, and venetoclax, which targets B-cell lymphoma 2, have finally become available after resolving the drug launch lag between Japan and the United States. The combination of venetoclax and azacitidine, which was simultaneously approved with venetoclax for AML, is expected to be more effective than conventional therapy in patients who are ineligible for transplantation. Herein, we review the National Comprehensive Cancer Network guidelines for intensive chemotherapy in Japan and the United States and discuss the future of AML treatment, including the development of novel agents.

About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

Precision medicine, which provides personalized treatments based on individual genomic profiles, has made remarkable progress especially in the oncology area, since when 2 types of comprehensive genomic profiling(CGP)tests, FoundationOne CDx and OncoGuide NCC Oncopanel have been reimbursed by national insurance system in June 2019. However, the application of CGP as a companion diagnostics(CDx)in addition to the single and the multi-CDx tests is now complicated. In this session, problems of the personalized treatment system based on the results of the cancer genomic test will be discussed.