FLT3 is a type III receptor tyrosine kinase. Mutations of FLT3 comprise one of the most frequently identified types of genetic alterations in acute myeloid leukemia. One-third of acute myeloid ...leukemia patients have mutations of this gene, and the majority of these mutations involve an internal tandem duplication in the juxtamembrane region of FLT3, leading to constitutive activation of downstream signaling pathways and aberrant cell growth. This review summarizes the current understanding of the effects of the downstream molecular signaling pathways after FLT3 activation, with a particular focus on the effects on transcription factors. Moreover, this review describes novel FLT3-targeted therapies, as well as efficient combination therapies for FLT3-mutated leukemia cells.
Targeting kinase activity is considered to be an attractive therapeutic strategy to overcome acute myeloid leukemia (AML) since aberrant activation of the kinase pathway plays a pivotal role in ...leukemogenesis through abnormal cell proliferation and differentiation block. Although clinical trials for kinase modulators as single agents remain scarce, combination therapies are an area of therapeutic interest. In this review, the author summarizes attractive kinase pathways for therapeutic targets and the combination strategies for these pathways. Specifically, the review focuses on combination therapies targeting the FLT3 pathways, as well as PI3K/AKT/mTOR, CDK and CHK1 pathways. From a literature review, combination therapies with the kinase inhibitors appear more promising than monotherapies with individual agents. Therefore, the development of efficient combination therapies with kinase inhibitors may result in effective therapeutic strategies for AML.
The development of acute myeloid leukemia (AML) is a multistep process that requires at least two genetic abnormalities for the development of the disease. The identification of genetic mutations in ...AML has greatly advanced our understanding of leukemogenesis. Recently, the use of novel technologies, such as massively parallel DNA sequencing or high-resolution single-nucleotide polymorphism arrays, has allowed the identification of several novel recurrent gene mutations in AML. The aim of this review is to summarize the current findings for the identification of these gene mutations (Dnmt, TET2, IDH1/2, NPM1, ASXL1, etc.), most of which are frequently found in cytogenetically normal AML. The cooperative interactions of these molecular aberrations and their interactions with class I/II mutations are presented. The prognostic and predictive significances of these aberrations are also reviewed.
Borderline resectable pancreatic cancer is a target for multidisciplinary therapeutic approaches. Reviews of recent articles and on-going studies identified the status and future directions of ...therapy.
Abstract
Borderline resectable pancreatic cancer (BRPC) is an advanced tumor in contact with the surrounding major vessels, making R0 resection difficult to achieve. Neoadjuvant treatment is expected to provide substantial local control and prolong survival. However, there is no standard treatment. I therefore conducted a strategic literature search from January 2013 to September 2017 and identified 37 clinical studies of pancreatic cancer, including BRPC, to evaluate treatment interventions. Twenty (54%) studies were prospective. Neoadjuvant regimens were as follows: chemotherapy (CT) followed by chemoradiotherapy (CRT) or radiotherapy (RT) (n = 16, 43%), CT alone (n = 11, 30%), CRT alone (n = 9, 24%) and RT alone (n = 1, 3%). Radiotherapy was employed in 70% of the studies. Phase II studies were most frequent (55%), and we were unable to identify a Phase III study. The National Comprehensive Cancer Network’s classifications were most frequently used as criteria for BRPC, although resectability status is not standardized. Radiological central review was used in three of eight multi-institutional studies. Assessing on-going or planned clinical trials for BRPC, administration of oxaliplatin, irinotecan, fluorouracil and leucovorin therapy or albumin-bound paclitaxel plus gemcitabine therapy, and randomized trials that evaluate the significance of CRT or RT combined with CT were identified as important topics for further consideration. Although standardization of classifications and improvement of infrastructure are required, a standard treatment of BRPC will likely be developed, which will improve prognosis in the near future because several important randomized trials are running.
This review describes the effects of FLT3 mutations that alter its intracellular localization and modify its glycosylation, leading to differences in downstream signaling pathways. The most common ...type of FLT3 mutation, internal tandem duplication (FLT3-ITD), leads to localization in the endoplasmic reticulum and constitutive strong activation of STAT5. In contrast, the ligand-activated FLT3-wild type is mainly expressed on the cell surface and activates MAP kinases. Based on these backgrounds, several reports have demonstrated that glycosylation inhibitors are effective for inhibition of FLT3-ITD expression and intracellular localization. The general subcellular localization regulatory mechanisms for receptor tyrosine kinases are also discussed.
Metallothionein (MT) was reported to be a potential negative regulator of apoptosis, and various reports have suggested that it may play roles in carcinogenesis and drug resistance, in at least a ...portion of cancer cells. The author summarizes the current understanding of the molecular functions of MT for tumor cell growth and drug resistance. These activities are regulated through intracellular metal ion modulation and free radical scavenging. Compared with analyses of solid tumors, few studies have analyzed the roles of MT in hematological malignancies. This review mainly describes the functions of MT in hematopoietic cells. Furthermore, through expression analyses of leukemias and lymphomas, the roles of MT in the biology of these diseases are particularly focused upon.
Arsenic trioxide (ATO) has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). However, the risk/benefit ratios of ATO in hematologic ...malignancies other than APL are still unclear. In this review, the author attempts to provide current experimental and clinical challenges to gain more knowledge of the effects of ATO by examining combination therapies with other agents, especially for non-APL hematologic malignancies, such as acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphoid leukemia (CLL) and multiple myeloma (MM). The drugs combined with ATO can be roughly classified into (1) signaling inhibitors (imatinib, PD184352, LY294002, 17-Allylamino-17-demethoxygeldanamycin: 17-AAG), (2) oxidative stress pathway modulators (ascorbic acid, 2-methoxyestradiol: 2-ME, dl-buthionine-S,R-sulfoximine: BSO), (3) a chemotherapeutic drug (melphalan) and (4) others (bortezomib, ATRA). Some of these combination therapies have shown promising results in MM not only at the experimental level but also at the clinical level. However, studies are still ongoing for other non-APL hematologic malignancies. Since ATO is well tolerated and its toxicities are manageable and reversible, cell type-specific and efficient combination therapies with ATO are advantageous for non-APL hematological malignancies and should be developed in the near future.
Generally, cancer tissue is palpated as a hard mass. However, the elastic nature of cancer tissue is not well understood. The aim of the present study was to evaluate the clinical utility of ...measuring the elastic modulus (EM) in colorectal cancer tissue. Using a tactile sensor, we measured the EM of 106 surgically resected colorectal cancer tissues. Data on the EM were compared with clinicopathological findings, including stromal features represented by Azan staining and the α‐SMA positive area ratio of the tumor area. Finally, a cDNA microarray profile of the tumors with high EM were compared with the findings of tumors with low EM. A higher EM in tumors was associated with pathological T, N, and M‐stage tumors (P < 0.001, P = 0.001 and P = 0.011, respectively). Patients with high EM tumors had shorter disease‐free survival than had patients with low EM. The EM showed strongly positive correlation with the Azan staining positive area ratio (r = 0.908) and the α‐SMA positive area ratio (r = 0.921). Finally, the cDNA microarray data of the tumors with high EM revealed a distinct gene expression profile compared with data from those tumors with low EM. The assessment of the elasticity of colorectal cancer tissue may allow a more accurate clinical stage and prognosis estimation. The distinct phenotypical features of the high EM tumors and their strong association with stromal features suggest the existence of a biological mechanism involved in this phenomenon that may contribute to future therapy.
Cancer tissue is palpated as a hard tissue, but the nature of cancer tissue elasticity is not known. We investigated the elastic modulus (EM) of resected colorectal cancer specimens using an objective and quantitative approach, and found strong association with TNM classification and disease‐free survival, which suggested future clinical implications. Finally, we are the first to elucidate the elasticity‐dependent phenotypical features of colorectal cancer tissue using global gene expression analysis.
There is no established postoperative adjuvant therapy for hepatocellular carcinoma (HCC), and improvement of patient prognosis has been limited. We conducted long‐term monitoring of patients within ...a phase II trial that targeted a cancer antigen, glypican‐3 (GPC3), specifically expressed in HCC. We sought to determine if the GPC3 peptide vaccine was an effective adjuvant therapy by monitoring disease‐free survival and overall survival. We also tracked GPC3 immunohistochemical (IHC) staining, CTL induction, and postoperative plasma GPC3 for a patient group that was administered the vaccine (n = 35) and an unvaccinated patient group that underwent surgery only (n = 33). The 1‐y recurrence rate after surgery was reduced by approximately 15%, and the 5‐y and 8‐y survival rates were improved by approximately 10% and 30%, respectively, in the vaccinated group compared with the unvaccinated group. Patients who were positive for GPC3 IHC staining were more likely to have induced CTLs, and 60% survived beyond 5 y. Vaccine efficacy had a positive relationship with plasma concentration of GPC3; high concentrations increased the 5‐y survival rate to 75%. We thus expect GPC3 vaccination in patients with HCC, who are positive for GPC3 IHC staining and/or plasma GPC3 to induce CTL and have significantly improved long‐term prognosis.
This phase II study demonstrated that postoperative adjuvant vaccination may reduce the 1‐y recurrence rate and prolong overall survival in patients who are positive for GPC3 IHC staining. The GPC3 peptide vaccine used induces specific CTLs and can be expected to improve patient prognosis.
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