Journal of Hematology & Oncology - Latest Articles

Novel agents and biomarkers for acute lymphoid leukemia

Yanmin Zhao — 2013-06-18T00:00:00Z

New genetic markers for adult acute lymphoblastic leukemia (ALL) have been found to have prognostic impact, such as the lymphoid transcription factor gene IKZF1 alterations, which are associated with a high rate of leukemic relapse in B-ALL. Although complete remission rates by induction chemotherapy in ALL are now high, the long-term survival is still disappointing. Improvements in the survival outcome of ALL have been observed in young adults as a result of the use of pediatric inspired regimens and the broadening of the number of patients who are eligible for allogeneic SCT. Development of new and less toxic agents also provide promise to improve the outcome in adult ALL, such as tyrosine kinase inhibitors in Ph-positive ALL, rituximab in CD20-positive disease, blinatumomab in precursor B-ALL and nelarabine in T-lineage ALL. Challenges for the future are to implement genomic profiling into the clinical setting to guide risk stratification and providing novel targets for tailored therapies.

Rapid induction of complete molecular remission by sequential therapy with LDAC and sorafenib in FLT3-ITD-positive patients unfit for intensive treatment: two cases and review of the literature

Denise Wolleschak — 2013-06-11T00:00:00Z

Treatment of acute myeloid leukemia remains a therapeutic challenge. Even in younger patients with a low rate of co-morbidities less than 50% of patients can be cured. For older patients or patients with significant co-morbidities, the situation appears even worse. In patients not eligible for intensive treatment approaches - e.g. due to underlying medical conditions - therapeutic approaches remain almost exclusively palliative. However, even with less intense treatment approaches, temporary remission can be achieved and this contributes to prolonged survival and improved quality of life of the respective patient. Targeted therapies have been widely used as palliative treatment in- and outside clinical trials as single agents. Combination with low-dose cytarabine (LDAC) potentially improves remission rates and can be safely administered in an outpatient setting.Previous studies showed that additive hematologic toxicity of combinatory therapeutic approaches may arise from simultaneous treatment (e.g. chemotherapy plus targeted therapies). However, sequential therapies have already proven their feasibility in clinical trials. Here, we report two cases of rapid induction of complete molecular remission by sequential therapy with LDAC and sorafenib in patients unfit for intensive chemotherapy without significant long-term toxicity.

Targeted therapy for HER2 positive breast cancer

Jason Incorvati — 2013-06-03T00:00:00Z

IntroductionBreast cancer is the second most common cause of death for women behind lung cancer and the most common cause of cancer deaths for women aged 45--55 years old [1]. Although there continue to be enormously large numbers of disease incidence, deaths have been declining due to the disease with two hallmark time frames. The first occurred during the mid to late 1980's when hormonal therapy was introduced as a treatment for ER/PR positive breast cancer. The second occurred in the late 1990's when trastuzumab was introduced in treating HER2 positive breast cancer. These remarkable accomplishments in developing novel targeted therapies for breast cancer, along with a better understanding of the disease biology have improved disease outcome over the past 20 years.This article reviews the data presented at 2012 American Society of Clinical Oncology and 2012 San Antonio Breast Cancer Symposium regarding progress made in the field of HER2 positive breast cancer and examines the future of HER2 targeted therapy.

Long non-coding RNA: a new player in cancer

Hua Zhang — 2013-05-31T00:00:00Z

Emerging evidence showed that long non-coding RNAs (lncRNAs) play important roles in a wide range of biological processes and dysregulated lncRNAs are involved in many complex human diseases, including cancer. Although a few lncRNAs' functions in cancer have been characterized, the detailed regulatory mechanisms of majority of lncRNAs in cancer initiation and progression remain largely unknown. In this review, we summarized recent progress on the mechanisms and functions of lncRNAs in cancer, especially focusing on the oncogenic and tumor suppressive roles of the newly identified lncRNAs, and the pathways these novel molecules might be involved in. Their potentials as biomarkers for diagnosis and prognosis in cancer are also discussed in this paper.

Novel agents for chronic lymphocytic leukemia

Mei Wu — 2013-05-16T00:00:00Z

Chronic lymphocytic leukemia (CLL) is a heterogeneous group of B-cell neoplasm. CLL is typically sensitive to a variety of cytotoxic agents, but relapse frequently occurs with conventional approaches. The treatment of CLL is evolving rapidly with the introduction of novel drugs, such as bendamustine, ofatumumab, lenalidomide, ibrutinib, idelalisib, veltuzumab, XmAb5574, navitoclax, dasatinib, alvespimycin, and TRU-016. This review summarizes the most current clinical experiences with these agents in the treatment of CLL.

Induction of long intergenic non-coding RNA HOTAIR in lung cancer cells by type I collagen

Yan Zhuang — 2013-05-13T00:00:00Z

Background: The tumor microenvironment is a crucial determinant in tumor progression. Interstitial extracellular matrix (ECM), such as type I collagen (Col-1), is aberrantly enriched in the tumor microenvironment and promotes tumor progression. Long intergenic non-coding RNAs (lincRNA) are a new family of regulatory RNAs that modulate fundamental cellular processes via diverse mechanisms.FindingsWe investigated whether the expression of lincRNAs was regulated by the tumor promoting Col-1. In a three-dimensional organotypic culture model using the reconstituted basement membrane ECM Matrigel (rBM 3-D), supplementation of Col-1 disrupted acini, a differentiation feature of well-differentiated lung adenocarcinoma cells, and concurrently induced the expression of a tumor-promoting lincRNA, HOX transcript antisense RNA (HOTAIR). Induction of HOTAIR by Col-1 was diminished by a neutralizing antibody against the Col-1 receptor α2β1 integrin. Col-1 activates the expression of a reporter gene controlled by the human HOTAIR promoter. Moreover the expression of HOTAIR and Col-1 was concurrently up-regulated in human non-small cell lung cancer. Conclusions: Our findings indicate that tumor-promoting Col-1 up-regulates the expression of HOTAIR in NSCLC cells. These initial results warrant further investigation of HOTAIR and other lincRNA genes in lung tumorigenesis.

Activated N-Ras signaling regulates arterial-venous specification in zebrafish

Chun-Guang Ren — 2013-05-12T00:00:00Z

Background: The aberrant activation of Ras signaling is associated with human diseases including hematological malignancies and vascular disorders. So far the pathological roles of activated Ras signaling in hematopoiesis and vasculogenesis are largely unknown. Methods: A conditional Cre/loxP transgenic strategy was used to mediate the specific expression of a constitutively active form of human N-Ras in zebrafish endothelial and hematopoietic cells driven by the zebrafish lmo2 promoter. The expression of hematopoietic and endothelial marker genes was analyzed both via whole mount in situ hybridization (WISH) assay and real-time quantitative PCR (qPCR). The embryonic vascular morphogenesis was characterized both by living imaging and immunofluorescence on the sections with a confocal microscopy, and the number of endothelial cells in the embryos was quantified by flow cytometry. The functional analyses of the blood circulation were carried out by fluorescence microangiography assay and morpholino injection. Results: In the activated N-Ras transgenic embryos, the primitive hematopoiesis appeared normal, however, the definitive hematopoiesis of these embryos was completely absent. Further analysis of endothelial cell markers confirmed that transcription of arterial marker ephrinB2 was significantly decreased and expression of venous marker flt4 excessively increased, indicating the activated N-Ras signaling promotes the venous development at the expense of arteriogenesis during zebrafish embryogenesis. The activated N-Ras-expressing embryos showed atrophic axial arteries and expansive axial veins, leading to no definitive hematopoietic stem cell formation, the blood circulation failure and subsequently embryonic lethality. Conclusions: Our studies revealed for the first time that activated N-Ras signaling during the endothelial differentiation in vertebrates can disrupt the balance of arterial-venous specification, thus providing new insights into the pathogenesis of the congenital human vascular disease and tumorigenic angiogenesis.

Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma

Chan-Juan Shen — 2013-05-09T00:00:00Z

Background: Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells appears to be a promising immunotherapeutic strategy. CAR combines the specificity of antibody and cytotoxicity of cytotoxic T lymphocytes, enhancing T cells’ ability to specifically target antigens and to effectively kill cancer cells. Recent efforts have been made to integrate the costimulatory signals in the CAR to improve the antitumor efficacy. Epidermal growth factor receptor variant III (EGFRvIII) is an attractive therapeutic target as it frequently expresses in glioma and many other types of cancers. Our current study aimed to investigate the specific and efficient antitumor effect of T cells modified with CAR containing inducible costimulator (ICOS) signaling domain. Methods: A second generation of EGFRvIII/CAR was generated and it contained the EGFRvIII single chain variable fragment, ICOS signaling domain and CD3ζ chain. Lentiviral EGFRvIII/CAR was prepared and human CD3+ T cells were infected by lentivirus encoding EGFRvIII/CAR. The expression of EGFRvIII/CAR on CD3+ T cells was confirmed by flow cytometry and Western blot. The functions of EGFRvIII/CAR+ T cells were evaluated using in vitro and in vivo methods including cytotoxicity assay, cytokine release assay and xenograft tumor mouse model. Results: Chimeric EGFRvIIIscFv-ICOS-CD3ζ (EGFRvIII/CAR) was constructed and lentiviral EGFRvIII/CAR were made to titer of 106 TU/ml. The transduction efficiency of lentiviral EGFRvIII/CAR on T cells reached around 70% and expression of EGFRvIII/CAR protein was verified by immunoblotting as a band of about 57 kDa. Four hour 51Cr release assays demonstrated specific and efficient cytotoxicity of EGFRvIII/CAR+ T cells against EGFRvIII expressing U87 cells. A robust increase in the IFN-γ secretion was detected in the co-culture supernatant of the EGFRvIII/CAR+ T cells and the EGFRvIII expressing U87 cells. Intravenous and intratumor injection of EGFRvIII/CAR+ T cells inhibited the in vivo growth of the EGFRvIII expressing glioma cells. Conclusions: Our study demonstrates that the EGFRvIII/CAR-modified T cells can destroy glioma cells efficiently in an EGFRvIII specific manner and release IFN-γ in an antigen dependent manner. The specific recognition and effective killing activity of the EGFRvIII-directed T cells with ICOS signaling domain lays a foundation for us to employ such approach in future cancer treatment.

Azacitidine in patients with WHO-defined AML ¿ Results of 155 patients from the Austrian Azacitidine Registry of the AGMT-Study Group

Lisa Pleyer — 2013-04-29T00:00:00Z

ObjectiveThe Austrian Azacitidine Registry is a multi-center database (ClinicalTrials.gov: NCT01595295). The nature and intent of the registry was to gain a comprehensive view of the use, safety and efficacy of the drug in a broad range of AML-patients treated in real-life scenarios.Patients and methodsThe sole inclusion criteria were the diagnosis of WHO-AML and treatment with at least one dose of azacitidine. No formal exclusion criteria existed. A total of 155 AML-patients who were mostly unfit/ineligible for intensive chemotherapy, or had progressed despite conventional treatment, were included. True ITT-analyses and exploratory analyses regarding the potential prognostic value of baseline-variables/performance-/comorbidity-/risk-scores on overall survival (OS), were performed. Results: In this cohort of 155 pretreated (60%), and/or comorbid (87%), elderly (45% ≥75 years) AML-patients, azacitidine was well tolerated and efficacious, with an overall response rate (CR, mCR, PR, HI) of 45% in the total cohort (ITT) and 65% in patients evaluable according to IWG-criteria, respectively. Pre-treatment with conventional chemotherapy (P = .113), age ≤/>80 years (P = .853), number of comorbidities (P = .476), and bone marrow (BM) blast count (P = .663) did not influence OS. In multivariate analysis hematologic improvement alone (without the requirement of concomitant bone marrow blast reduction), although currently not regarded as a standard form of response assessment in AML, was sufficient to confer OS benefit (18.9 vs. 6.0 months; P = .0015). Further deepening of response after first response was associated with improved OS (24.7 vs. 13.7 months; P < .001). Conclusions: In this large cohort of AML-patients treated with azacitidine, age >80 years, number of comorbidities and/or BM-blasts >30% did not adversely impact OS.

Development and characterization of a high-throughput in vitro cord formation model insensitive to VEGF inhibition

Beverly Falcon — 2013-04-27T00:00:00Z

Background: Anti-VEGF therapy reduces tumor blood vessels, however, some vessels always remain. These VEGF insensitive vessels may help support continued tumor growth and metastases. Many in vitro assays examining multiple steps of the angiogenic process have been described, but the majority of these assays are sensitive to VEGF inhibition. There has been little focus on the development of high-throughput, in vitro assays to model the vessels that are insensitive to VEGF inhibition. Methods: Here, we describe a fixed end-point and kinetic, high-throughput stem cell co-culture model of cord formation. Results: In this system, cords develop within 24 hours, at which point they begin to lose sensitivity to VEGF inhibitors, bevacizumab, and ramucirumab. Consistent with the hypothesis that other angiogenic factors maintain VEGF-independent vessels, pharmacologic intervention with a broad spectrum anti-angiogenic antagonist (suramin), a vascular disrupting agent (combretastatin), or a combination of VEGF and Notch pathway inhibitors reduced the established networks. In addition, we used our in vitro approach to develop an in vivo co-implant vasculogenesis model that connects with the endogenous vasculature to form functional blood vessels. Similar to the in vitro system, over time these vessels become insensitive to VEGF inhibition. Conclusion: Together, these models may be used to identify novel drugs targeting tumor vessels that are not sensitive to VEGF inhibition.