Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival.

Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. J Clin Invest. 2014 May 8; Authors: Tang CH, Ranatunga S, Kriss CL, Cubitt CL, Tao J, Pinilla-Ibarz JA, Del Valle JR, Hu CC Abstract Activation of the ER stress response is associated with malignant progression of B cell chronic lymphocytic leukemia (CLL). We developed a murine CLL model that lacks the ER stress-associated transcription factor XBP-1 in B cells and found that XBP-1 deficiency decelerates malignant progression of CLL-associated disease. XBP-1 deficiency resulted in acquisition of phenotypes that are disadvantageous for leukemic cell survival, including compromised BCR signaling capability and increased surface expression of sphingosine-1-phosphate receptor 1 (S1P1). Because XBP-1 expression requires the RNase activity of the ER transmembrane receptor IRE-1, we developed a potent IRE-1 RNase inhibitor through chemical synthesis and modified the structure to facilitate entry into cells to target the IRE-1/XBP-1 pathway. Treatment of CLL cells with this inhibitor (B-I09) mimicked XBP-1 deficiency, including upregulation of IRE-1 expression and compromised BCR signaling. Moreover, B-I09 treatment did not affect the transport of secretory and integral membrane-bound proteins. Administration of B-I09 to CLL tumor-bearing mice suppressed leukemic progression by inducing apoptosis and did not cause systemic toxicity. Additionally, B-I09 and ibrutinib, an FDA-app...
Source: Clinical Lymphoma and Myeloma - Category: Cancer & Oncology Authors: Tags: J Clin Invest Source Type: research

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ConclusionVenetoclax therapy in a real-world cohort offered modest benefits in heavily pretreated patients. Adverse events were observed at a greater incidence than in the clinical trials. A wide heterogeneity of venetoclax dose escalation, multiagent combinations, and timing of initiation were identified and require investigation in subsequent clinical trials.
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
This study compared time to next treatment (TTNT), health care resource utilization (HRU), and total direct costs among patients with chronic lymphocytic leukemia (CLL) initiating front-line ibrutinib single agent (Ibr) or CIT.Materials and MethodsOptum Clinformatics Extended DataMart De-Identified Databases were used to identify adults with ≥ 2 claims with a CLL diagnosis initiating front-line Ibr or CIT from February 12, 2014 to June 30, 2017. Inverse probability of treatment weighting was used to control for potential differences in baseline characteristics between the Ibr and CIT cohorts. Two periods were consi...
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Chimeric antigen receptor (CAR)-T cell therapy is a new and powerful class of cancer immunotherapy [1,2]. Clinical trials of CAR-T cell therapy targeting the B-cell marker CD19 have shown promising results for the treatment of hematologic malignancies, including acute lymphoblastic leukemia (ALL) [3 –7], chronic lymphocytic leukemia (CLL) [8,9], and non-Hodgkin lymphoma (NHL) [10,11]. CAR-T cell therapy targeting B-cell maturation antigen (BCMA) has also been demonstrated to be effective for treating multiple myeloma (MM) [12–15].
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
ConclusionsThe comprehensive analysis of clinical characteristics, immunophenotypic profiles and cytogenetic features can be helpful in differential diagnosis, especially for patients without an available non-bone marrow biopsy specimen. Universal prognostic factors may help with the early detection of high-risk patients and with stratification in risk-adapted therapy.
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
CONCLUSION: In a real-world setting, the QLQ-C30 summary score has a strong prognostic value for overall survival for a number of populations of patients with cancer above and beyond that provided by clinical and sociodemographic variables. The QLQ-C30 summary score appears to have more prognostic value than the global QoL, physical functioning, or any other scale within the QLQ-C30. IMPLICATIONS FOR PRACTICE: The finding that health-related quality of life provides distinct prognostic information beyond known sociodemographic and clinical measures, not only around cancer diagnosis (baseline) but also at follow-up, ha...
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Oncologist Source Type: research
Authors: Zi F, Yu L, Shi Q, Tang A, Cheng J Abstract B-cell receptor (BCR) signaling is important for the development and maturation of normal B-cells and plays a key role in B-cell malignancies. Bruton's tyrosine kinase (BTK), a crucial terminal kinase enzyme in BCR signaling, has emerged as an attractive target and has been successfully applied in the treatment of hematological malignancies. Ibrutinib, a BTK inhibitor, has demonstrated marked efficacy and tolerability in treatment-naïve, relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). Ibru...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
ConclusionOur findings indicate that prognostic testing rates were poor, and approximately one-third of high-risk patients (del[17p] and TP53) received chemoimmunotherapy, which is not aligned with current CLL treatment recommendations. This represents an opportunity to educate and alert healthcare professionals about the necessity of prognostic testing to guide optimal CLL treatment decisions. Study registration: NCT02582879 (ClinicalTrials.gov).
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
informCLL is the first US-based registry of patients with CLL that initiated enrollment after approval of novel-targeted agents. Prognostic/predictive testing rates and CLL treatment selection, with availability of novel agents, in clinical practice has not been previously investigated. Results from this interim analysis demonstrate that prognostic/predictive testing was infrequently used to guide treatment selection, potentially inhibiting beneficial outcomes for patients.
Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Tags: Original Study Source Type: research
We present a very rare case of adquired A-Hemophilia due to an abnormal paraprotein
Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
ConclusionVenetoclax therapy in a real-world cohort offered modest benefits in heavily-pretreated patients. Adverse events were observed at higher incidence compared to clinical trials. A wide heterogeneity of venetoclax dose escalation, multi-agent combinations, and timing of initiation were identified and would best be investigated in subsequent clinical trials.
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
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