Destabilization of ROR1 enhances activity of ibrutinib against chronic lymphocytic leukemia in vivo

Publication date: Available online 12 November 2019Source: Pharmacological ResearchAuthor(s): Zhuojun Liu, Jia Liu, Tianming Zhang, Mingxia Shi, Xiaofang Chen, Yun Chen, Jian YuAbstractReceptor tyrosine kinase-like orphan receptor 1 (ROR1) is an onco-embryonic antigen presented on chronic lymphocytic leukemia (CLL), but not on normal adult tissues, which promotes CLL-cell survival. Here, ROR1 was identified as a new client of Heat Shock Protein 90 (HSP90) via a mass spectrometry-based screen for ROR1-associated partners followed by co-immunoprecipitation (co-IP) analysis. A binding motif (ELHHPNIV) on ROR1 for HSP90 was revealed, which forms a αC-β4 loop and is necessary for HSP90-facilitated ROR1 stabilization. We also found that targeting HSP90 leads to ROR1 degradation in a ubiquitin-proteasome dependent pathway, by which pro-survival ROR1 signaling was attenuated in CLL. Based on our previous finding that a humanized monoclonal antibody against ROR1 increases the activity of Ibrutinib against CLL, which is currently undergoing evaluation in clinical trials for the treatment of B-cell lymphoid malignancies, we then provided evidence that treatment with HSP90i (17-DMAG) enhances anti-CLL activity of Ibrutinib in vitro and in vivo, by down-modulating ROR1. iTRAQ-based quantitative proteomic analysis of other HSP90 oncogenic clients in addition to ROR1, followed by GO/KEGG enrichment analysis, showed that Bruton's Tyrosine Kinase (BTK), B-lymphoid Tyrosine Kinase (...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research

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· Follow-up data from Phase 3 E1912 study (Abstract #33) evaluating the investigational use of IMBRUVICA® in combination with rituximab versus fludarabine, cyclophosphamide and rituximab showed statistically significant difference in progression-free survival (PFS) and overall survival (OS) were m aintained in previously untreated patients (ages 70 or younger) with chronic lymphocytic leukemia (CLL)· Integrated analysis from RESONATETM and RESONATETM-2 studies in CLL (Abstract #3054) reported long-term PFS, OS and response rates with earlier treatment with IMBRUVICA® · IMBRUVICA® plus ven e...
Source: Johnson and Johnson - Category: Pharmaceuticals Source Type: news
Drug giant Merck&Co. announced Monday that it will spend billions to buy a 26-year old biotech company that's struggled to bring a cancer drug to market.   Merck (NYSE: MRK) will spend approximately $2.7 billion to acquire Burlington-based ArQule Inc. (Nasdaq: ARQL). The biotech's drug that's furthest along in clinical trials is in the mid-stage tests against relapsed or refractory chronic lymphocytic leukemia. ArQule is expected to disclose more clinical data at an industry conference Monday. ArQule,…
Source: bizjournals.com Health Care:Pharmaceuticals headlines - Category: Pharmaceuticals Authors: Source Type: news
The combination of ibrutinib and rituximab demonstrated superior progression-free survival in older patients with previously untreated chronic lymphocytic leukemia.
Source: CancerNetwork - Category: Cancer & Oncology Authors: Source Type: news
Authors: Ivanescu AM, Oprea M, Momanu R, Coles E, Colita A, Lupu AR Abstract Chronic lymphocytic leukemia is still one of the most common hematologic malignancies. Finding a curative solution is the objective of numerous followed cases and clinical trials. Diagnosis is based on the interlocking of classic elements and newly identified prognostic factors but time to first treatment is still an open issue. CD38, ZAP 70, IgHV gene mutational status and cytogenetic changes are proven negatively influence the evolution of chronic lymphocytic leukemia. Whether through aggressive rapid evolution or by the difficulty of ob...
Source: Journal of Medicine and Life - Category: General Medicine Tags: J Med Life Source Type: research
Authors: Oprea MM, Ivanescu AM, Colita A, Coles E, Momanu RC, Berbec N, Lupu AR Abstract Biological complexity of mechanisms of autoimmune hemolytic anemia (AHAI) in chronic lymphocytic leukemia B (CLL) and the relation cause / effect between these two diseases has been extensively researched, but currently is still far from being completely understood. It is known that the immune system has an important role in the pathogenesis of autoimmune diseases but also in the chronic lymphoproliferative malignancies. In this process of autoimmunity associated with immunodeficiency, the CLL neoplastic cells, the non-malignan...
Source: Journal of Medicine and Life - Category: General Medicine Tags: J Med Life Source Type: research
We present the case of a 61-year-old male patient, diagnosed with chronic lymphocytic leukemia in 2007, who developed myelodysplastic features three years later and then acute myeloid leukemia. At diagnosis, the blood tests showed leucocytosis, with lymphocytosis in the peripheral blood and bone marrow. Due to the negative prognostic factors, the patient received treatment with an alkylating agent (FC protocol) and then with alemtuzumab. Three years after being diagnosed with CLL, the patient presented with malaise, recent faintness and fever, with severe anemia and thrombocytopenia. The results from the bone marrow aspira...
Source: Journal of Medicine and Life - Category: General Medicine Tags: J Med Life Source Type: research
Publication date: Available online 7 December 2019Source: Urology Case ReportsAuthor(s): Margaret M. Mansbridge, Jonathon R. Parker, Sewwandi Francisco, Scott T. McClintockAbstractIncidental diagnosis of haematolymphoid disorders in prostate tissue is rare, with the largest study in the literature reporting a 0.37% incidental lymphoma diagnosis in prostate and associated lymph node tissue. B cell lymphocytosis (MBL) is a relatively recently defined disease entity. The authors present the diagnosis and management of a patient diagnosed with incidental MBL on transurethral resection of prostate (TURP), performed for symptoma...
Source: Urology Case Reports - Category: Urology & Nephrology Source Type: research
Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced updated data from two pivotal phase III Venclexta ®/Venclyxto® (venetoclax) studies (MURANO and CLL14) that highlight Venclexta/Venclyxto combination treatments as chemotherapy-free, fixed-duration options that achieve minimal residual disease (MRD)-negativity, in people with chronic lymphocytic leukaemia (CLL).
Source: Roche Media News - Category: Pharmaceuticals Source Type: news
First-line treatment with ibrutinib plus venetoclax provided high rates of undetectable minimal residual disease in peripheral blood and bone marrow of patients with chronic lymphocytic leukemia.
Source: CancerNetwork - Category: Cancer & Oncology Authors: Source Type: news
Acalabrutinib alone and in combination with obinutuzumab significantly improved progression-free survival, compared with obinutuzumab plus chlorambucil in treatment-na ïve patients with chronic lymphocytic leukemia
Source: CancerNetwork - Category: Cancer & Oncology Authors: Source Type: news
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