New Computer Program Can Help Uncover Hidden Genomic Alterations that Drive Cancers

Cancer is rarely the result of a single mutation in a single gene. Rather, tumors arise from the complex interplay between any number of mutually exclusive abnormal changes in the genome, the combinations of which can be unique to each individual patient. To better characterize the functional context of genomic variations in cancer, researchers at University of California San Diego School of Medicine and the Broad Institute developed a new computer algorithm they call REVEALER.

To continue reading click here: Program to uncover hidden genomic alteration

 

Protein-Protein Interaction Activates and Fuels Leukemia Cell Growth

Findings also show how an experimental monoclonal antibody treatment inhibits growth and spread of cancer

Stained chronic lymphocytic leukemia cells.

Stained chronic lymphocytic leukemia cells.

Building upon previous research, scientists at University of California, San Diego School of Medicine and UC San Diego Moores Cancer report that a protein called Wnt5a acts on a pair of tumor-surface proteins, called ROR1 and ROR2, to accelerate the proliferation and spread of chronic lymphocytic leukemia (CLL) cells, the most common form of blood cancer in adults.

They note, however, that these effects of Wnt5a were blocked by a humanized monoclonal antibody specific for ROR1, called cirmtuzumab (or UC-961), which inhibited the growth and spread of CLL cells in both cell lines and mouse models of leukemia. The findings are published in the December 21, 2015 issue of The Journal of Clinical Investigation.

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Cirmtuzumab: Here About the Promising New Therapy

Researchers at UC San Diego are developing a new drug to treat CLL. The drug, cirmutuzumab, is an antibody designed to attach to a protein on the surface of CLL cells. Researchers hope that this process will block cancerous cell growth and survival. Right now, cirmtuzumab is being tested for its safety and effectiveness in humans in a Phase One clinical trial.  “A brand new way to target and kill blood cancer,” WNDU, features Thomas Kipps, MD, PhD.
(Source: http://www.utsandiego.com/news/2014/sep/17/ucsd-leukemia-cll-trial-kipps-cirm/, https://clinicaltrials.gov/ct2/show/NCT02222688?term=cirmtuzumab&rank=1 )

And see: http://medicalxpress.com/news/2014-10-first-in-human-trials-therapeutic-stem-cell.html

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Understanding ROR1

ROR1, an oncogene recently discovered on chronic lymphocytic leukemia (CLL) B cells, is being studied by researchers as a potential target for CLL treatment. Dr. Brian Koffman met with Dr. Thomas Kipps, who is researching ROR1, at the 2014 American Society of Clinical Oncology (ASCO) meeting to discuss this oncogene and its potential use in treating CLL.

Click HERE: https://www.youtube.com/watch?v=Zji6Fux_WGo

Thanks to Patient Power!fig1

 

PCR duplicates in deep sequencing experiments and potential biasing

Published on the August 7th (2014) in the journal of Genome Biology:

Accurate allele frequencies are important for measuring subclonal heterogeneity and
clonal evolution. Deep-targeted sequencing data can contain PCR duplicates, inflating perceived read depth. Here we adapted the Illumina TruSeq Custom Amplicon kit to include single molecule tagging (SMT) and show that SMT-identified duplicates arise from PCR. We demonstrate that retention of PCR duplicate reads can imply clonal evolution when none exists, while their removal effectively controls the false positivhiseqe rate. Additionally, PCR duplicates alter estimates of subclonal heterogeneity in tumor samples. Our method simplifies PCR duplicate identification and emphasizes their removal in studies of tumor heterogeneity and clonal evolution.

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Prolonged lymphocytosis during Ibrutinib therapy

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments.

This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation.

Progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.

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Idelalisib and Rituximab in relapsed chronic lymphocytic leukemia.

Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population.

The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).

For More information about this publication: CLICK HERE

Hot on the ROR1 t(r)ail

ROR1 can interact with TCL1 and enhance leukemogenesis in Eμ-TCL1 transgenic mice.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen found on chronic lymphocytic leukemia (CLL) B cells, but not on normal adult tissues. We generated transgenic (Tg) mice with human ROR1 regulated by the murine Ig promoter/enhancer. In contrast to nontransgenic littermates, such animals had B-cell-restricted expression of ROR1 and could develop clonal expansions of ROR1(bright)CD5(+)B220(low) B cells resembling human CLL at ≥ 15 mo of age. Because immune-precipitation and mass spectrometry studies revealed that ROR1 could complex with T-cell leukemia 1 (TCL1) in CLL, we crossed these animals with Eµ-TCL1-Tg (TCL1) mice. Progeny with both transgenes (ROR1 × TCL1) developed CD5(+)B220(low) B-cell lymphocytosis and leukemia at a significantly younger median age than did littermates with either transgene alone. ROR1 × TCL1 leukemia B cells had higher levels of phospho-AKT than TCL1 leukemia cells and expressed high levels of human ROR1, which we also found complexed with TCL1.

Transcriptome analyses revealed that ROR1 × TCL1 leukemia cells had higher expression of subnetworks implicated in embryonic and tumor-cell proliferation, but lower expression of subnetworks involved in cell-cell adhesion or cell death than did TCL1 leukemia cells. ROR1 × TCL1 leukemia cells also had higher proportions of Ki-67-positive cells, lower proportions of cells undergoing spontaneous apoptosis, and produced more aggressive disease upon adoptive transfer than TCL1 leukemia cells. However, treatment with an anti-ROR1 mAb resulted in ROR1 down-modulation, reduced phospho-AKT, and impaired engraftment of ROR1 × TCL1 leukemia cells. Our data demonstrate that ROR1 accelerates development/progression of leukemia and may be targeted for therapy of patients with CLL.

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Our New Newsletter is HOT off the Press!

We have our new newsletter is available!!  New news and articles letting you know the latest news in regards to CLL and the Blood Cancer Research Fund. Special thanks to Carolina Bump for her tireless efforts to get this information together!

Click here: Insight – BCRF Winter 2013 Newsletter