Hitting a CLL Treatment “Home Run”

As more chronic lymphocytic leukemia CLL treatments are approved, with many more in development, are researchers closer to hitting a “home run” in treating the disease? Patient advocate Dr. Brian Koffman met with CLL expert Dr. Thomas Kipps at ASCO 2014 to explore emerging therapies and the goal for patients to achieve deep remission.

Click here:  https://www.youtube.com/watch?v=CYS78SbXjKAHome run

Thanks to Patient Power!

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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Monoclonal Antibodies Could Add Power to CLL Treatment

Andrew Schorr from Patient Power in partnership with the CLL Global Research Foundation interview Dr. Thomas Kipps, Director of the Blood Cancer Research Fund and the CLL Research Consortium about the use of rituximab, a monoclonal antibody used to treat patients with chronic lymphocytic leukemia

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UCSD-based Cancer Consortium Receives 5-Year, $20 Million Grant Renewal

NCI funding continues work focused on chronic lymphocytic leukemia  

An international consortium of scientists studying chronic lymphocytic leukemia (CLL), based at the University of California, San Diego School of Medicine, has been awarded a 5-year, $20 million grant by the National Cancer Institute, part of the National Institutes of Health. The grant is the second renewal of funding for a broad-based effort designed to better understand the pathology of CLL – the most common form of leukemia in the Western world – and develop new drugs and treatments.

CLL cells
Magnified blood smear showing darker CLL cells.

“This funding allows us to continue critical research that has already produced substantial, new insights into how and why CLL develops and progresses differently in patients,” said Thomas J. Kipps, MD, PhD, professor of medicine in the UCSD School of Medicine, deputy director of research at UC San Diego Moores Cancer Center and director of the Chronic Lymphocytic Leukemia Research Consortium (CRC). “Our work has revealed new targets and approaches for both mitigating the disease and perhaps eventually preventing it.”

miR-125b and CLL

The downregulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state.

MiR-125b-1 maps at 11q24, a chromosomal region close to the epicenter of 11q23 deletions in chronic lymphocytic leukemias (CLLs). Our results establish that both aggressive and indolent CLL patients show reduced expression of miR-125b. Overexpression of miR-125b in CLL-derived cell lines resulted in the repression of many transcripts encoding enzymes implicated in cell metabolism.