CLL Global Research Foundation

 

Upcoming Events
  • Home
  • CLL Information
    • Biology
    • Age & Symptoms
    • Diagnosis
    • Immunology
    • Prognostic Factors
    • Treatments
    • Familial CLL
    • Other
  • News & Views
    • Latest News
    • Upcoming Events
    • President’s Corner
    • Newsletters
    • Multimedia
  • Funded Research
    • Individual Grants
    • Alliance Grants
    • Research Success
    • Other Funding
  • Grant Applications
  • About
    • About Us
    • Mission & Objectives
    • Board of Directors
    • Scientific Advisory Board
  • Donate
  • Contact Us

Individual Grants

We have awarded $10 million since December 2004 to investigators working on promising CLL projects. There have been several rounds of funding.

See a list of previously funded projects.

Therapy/Prognostic

Chiorazzi2
Exploring the effect of BCR pathway inhibitors on subclonal fractions of CLL for targeted therapy
Grant awarded in 2015

Nicholas Chiorazzi, M.D.
The Feinstein Institute for Medical Research
Click here for Abstract and Update
AbstractUpdate
The current hypothesis is “the molecule/ molecules that are most highly modulated in response to the commonly used cell signaling- BCR pathway,in CLL are the best drug target and, the extent of these responses will differ within members of the clone”. Using single cell network profiling and functional assays such as drug sensitivity, cell proliferation and apoptosis assays on total cell populations and on sorted CLL subclones we propose to dissect out differences in responsiveness of resting/ proliferative and other subclones to pathway agonists in the presence or absence of BTK and PLC gamma2 inhibitors. We will also test the role of autologous accessory immune cells and stromal cells/cell lines in promoting the rescue of CLL cells from being susceptible to these inhibitors. The findings from these studies will help devise better combination therapies for CLL in the near future..
No update is available at this time. Please check back soon.
bernardi
Exploiting HIF inhibition as a new therapeutic strategy for CLL
Grant awarded in 2013

Rosa Bernardi, Ph.D.
San Raffaele Scientific Institute
Ospedale San Raffaele, Milan, Italy
Click here for Abstract and Update
AbstractUpdate
Our project will study a group of specific proteins called Hypoxia-inducible transcription factors (HIFs).  These proteins play a role in the regulation of gene expression in response to low oxygen levels in the cellular environment.  When oxygen decreases occur, these proteins induce a wide array of responses, ranging from new vessel formation to metabolic adaptation and cell migration. This group of proteins is increasingly associated with the development of solid tumors and some hematological malignancies. Accordingly, we are interested in inhibiting these factors as a potential cancer treatment.

The specific protein HIF-1a is highly expressed in CLL cells compared to normal B cells. This protein has been suggested to stimulate new vessel formation and resistance to cell death. We found that in CLL B cells HIF-1a also regulates the expression of a number of receptors and molecules known to promote the interaction of leukemic cells with protective stromal microenvironments. Based on these data, we now hypothesize that in addition to preventing new vessel formation, compounds with HIF-inhibitory activity may also work as chemosensitizers in CLL, by promoting the release of CLL B cells from protective niches and exposing them to the toxic effects of chemotherapy.

In our laboratory we are characterizing the role of hypoxia-inducible factors (HIF) in the pathogenesis of CLL, with the final aim to test HIF inhibitors as possible new therapeutic strategies for treating CLL. HIF factors have been reported to regulate umor progression both in solid tumors and leukemia through several mechanisms. In CLL, previous work had suggested that HIF-1α might regulate the formation of new blood vessels, thus accelerating leukemia progression. However, preliminary experiments conducted in our laboratory following specific inhibition of HIF-1α led us to hypothesize that HIF-1α may also mediate the interaction of CLL cells with protective niches in bone marrow and secondary lymphoid organs, and that pharmaceutical compounds that inhibit HIF factors may promote the mobilization of CLL cells from these protective locations thus sensitizing them to chemotherapy. By modulating HIF-1α levels in CLL (cell lines, primary mouse CLL cells and primary human CLL cells) we have currently demonstrated that HIF-1α is an important regulator of the interaction of CLL cells with protective niches, and its inhibition promotes CLL cells mobilization and cell death. Also, by analyzing HIF-1α expression in CLL patients we are finding that high HIF-1α levels correlate with markers of bad prognosis. Our work may lead to the identification of specific group of patients that may be treated with HIF-inhibiting strategies.

Biology

ghosh
Microvesicles in CLL: Predictors of Disease Progression and Therapeutic Outcome?
Grant awarded in 2013

Asish Ghosh, BS, MS, Ph.D.
Mayo Clinic
Click here for Abstract and Update
AbstractUpdate

We have detected that CLL plasma contains elevated levels of extracellular vesicles termed “microvesicles”. These microvesicles play a critical role in CLL by modulating, or altering, stromal cell function. Aberrant modulation of stromal cell function is likely to enhance the progression of CLL. Our recent findings demonstrate that with therapy, microvesicle levels in CLL plasma fall in some patients. In other patients there is no change or an increase. We predict that these latter patients will relapse more quickly given the microvesicles’ ability to modify host stromal function.

Thus we hypothesize that 1) microvesicle levels in CLL are dynamic, 2) increase with progression of CLL and 3) that while levels may decrease with therapy they will persist with residual disease and rise with relapse. CLL microvesicles contain, and can transfer, specific non-coding RNAs (small genes that regulate the expression of proteins.) These particular non-coding RNAs are linked to CLL progression and may explain how microvesicles are able to modify stromal cell function. During our study, we will examine microvesicle parameters including levels, phenotypes, and contents in CLL plasma as patients progress through their clinical course and treatments. This study can help direct and/or modify approaches for understanding and preventing disease progression and better predict clinical/therapeutic outcomes for CLL patients.

During the last 18 months, we made significant progress to further define the dynamic regulation of microvesicles in CLL plasma and in in vitro cell culture system. Unique findings were:

  1. Detection of a unique cell surface marker (CD52) on CLL MVs both in vitro and in vivo
  2. Shedding of CD52+ MVs is a characteristic of B-lymphocytes
  3. Increased accumulation of CD52+ MVs in CLL patients with progressive disease
  4. Accumulation of CD52+ MVs in post-therapy CLL plasma may predict relapse of the responding patients Collectively, this study emphasizes the dynamic production of CD52+ MVs in CLL plasma can be used to study disease progression and may be a useful biomarker for patients entering onto therapy and then after remission
Catherine Wu
Dissecting the clonal dynamics of early chronic lymphocytic leukemia
Grant awarded in 2015

Catherine Wu, M.D.
Dana Farber Cancer Institute, Inc.
Click here for Abstract and Update
AbstractUpdate

Clonal evolution represents a central feature of tumor progression and relapse. Chronic lymphocytic leukemia (CLL) is a valuable model to study this process due to its prevalence, initially slow progression and ready availability of leukemia samples from blood and marrow. Our recent large-scale sequencing studies have identified putative CLL driver genetic events, uncovered the vast inter-personal and intratumoral genetic heterogeneity in CLL and have linked the presence of aggressive subclonal mutations with clonal evolution and poorer outcome (Landau, Cell 2013). Based on the analysis of somatic aberrations that were predominantly clonal or subclonal, we could hypothesize that a stepwise acquisition of genetic events leads the disease from diagnosis to later more aggressive stages. To directly test this, we have established a collaboration with the CLL Research Consortium to systematically examine the clonal dynamics within a unique cohort of 17 patients that were recurrently sampled over years from diagnosis until the time of first treatment. Through this longitudinal study, we will identify the early genetic and epigenetic events in this initially indolent malignancy leading to disease progression. This will be achieved through integrative analysis of tumor RNA and DNA sequencing data using established as well as novel advanced analysis algorithms. To directly test the impact of these early genetic events on B cell biology, we will utilize novel genome-engineering technologies to generate isogenic cell lines harboring key mutation events and test their functional effects on B cell proliferation and activity. Development of these valuable reagents would enable important future studies, such as determining the relative fitness of putative CLL drivers in vitro and studying the effect of established and novel cytotoxic and targeted drugs on the dynamics amongst CLL subpopulations. Altogether, the proposed studies are anticipated to facilitate the development of individualized diagnostic and therapeutic management of CLL

The project has progressed as planned. We have focused our sequencing analyses on a series of samples collected at up to 6 distinct timepoints from the same patient in 21 individuals with CLL from the time of diagnosis until progression and relapse after treatment. We have completed the characterization of changes in DNA gene mutations over time in these samples. The next step is to understand in which order and to which proportion these various changes lead to progression of CLL, and are related to disease prognosis. Ultimately, we aim to gain insights that will help to improve prediction of time and accuracy of disease progression as well as to aid in the selection of optimal treatment strategies for individual patients.

In parallel, we have made substantial progress in developing cell lines models, which will enable us to study in vitro the impact of therapeutic agents in relationship to key CLL genetic events. These studies are anticipated to help us link the risk of therapeutic resistance with presence of specific genetic features in patient samples.

Therapy/Prognostic

packham
B-cell receptor and CXCR4 cross-talk in chronic lymphocytic lymphoma; relevance for new signaling inhibitors
Grant awarded in 2013

Graham Packham, Ph.D.
University of Southampton, United Kingdom
Click here for Abstract and Update
AbstractUpdate
The B-cell receptor (BCR) is a specialized protein that sits on the surface of chronic lymphocytic leukemia (CLL) cells. It can “sense” cues from outside the cell and then trigger responses within the cell that promote the survival and growth of leukemic cells. The BCR also communicates with other proteins on the surface of CLL cells, including CXCR4, which helps to control how CLL cells move around the body. The project will investigate the detailed mechanisms that CLL cells use to allow communication between the BCR and CXCR4. By studying these pathways, we hope to identify markers that can be used to select optimal treatment regimens for patients. It may also be possible to develop new treatment strategies to interfere with BCR/CXCR4 communication.
The B-cell receptor (BCR) and CXCR4 are two key receptors that are expressed on the surface of chronic lymphocytic leukaemia (CLL) cells. These receptors co-ordinate key survival and migratory responses that drive the accumulation and redistribution of the malignant cells. The goal of the project is to identify the pathways that operate within the CLL cells by which activation of the BCR triggers decreased expression of CXCR4. Although this pathway has been studied in other cell types, our latest data reveal that a new pathway operates in CLL cells. Understanding how this pathway operates will provide critical new insight into how new drugs targeted against BCR-signaling pathways modulate behavior of CLL cells.

Therapy/Prognostic

quintas-cardama
Understanding and overcoming mutant p53 mediated resistance in CLL
Alfonso Quintás-Cardama, M.D.
University of Texas MD Anderson Cancer Center
Click here for Abstract and Update
AbstractUpdate

Patients with CLL that have a loss of the short arm of chromosome 17 (17p deletions) fail to respond to standard treatment and generally have very poor outcomes. This is due to the loss of the tumor suppressor p53, which maps to 17p-. In patients that lose the short arm of chromosome 17 (and therefore lose one copy of p53), the remaining p53 copy is mutated. p53 mutations are detected in 7–9% of newly diagnosed patients with CLL and in 30-40% of patients who have failed frontline chemoimmunotherapy. Recently, ibrutinib, an inhibitor of the Bruton’s tyrosine kinase (Btk), has shown preliminary activity in CLL with 17p-.

In our project, we will take advantage of the power of a genetically engineered mouse. We will use a mouse model of CLL (TCL1) with or without p53 mutations to study the impact of the mutation on response and survival to conventional (fludarabine) or Btk inhibitor (ibrutinib) therapy. In addition to the mouse model, we will study the signaling and activation response of B-CLL cells obtained from 17p- patients receiving ibrutinib in a clinical trial at our facility. The results from this study could be extended to other high-risk B-CLL patient populations and may facilitate combination approaches using ibrutinib.

No update is available at this time. Please check back soon.
Donate to CLL
Join Our Mailing List

CLL: Where We Have Been and Looking to the Future

Renowned CLL experts Dr. Michael Keating and Dr. William Wierda talk with Patient Power Founder Andrew Schorr about the evolution of CLL care and the ways CLL Global Research Foundation is investing in the future.

Watch the interview


CLL GLOBAL RESEARCH FOUNDATION

P.O. Box 301402
Houston, TX 77230

MISSION STATEMENT

Our mission is to abolish chronic lymphocytic leukemia (CLL) as a threat to the life and health of patients by accelerating CLL research.

NEWSLETTER

Join Our Mailing List

Join Us on facebook

f_logo small

Copyright © 2021 CLL Global · Website designed by White Space Web Studio · Log in