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.
Grant awarded in 2015
Nicholas Chiorazzi, M.D.
The Feinstein Institute for Medical Research
Grant awarded in 2013
Rosa Bernardi, Ph.D.
San Raffaele Scientific Institute
Ospedale San Raffaele, Milan, Italy
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.
Grant awarded in 2013
Asish Ghosh, BS, MS, Ph.D.
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:
- Detection of a unique cell surface marker (CD52) on CLL MVs both in vitro and in vivo
- Shedding of CD52+ MVs is a characteristic of B-lymphocytes
- Increased accumulation of CD52+ MVs in CLL patients with progressive disease
- 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
Grant awarded in 2015
Catherine Wu, M.D.
Dana Farber Cancer Institute, Inc.
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
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.
Grant awarded in 2013
Graham Packham, Ph.D.
University of Southampton, United Kingdom
Alfonso Quintás-Cardama, M.D.
University of Texas MD Anderson Cancer Center
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.