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Dual targeting of tyrosine kinase and BCL6 signaling for leukemia stem cell eradication

Funding Type: 
Early Translational II
Grant Number: 
TR2-01816
Principle Investigator: 
Funds requested: 
$3 607 305
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Leukemia is the most frequent form of cancer in children and teenagers, but is also common in adults. Chemotherapy has vastly improved the outcome of leukemia over the past four decades. However, many patients still die because of recurrence of the disease and development of drug-resistance in leukemia cells. In preliminary studies for this proposal we discovered that in most if not all leukemia subtypes, the malignant cells can switch between an “proliferation phase” and a “quiescence phase”. The “proliferation phase” is often driven by oncogenic tyrosine kinases (e. g. FLT3, JAK2, PDGFR, BCR-ABL1, SRC kinases) and is characterized by vigorous proliferation of leukemia cells. In this phase, leukemia cells not only rapidly divide, they are also highly susceptible to undergo programmed cell death and to age prematurely. In contrast, leukemia cells in “quiescence phase” divide only rarely. At the same time, however, leukemia cells in "quiescence phase" are highly drug-resistant. These cells are also called 'leukemia stem cells' because they exhibit a high degree of self-renewal capacity and hence, the ability to initiate leukemia. We discovered that the BCL6 factor is required to maintain leukemia stem cells in this well-protected safe haven. Our findings demonstrate that the "quiescence phase" is strictly dependent on BCL6, which allows them to evade cell death during chemotherapy treatment. Once chemotherapy treatment has ceased, persisting leukemia stem cells give rise to leukemia clones that reenter "proliferation phase" and hence initiate recurrence of the disease. Pharmacological inhibition of BCL6 using inhibitory peptides or blocking molecules leads to selective loss of leukemia stem cells, which can no longer persist in a "quiescence phase". In this proposal, we test a novel therapeutic concept eradicate leukemia stem cells: We propose that dual targeting of oncogenic tyrosine kinases (“proliferation”) and BCL6 (“quiescence”) represents a powerful strategy to eradicate drug-resistant leukemia stem cells and prevent the acquisition of drug-resistance and recurrence of the disease. Targeting of BCL6-dependent leukemia stem cells may reduce the risk of leukemia relapse and may limit the duration of tyrosine kinase inhibitor treatment in some leukemias, which is currently life-long.
Statement of Benefit to California: 
Leukemia represents the most frequent malignancy in children and teenagers and is common in adults as well. Over the past four decades, the development of therapeutic options has greatly improved the prognosis of patients with leukemia reaching 5 year disease-free survival rates of ~70% for children and ~45% for adults. Despite its relatively favorable overall prognosis, leukemia remains one of the leading causes of person-years of life lost in the US (362,000 years in 2006; National Center of Health Statistics), which is attributed to the high incidence of leukemia in children. In 2008, the California Cancer Registry expected 3,655 patients with newly diagnosed leukemia and at total of 2,185 death resulting from fatal leukemia. In addition, ~23,300 Californians lived with leukemia in 2008, which highlights that leukemia remains a frequent and life-threatening disease in the State of California despite substantial clinical progress. Here we propose the development of a fundamentally novel treatment approach for leukemia that is directed at leukemia stem cells. While current treatment approaches effectively diminish the bulk of proliferating leukemia cells, they fail to eradicate the rare leukemia stem cells, which give rise to drug-resistance and recurrence of the disease. We propose a dual targeting approach which combines targeted therapy of the leukemia-causing oncogene and the newly discovered leukemia stem cell survival factor BCL6. The power of this new therapy approach will be tested in clinical trials to be started in the State of California.
Review Summary: 
This is a Development Candidate (DC) application that proposed to develop agents to target the leukemic stem cell self-renewal factor BCL6. The applicants proposed to improve current leukemia therapy that fails to eradicate the leukemic stem cells. The proposed approach will eliminate these cells by dual-targeting of two cellular components, BLC6 and tyrosine kinases. The applicants proposed to identify, characterize, and optimize lead class BCL6 inhibitors using computer-assisted drug design. They have developed a large-scale assay that will allow them to identify BCL6 inhibitors that act on leukemic stem cell self-renewal both in vitro and in vivo. Selected BCL6 inhibitors will be optimized for dose scheduling and delivery. The applicants expect to develop methods for cGMP-grade large-scale production, pharmacokinetic analysis and toxicity studies to advance lead molecules to preclinical and clinical development. Reviewers felt that the approach is based on very solid and supportive preliminary studies. The dual-targeting proposal, if successful, could substantially reduce the risk of leukemic relapse and limit the duration of tyrosine kinase inhibitor treatment. Thus, the potential impact on treatment of leukemia is great. Reviewers considered this application a very well written grant proposal with considerable preliminary data. The proposal was thought to be generally feasible and, from a regulatory perspective, the proposed activities should position the applicants to begin IND-enabling studies at the conclusion of the award period. However, reviewers did identify two issues that might impact the overall success of this project. First, the proposal is highly dependent on finding relevant BCL6 inhibitors by in silico screening; the track record for identifying inhibitors by this approach has been generally poor. Second, the description for the proposed screening experiments is essentially the same as that already previously performed and published by one of the collaborators. It was unclear how the proposed screen would differ and improve upon the results of the prior effort. With the assumption that some novel features would be incorporated into the screen, reviewers felt that some preliminary data establishing feasibility for new compounds would have been helpful. Nevertheless, the overall approach was viewed as focused and on track toward the development of candidate drugs capable of interfering in the maintenance leukemic stem cells. It was recommended that specific milestones be more clearly defined, and if a lead compound is not identified in the early part of the study, the project could be terminated. Reviewers felt the PI is qualified to lead this project and has an outstanding publication record. The multidisciplinary team includes appropriate collaborators and seems capable of achieving the project's objective and aims. The PI has a reasonable plan in place for communication and coordination among the team members. The resources and environment available to the PI were thought to be excellent for carrying out the proposed work. Overall, reviewers liked this proposal and felt that the focused approach could reasonably result in identification of lead compounds that may impact treatment of leukemias in combination with tyrosine kinase inhibitors.
Conflicts: 

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