Grant: 6480-16 | Translational Research Program (TRP):
Location:New York University School of Medicine, Boston, Massachusetts 02241-415026
Project Title: Therapeutic Targeting Of The Bone Marrow ALL NicheProject Summary:
Although much is known about the cell-intrinsic factors that support leukemia, little is understood about the role of the leukemia microenvironment (niche) in distinct tissues, including the bone marrow, one of the initial sites of acute leukemia initiation. We were able to show that in pediatric T cell acute leukemia (T-ALL), cancer cells are in direct, stable contact with bone marrow niche cells that express the chemokine CXCL12. We have also shown that CXCL12 inhibition severely impeded tumor growth, leading to prolonged disease remission, suggesting that targeting the chemokine: receptor interaction could be a future therapeutic. Here we present data that extensively support this hypothesis, visualizing for the first time leukemia:niche interactions in live animals and targeting niche functions. In this application we target the leukemia microenvironment using compounds (i.e. CXCL12 inhibitors) currently on clinical trials and we discover novel factors expressed by the T-ALL niche that can be targeted pharmacologically. This is one of the first studies that proposes the targeting of tumor microenvironment in acute leukemia.
Grant: 6500-16 | Translational Research Program (TRP):
Location:Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-7037
Project Title: Novel Approach For NK Cell Therapy For Hematopoietic MalignanciesProject Summary:
Despites advances in drug development, a large number of patients with blood cancers still lack effective therapies. Instead of drug therapy, an alternative strategy that has shown promise for blood cancers is to utilize cell therapy. In this case donor blood cells which can target cancer cells are isolated, expanded, and infused back into the patient. In particular, one promising donor blood cell type used for cell therapy is Natural Killer (NK) cells. We have identified a novel method to greatly enhance the efficacy and feasibility of utilizing these NK cells as a therapy for multiple types of cancer that shows high potential in cell and animal based studies. In this proposal, we will further develop this strategy in hopes of initiating clinical testing in the near future.
Grant: 5444-16 | Career Development Program (CDP):
Location:Brigham and Women’s Hospital, Boston, Massachusetts 02241-3149
Project Title: Oncogenic Genome Architecture By The B-cell Tumor Virus EBVProject Summary:
Epstein Barr Virus (EBV), the first human tumor virus discovered, causes lymphomas in HIV infected patients, transplant recipients, children co-infected with malaria, and increasingly, also with aging-associated immune senescence. In these contexts, EBV is an important causative agent of Burkitt lymphoma, Hodgkin lymphoma, and diffuse large B-cell lymphomas. EBV-associated lymphomas are a major cause of death in HIV infected people, even those on medications that successfully block HIV replication. EBV encodes a series of proteins that subvert the normal checks and balances on cell growth, and that transform infected B-cells into immortalized, continuously dividing cells. In this study, we will use cutting edge technologies to identify how viral proteins interact with and change the architecture of the human B-cell genome, to drive abnormal cell growth. We will then use recently devised genetic techniques to test the importance of virus effects on the B-cell genome. In particular, we will determine whether undoing viral effects at specific genome sites can successfully block EBV-infected B-cell growth and survival. If successful, this study will provide important insights into how EBV drives malignant B-cell growth, may highlight mechanisms operative in other types of B-cell lymphomas, and will identify novel therapeutic targets.
Grant: 0862-15 | Quest for CURES (QFC):
Location:The University of Melbourne, Parkville, Victoria 3052
Project Title: Circulating Tumour DNA To Monitor Treatment Response And Resistance In Mantle Cell LymphomaProject Summary:
Molecular approaches for monitoring therapeutic efficacy have enormous potential to transform the management of haematological malignancies including MCL. The analysis of ctDNA in plasma represents a unique opportunity in this context; ctDNA acts as a ‘liquid biopsy’ alternative to tissue biopsies allowing patient specific cancer mutations to be tracked in real-time during clinical management. This provides a noninvasive opportunity to monitor tumour dynamics, treatment responses and the presence of minimal residual disease. Moreover, serial ctDNA analysis allows the evolving genomic landscape of the tumour to be studied, thus providing a powerful tool to define, understand and eventually overcome the molecular events that underpin resistance to current and emerging therapies.
MCL typically responds transiently to frontline therapy. Two emerging therapeutic agents, ibrutinib and ABT-199, are considered the most effective new drugs for MCL, and the combination has the potential to eradicate all detectable disease. To investigate the role of ctDNA as a molecular biomarker for disease monitoring in MCL we propose to utilize this novel methodology on plasma collected within a clinical trial of ibrutinib and ABT-199. The study has potential to provide a new strategy for minimal residual disease monitoring in MCL and aims to provide key insights into the mechanisms of acquired treatment resistance to these novel therapeutic agents.
Grant: 1333-16 | Career Development Program (CDP):
Location:Board of Trustees of the Leland Stanford Junior University, San Francisco, California 94144-4253
Project Title: Pre-Clinical Development Of Monoclonal And Bispecific Antibodies Targeting MDS/AML Stem CellsProject Summary:
Grant: 6496-16 | Translational Research Program (TRP):
Location:The Trustees of the University of Pennsylvania, Medical Center, Philadelphia, Pennsylvania 19104-6205
Project Title: A Phase 2 Trial Of The Novel Toll-Like Receptor Agonist Resiquimod For Cutaneous T-cell LymphomaProject Summary:
Cutaneous T-cell lymphoma (CTCL) is a malignancy of helper T lymphocytes with skin-trafficking characteristics. Long-term remissions during therapy remain elusive and patients who present with advanced stages of CTCL have a poor prognosis. Thus, there is still a critical unmet need for new therapeutic approaches. In that regard, we have developed significant in vitro data that the novel Toll-like receptor 7/8 agonist, resiquimod, which is known to be a potent activator of the innate immune response, can markedly boost critical anti-tumor immune responses among patients with poor prognostic CTCL. Thus, a phase I open-label trial of skin applied resiquimod gel for the treatment of patients with stage IA-IIA CTCL was recently completed by the P.I. 12 highly treatment resistant patients (1 stage 1A; 10 stage IB; 1 stage IIA) who had failed on average more than 6 previous treatments applied 0.06% or 0.03% resiquimod gel. In an unprecedented manner, quite high response rates were achieved with 11 of 12 (2 CR, 9 PR) having decreased or resolved itching and clearing of treated target lesions, and, notably, improvement or resolution in non-treated distant lesions. Peripheral blood analysis demonstrated that topical skin therapy was associated with stimulation of circulating immune cells in many subjects tested, suggesting good absorption through the skin with systemic immune effects associated with topical therapy. Analysis of immune cells isolated from skin biopsies before and after treatment demonstrated a dense influx of killer T cells indicating a brisk host anti-tumor response induced by therapy. Quite uniquely, a highly sensitive assay demonstrated elimination of the malignant cells from resolving treated lesions. These results suggest that topical resiquimod induces systemic immune activation, is highly efficacious in the treatment of resistant CTCL skin lesions and leads to regression of both treated and distant, untreated lesions, and, importantly, results in possible elimination of the malignant cells. The P.I. has been provided the drug for a more advanced phase II trial. During this study, the investigators will have the opportunity to more fully elucidate the overall effectiveness of resiquimod, the ability to augment systemic immunity with this unique topical agent, and the ability to eradicate minimal residual disease not only within skin lesions of CTCL, but possibly within the peripheral blood compartment as well, as significantly, our patients with complete responses have remained in remission for more than 12 months.
Grant: 6484-16 | Translational Research Program (TRP):
Location:Emory University, Atlanta, Georgia 30322-4250
Project Title: Development Of A Novel FLT3 Tyrosine Kinase Inhibitor With Activity Against D835Y And F691L Mutant ProteinsProject Summary:
Acute myeloid leukemia (AML) is the second most common cancer in adults and is an aggressive disease with 5 year overall survival rates of less than 30%. Traditional chemotherapies are relatively non-specific and treatment often results in a variety of toxic side-effects that can be devastating, both in older patients (> 65 years of age) where the incidence of death as a result of treatment approaches 30% and in children where severe, long-term, irreversible damage as a result of exposure to high-dose chemotherapy can have a significant health impact over a lifetime. For these reasons, new therapies for patients with AML are needed. Ideally, these therapies will specifically target cancer cells and will have fewer and/or less severe side effects compared to current therapies. One such target is Fms-like tyrosine kinase 3 (FLT3). In 30% of patients with AML, a genetic mutation results in abnormal activation FLT3 and the presence of activating mutations in FLT3 is associated with a worse prognosis. Therapies targeting FLT3 (e.g. quizartinib) have been developed and are effective in patients with AML, but do not work in all cases and/or can cause severe depletion of normal blood cells. Also, many patients develop resistance to these agents during treatment. New therapies targeting FLT3 are needed to address these limitations and to provide options for patients whose tumors are resistant to current FLT3 inhibitors. We have discovered a new and highly effective inhibitor of FLT3 called UNC2371. UNC2371 can be taken orally and is well-tolerated in animals with few and manageable side effects. Treatment with UNC2371 slows leukemia progression and prolongs survival by more than two-fold in a mouse model of FLT3-dependent AML and inhibits FLT3 mutant proteins that are resistant to other FLT3-targeted therapies. Based on these observations, UNC2371 is being developed for clinical use. This proposal describes studies to test whether UNC2371 is effective in cell culture and animal models. If successful, the results will be used to apply to the FDA for approval to conduct clinical trials to see if UNC2371 is safe and effective for patients with FLT3-dependent AML that does not respond to other therapies. Because these studies may directly enable clinical trials, they have the potential to improve both the length and quality of life for patients with AML.