Grant: 1332-16 | Career Development Program (CDP):
Location:University of Massachusetts Medical School, Worcester, Massachusetts 01655-0002
Project Title: Defining The Mechanisms Of Metabolic Control By MTORC2, A Bona Fide Therapeutic Target In Leukemias And Lymphomas With High PI3-kinase ActivityProject Summary:
In the last decade scientists have come to appreciate that for cancer cells to proliferate and survive, they must reprogram their metabolism to fuel these processes. In fact, it is now widely accepted that some of the major tumor promoting oncogenes and tumor suppressors directly control how cancer cells utilize nutrients and produce energy. Thus, targeting the metabolic circuitry of cancer cells offers an important new avenue of therapeutic development. My lab studies one of most important oncogenic signaling pathways in cancer metabolism. This pathway—called the PI3K-mTOR pathway—is hyperactive in most human cancers (including leukemia, lymphoma, and myeloma) and it controls the uptake and flow of nutrients through cancer cells. However, despite its widespread role in human cancer, we still only vaguely understand how PI3K-mTOR signaling drives tumor metabolism and consequently, there are only a handful of general therapeutic strategies to target it in development. A deeper understanding of this critical interface between signaling and metabolism would have broad impact in cancer biology. In this proposal, we develop innovative tools and utilize emerging technologies to address some of the major gaps in our understanding of how PI3K-mTOR signaling promotes cancer metabolism. Our long-term goal is to identify new drug targets and treatment strategies that will benefit patients suffering from blood and other forms of human cancer.
Grant: 0863-15 | Quest for CURES (QFC):
Location:University of Southern California, Los Angeles, California 90074-2095
Project Title: Characterizing Hematopoietic Stem And Progenitor Cell Senescence With Aging In HumansProject Summary:
Cells in our body including stem or mother cells accumulate damage in their DNA as they continue to divide with age. When a cell has accumulated excess DNA damage it is recognized by the cell machinery and makes the cell undergo permanent arrest from further multiplication. This is called senescence and is the principle mechanism of how we age. However, this helps keep damaged cells from spawning tumors. Loss of this process in the cell can lead to cancer. Several genes regulate senescence. TP53 is one such gene and is the most common gene mutated in cancer. TP53 mutation is common in blood cancers in the elderly. We have shown that that this occurs commonly in leukemia that arises from patients treated with chemotherapy and is the earliest event in leukemia development. Chemotherapy, which poisons fast-dividing cancer cells, also induces senescence in many normal cells. If these damaged cells escape from senescence, they can further mutate, and turn into cancer. We propose that the escape from senescence in blood stem cells is a key mechanism of how blood cancers arise in the elderly. The mechanism by which different compartments of blood cells undergo senescence in humans is poorly studied. We propose a comprehensive and systematic study of how the genetic material changes with aging in various blood compartments. We believe this could lead to a better understanding of both normal and cancerous changes that occur with aging, providing useful markers of both types.
Grant: 1330-16 | Career Development Program (CDP):
Location:Boston Children's Hospital, Boston, Massachusetts 02241-4413
Project Title: Clonal Analysis Of Hematopoietic Development And MalignancyProject Summary:
The technology developed by the investigator allows the tracking of thousands of single cell simultaneously. With this technology, we propose to understand how blood-forming stem cells function in an organism at the single cell level. Additionally, the same technology will be applied to study the development and evolution of single cells in a leukemia model in mice. Knowledge gained form these studies will be critical for understanding the cells-of-origin of hematopoietic disease, the clonal organization of tumor cells and their mechanisms of therapy resistance.
Grant: 6490-16 | Translational Research Program (TRP):
Location:Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud CH-1011
Project Title: Genetically Engineered Virus-specific T Cells To Prevent And Treat Relapse And Infection After Allogeneic Hematopoietic Stem Cell TransplantationProject Summary:
Transplantation of blood-forming stem cells from a healthy person to a patient with blood cancer (e.g. leukemia) can cure these diseases. However, the patient’s immune system is significantly weakened by this procedure, which frequently leads to serious or fatal viral infections, and unfortunately, the blood cancer can also come back. We propose a single approach that can overcome both problems. T cells are a part of the immune system with the capacity to fight against viral infections and to attack blood cancer cells in the patient’s body. Our group has previously shown that T cells from healthy people manipulated in our laboratories can be used to treat infections and blood cancer in patients. We take the T cells from the blood of the original stem cell donor, grow them in the laboratory and train the cells so that they recognize a few specific viruses as well as the blood cancer cells. We then give the T cells to the patient, where they can protect against viral infections and attack cancer cells, leading to cancer elimination from the patient’s body and preventing it from coming back. For the T cells to completely destroy the cancer, however, they need to be able to survive in the body for a long time. We will test new ways of ensuring these cells live longer in the patients by making them recognize viruses and cancer cells at the same time, and “trick” them into thinking the cancer cell is a type of virus infection. We will also engineer the cells to enable faster growth in the presence of a chemical that we know is produced in the same locations that the cancers grow. We think that this three-fold approach will protect patients from viral infections, improve the persistence and anti-cancer actions of the T cells and eradicate the cancer. We will test this new treatment strategy in the laboratory and if the results are promising, in later studies we will test it in patients after a stem cell transplant.
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: 6481-16 | Translational Research Program (TRP):
Location:Fondazione Centro San Raffaele , Milano, Lombardia 20132
Project Title: Targeting AML By Lipid Antigen-specific T Cells Restricted For CD1Project Summary:
The immune system controls cancer progression by detecting antigenic differences generated during the oncogenic process. Tumor-specific T lymphocytes and tumor associated antigens are exploited in cancer immunotherapy, a treatment that holds great promise. The T lymphocytes that are currently exploited in cancer immunotherapy recognize cancer protein fragments (peptides) bound in antigen-presenting molecules of the Major Histocompatiblity Complex (MHC). MHC molecules are extremely variable (polymorphic) among individuals and such variability is at the basis of immunological rejection in transplantation. In hematopoietic stem cell transplantation (HSCT) donor T lymphocytes recognize MHC-incompatible (allogeneic) cells of the patient (alloreactive reaction). Acute myeloid leukemia (AML) comprises a heterogeneous group of hematological disorders characterized by the growth of abnormal cells derived from hematopoietic precursors. High-risk AML is currently treated with conditioning chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). A major cause of treatment failure is the post-transplant re-growth of residual leukemia blasts that survive the conditioning regimen. The transfer alloreactive T lymphocytes of HSCT donors into patients can induce a beneficial graft versus leukemia (GVL) reaction capable of maintaining leukemia control (remission). The allogeneic T cells, however, recognize also non-hematopoietic tissues of the patients, resulting in a life threatening graft versus host disease (GVHD). A promising therapeutic strategy is the selective targeting of allogeneic T cells against malignant hematopoietic cells, while maintaining hematopoietic capacity among grafted cells and preserving organ functions in recipient patients. The recent discovery of T cells that recognize lipid antigens presented by CD1 molecules may provide a new perspective for this strategy: i The expression of CD1 antigen-presenting molecules is confined to mature leukocytes, thus avoiding potential harmful recognition of non-hematopoietic tissues; 2. Being CD1 molecules non-polymorphic, they can be recognized by any CD1-restricted T cell irrespective of the donor. We have recently shown that primary AML blasts express CD1 molecules and a new lipid antigen, called methyl-lyso phosphatidic acid (mLPA), which is specifically recognized by a large group of CD1-restricted T lymphocytes. In light of these considerations, our proposal aims at testing the hypothesis that CD1 autoreactive T cell responses might be harnessed to attack CD1 AML in adoptive immunotherapy, resulting in GVL without GVHD. We will assess efficacy and safety of adoptive cell therapy with CD1 autoreactive T cells for AML in different human and mouse leukemia model that we recently implemented. This study may provide a novel conceptual framework for a safer and more efficacious cure of AML based on the effector properties of T cells specific for self-lipids.
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.