The Clinical Grants and Contracts Branch (CGCB) in CTEP manages a grant portfolio of investigator-initiated research with a heavy translational focus, funded by a number of mechanisms, specifically including R01, R21, R33, R37, RC1, RC2, and P01 research project grants and U01, U10, U19, U24, and U54 cooperative agreements. The P01 grant in particular, composed of three or more thematically-related projects, and supported by core facilities, serves as an important bridge between the preclinical and clinical sciences, as scientific advances which are discovered in basic science projects are then refined and developed into testable clinical hypotheses. Results from clinical studies in the PO1 often then, in turn, influence the next generation of basic science studies so the desired synergistic effects are achieved. The cooperative agreement mechanism provides funding for larger consortia of investigators, with CTEP program officer involvement, to provide highly integrated performance of the clinical research at multiple sites and with centralized data monitoring. Ongoing research project grants, cooperative agreements, and other mechanisms managed in CGCB that have significant impact in each of various therapeutic areas follow.
Current treatments of acute lymphoblastic leukemia (ALL) do not include molecularly targeted therapies except for a small proportion of patients with Ph+ AL. About 90 percent of patients who relapse after primary treatment will die. This grant, funded by the American Recovery and Investment Act (ARRA), supports a large comprehensive study to validate novel, previously unrecognized mutations and pathway alterations in childhood ALL that can serve as molecularly targeted therapy.
The goal of this P01 is to develop more effective and less toxic therapies for acute and chronic leukemias and overcome resistance to current therapies. The project focuses on approaches that use drug combinations that target selected signal transduction and transcriptional pathways.
The goal of this P01 is to target B-cell receptor and NFkB signaling and survival pathways, deregulated BCl-6 expression, deregulated apoptosis, and transcriptional programs. In addition, the project is developing a better understanding of the molecular subtypes of B-cell lymphoma, each with a unique pathogenic mechanism so as to devise more rational therapeutic targets for each of these diverse subtypes.
This project provides a comprehensive study of molecular pathophysiology of chronic myelogenous leukemia (CML) with translation to novel and more effective therapies for this disease. The P01 includes chemo-biologic studies assessing tyrosine kinase inhibitors, antigen-specific therapies, and hypomethylating therapy designed to overcome imatinib resistance; mechanisms of resistance to tyrosine kinase inhibitors in CML stem cells and potential therapeutic interventions to circumvent resistance; molecular mechanisms of bcr-abl oncogenesis and signaling through Jak-2; the epigenome in CML, including predictive and prognostic testing of epigenome markers; the interaction of the microenvironment in CML; and novel strategies for hematopoietic transplantation.
A goal of this P01 is to discover the signal transduction pathways and networks that govern lymphoma behavior. Investigators will use a new method of assessing the signaling profiles of phosphoproteins that uses multiparameter flow cytometry to compare basal vs. cytokine- stimulated signaling pathways.
In this merit award grant, the significance of non-stochastic IgV expressed in chronic lymphocytic leukemia is being addressed, together with the significance of Ig-receptor signaling through ZAP-70, a tyrosine kinase which appears to be required for chronic lymphocytic leukemia (CLL) cell survival. Finally the project will also use mouse models to evaluate the potential of idiotype-directed immune therapy of CLL as a novel immunotherapy for this disease. The project is significant in that the elucidation of the antibody repertoire and key intracellular signaling molecules involved in antibody-signaling pathways provides for new targets at which to direct anti-leukemia therapies.
The Adult Brain Tumor Consortium (ABTC) performs innovative, multidisciplinary phase 1 and 2 clinical trials that focus predominantly on adult patients with grade IV gliomas (glioblastoma multiforme). This consortium is focused on novel, targeted agents, alone and in combination with other agents or with radiation therapy. Imaging studies to assess endpoints and target modulation, as well as pharmacokinetic and pharmacodynamic endpoints, are commonly incorporated in the consortium’s clinical trials. ABTC is an essential interface between early discovery mechanisms such as CTEP’s new agent evaluation program and late trials mechanisms typified by the NCI-sponsored Cooperative Groups.
This P01 focuses on studying the fundamental mechanisms of cancer biology and translating them into novel therapeutic approaches for lung cancer. The overall hypothesis is that cell survival signaling, induced during targeted therapy, counteracts therapeutic efficacy and ultimately confers therapeutic resistance. Thus, the development of mechanism driven strategies for preventing or disrupting the activation of cell survival signaling should greatly enhance targeted cancer therapy against lung cancer.
This grant involves an integrated, multidisciplinary investigation of the biology, pathogenesis, and progression of the most common of soft tissue sarcoma: well-differentiated and de-differentiated liposarcoma. While liposarcomas can be treated surgically, there are few systemic therapies for advanced disease. The P01 aims to define the molecular mechanisms of liposarcoma development and progression so as to identify new therapeutic targets. The investigators also seek to understand the molecular mechanisms responsible for response or resistance to targeted therapies, which will be validated in clinical studies.
To understand and circumvent acquired drug resistance, the investigators are monitoring acquired tumor genotypes in circulating tumor cells from cancer patients treated with kinase inhibitors. The team is also developing strategies to circumvent resistance to epidermal growth factor receptor (EGFR) inhibitors and mesenchymal to epithelial (MET) antagonists; model and abrogate epithelial to mesenchymal (EMT); and define “kinase independent” oncogenic activity.
This project will further define the role of specific histone deacetylases (HDACs) in modulating HIF-1a and angiogenesis in renal cell carcinoma (RCC). Other objectives are to evaluate combination strategies in xenograft models with targeted agents such as mammalian-target-of-rapamycin (mTOR) and microtubule inhibitors; and to conduct clinical studies with a rational combination strategy of HDAC and mTOR inhibitors in renal cell carcinoma.
This network, funded in fall 2010, is a large national consortium of leading investigators in the field of immunotherapy. Investigators will design and conduct phase 1 and 2 clinical trials, and, in particular, use novel immune response modifiers that are ripe for testing in the clinic. This network will also integrate several tumor immunology laboratories to utilize specimens from patients on the trials for central immunomonitoring as well as developing and credentialing biomarkers to serve as predictors of response. Central data coordination will be facilitatedd by the NCI’s Cancer Trials Support Unit within CTEP.
The Immune Response Modifiers Pathway was chosen as the first of six translational pathways to receive funding through the new Special Translational Research Acceleration Project (STRAP) Program. Two administrative supplements to funded grants were awarded.
Genetically modified T-cells as a novel approach to cancer immunotherapy (Supplement):
The technique of genetically modifying T-cells to express chimeric antigen receptors (CARs) to target the CD19 molecule is an important technique to treat B-cell malignancies, but differences in the CAR construct and vector at the various institutions working on this problem make it difficult to move forward with an optimal approach. This supplement supports an effort to harmonize three ongoing clinical trials at two institutions so that all subsequent patients on these trials will be tested with the exactly the same vectors and CAR constructs.
Antibody-Targeted Radiation and Immunotherapy for the Treatment of Solid Tumors (P01):
This P01 focuses on investigating the role of anti-carcinoembryonic (CEA)- targeted therapies for the treatment of solid tumors. The CEA-positive cancers are treated with radioimmunotherapy combined with chemotherapy, pretreating strategies with anti-CEA monoclonal antibody (mAb), or an anti-CEA-IL2 immunocytokine fusion protein. This STRAP award supplement supports collaboration with an investigator who has identified a cyclic peptide, iRGD (an internalizing disulfide-based cyclic RGD peptide c[CRGDKGPDC]), which increases the uptake of drugs into tumors in animal models. The supplement aims to validate the activity of iRGD in a CEA-transgenic mouse model; develop the most appropriate MRI technique for validation of the iRGD activity in the clinic; establish an assay for measuring pharmacokinetics; conduct the IND-directed toxicology study; and submit an IND application for evaluation of iRGD with antibody-based immunotherapy.
The overall goal of this P01 is to develop strategies that will counter the passive and active immune evasion strategies in the tumor microenvironment that circumvent immune activation against the tumor, in order to increase and broaden the applicability of T-cell immunotherapy of cancer. This will be accomplished in projects, which include: evaluating techniques to render tumor-specific cytotoxic T-cells resistant to inhibition by Hodgkin’s tumors; using chimeric antigen receptor (CAR) T-cells engineered to express the ganglioside GD2 and the receptor for the chemokine CCL2 to target GD2+ neuroblastomas; performing a trial to increase the effectiveness of T-cell therapies for nasopharyngeal cancer (NPC); and elucidating immune suppression mechanisms in patients with Hodgkin’s disease and NPC.
The goal of this P01 is to develop more effective strategies for the use of radiolabeled monoclonal antibodies in conjunction with stem cell transplantation for trials for acute myeloid leukemia lymphoma.
A goal of one project in this P01 is to test a new strategy for inducing an immune response in lymphoma. Using in-situ vaccination, induction of tumor cell death is followed by injection of an immunostimulatory agent to induce a systemic immune response to the tumor.
This grant focuses on studies harnessing the human innate immune response to treat tumors. In one project, the cytokine IL-21, which induces activation signals in natural killer cells (active in innate immunity) is being tested in combination with CD37-SMIP, a novel engineered small modular immune pharmaceutical that directly promotes apoptosis in chronic lymphocytic leukemia cells. In another project, the role of TGF-beta in dampening the innate immune system is examined, with further tests of an anti-TGF monoclonal antibody to treat several types of solid tumors.
This P01 aims to develop a new means of directing the vaccination-induced effector-type T-cells into tumors and of limiting tumor infiltration with regulatory T-cells. The studies focus on the therapeutic application of interferons, toll-like receptor (TLR)-ligands, prostaglandin synthesis inhibitors, and viral vectors to induce the desirable modification of tumor-associated chemokine production. These are also used in combination with tumor-specific vaccination against colorectal cancer, melanoma, and malignant glioma. Analyses of the chemokine regulation in ovarian cancer and glioma, and myeloid-derived suppressor cells, are also included.
Plasmacytoid Dendritic Cells (pDCs) are central to the potent immune response to viruses, activating innate immune cells such as natural killers cells through TLRs, leading to activation of adaptive immunity. This P01 focuses on the role of pDCs in antitumor immunity, with a hypothesis that activation of pDCs with TLR agonist will yield an inflammatory cascade and then a strong anti-tumor response. The P01 will include a clinical trial in metastatic melanoma testing TLR agonists at the tumor site.
Glioblastoma multiforme (GBM), the most common primary malignant neoplasm of the CNS, remains universally fatal. Immunologic targeting of tumor-specific mutations holds the promise of more precisely eliminating neoplastic cells, without toxicity commonly observed with chemotherapeutic agents. A phase 2 trial was undertaken to assess the immunogenicity of epidermal growth factor receptor variant type vIII, which is constitutively activated GBM with a conjugated peptide vaccine. The initial results of the trial showed that vaccination with the peptide improved progression-free and overall survival; currently a placebo-controlled, randomized phase 3 study is under design.
These investigators have observed a 50percent objective response rate in metastatic renal cell carcinoma (mRCC) patients treated with autologous tumor lysate-dendritic cell (DC)-vaccine, IL-2 and interferon (IFN-alpha). Blocking vascular endothelial growth factor (VEGF) pathways has also shown to benefit mRCC patients significantly by impeding regulatory/inhibitory T-cells and re-establishing immune competence. This project aims to test if complementary mechanisms of immune activation and disruption of regulatory pathways improve clinical outcome in a phase 2 trial for treatment of 24 mRCC patients with bevacizumab, DC vaccine, IL-2 and IFN-alpha.
These investigators hypothesize that inefficient migration of T-cells to tumors is one of the rate-limiting steps in the generation of an effective anti-tumor response to reinfused autologous tumor infiltrating lymphocytes (TILs). In mouse models, murine T-cells transduced to express CXCR2, a chemokine receptor, showed enhanced trafficking to CXCL1-expressing tumors and led to improved anti-tumor responses and survival. This project proposes to translate these observations to humans by treating melanoma patients with autologous tumor-reactive TILs genetically modified to express CXCR2.
It has been hypothesized that lipopolysaccharide (LPS)-activated IFN-Dendritic cells (DCs) will improve clinical outcomes in patients with stage IV melanoma through the activation of cytotoxic effector cells, including CD8+ T-cells, NK cells, natural killer T-cells and gamma/delta T-cells. This grant supports a phase 2 trial in patients with stage IV melanoma: to determine if LPS activation of IFN-DCs improves the immune and clinical response; to analyze functions of elicited melanoma-specific CD8+ T-cells; and to measure generation of melanoma-specific CD4+ T-cell immunity.
The investigators have observed that breast cancer patients immunized with Human Epidermal Growth Factor Receptor 2 (HER2) T-helper (Th) peptide vaccines show increased numbers of circulating HER2-specific CD4+ Th1 cells, and their T-cells are more rapidly expanded ex-vivo than those from non-immunized patients. This project is to evaluate the safety of infusing escalated doses of HER2-specific Type 1 Th cells in patients with advanced stage breast cancer after priming patients with a HER2 vaccine. Then the magnitude of immunity achieved in vivo, the persistence of the immune response, and the potential therapeutic efficacy of the regimen will be assessed.
Programmed Death-1(PD-1), is involved in T cell regulation. Both PD-1 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are upregulated on activated CD4 and CD8 T-cells. When both PD-1 and CTLA-4 are blocked in animal models, additive or synergistic anti-tumor effects were observed. When both molecules were abrogated in-vitro with human melanoma-specific T-cells, antigen-specific functional T-cells were markedly increased. During the first phase 1 trial for treatment of 10 melanoma patients with escalating doses of anti-PD-1 antibody and a multi-peptide vaccine, safety, maximum tolerated dose, immune response, and a well-tolerated dose of anti-PD-1 antibody for optimal immunity was determined. During the second phase 1 trial, combination of PD-1 and CTLA-4 abrogating antibodies with a multi-peptide vaccine in chemotherapy-resistant patients will be evaluated.
In a dose-escalation phase 1 trial, safety, immunological, and clinical response to T-cells transduced with a high-affinity Melanoma Antigen Receptor Recognized by T-cells (MART)-1 T-cell receptor (TCR) and a herpes simplex virus (HSVsr39tk) Positron Emission Tomography (PET) reporter/imaging gene are evaluated. Clinical imaging and animal modeling with genetically-engineered human T-cells will also be conducted.
A mAb against CTLA-4 has been shown to extend overall survival in patients with metastatic melanoma. However, this therapeutic strategy needs to be improved considerably. Based on supportive preclinical data, the investigators hypothesize that higher potency T-cell activation and improved clinical activity can be achieved by combining activation of CD40, a cell-surface receptor mediating activation of antigen-presenting cells and thus enhanced tumor immunity, with CTLA-4 blockade in melanoma patients. This application proposes to determine for the first time the clinical impact and immunological mechanisms underlying simultaneous treatment of melanoma patients with the agonist CD40 mAb CP-870,893 (Pfizer) and the CTLA-4 blocking mAb tremelimumab (Pfizer).
A previous dose escalation study yielded a durable clinical response and small number of partial or minor responses in melanoma patients receiving CD4 T-cells alone. In order to enhance efficacy, a phase 1/2 clinical trial is planned to evaluate the contribution of pre-infusion conditioning to the in vivo persistence of adoptively transferred antigen-specific CD4 T-cell clones in melanoma patients by eliminating regulatory components. In preclinical studies, the investigators will also develop strategies to expedite the generation of antigen-specific CD4 T-cells and enrich a population with a desirable central memory and pro-inflammatory (Th17) phenotype.
The investigators hypothesize that immunotherapy after debulking with a taxane-based neoadjuvant chemotherapy will optimize tumor lysis and enhance immune responses leading to increased pathologic complete responses (pCRs) at the time of surgery. A phase 2 clinical trial in stage II-III triple-negative breast cancer patients is proposed to determine whether a regimen of neoadjuvant chemotherapy followed by immunotherapy with infusions of anti-CD3 x anti-Her2/neu bi-specific antibody-armed activated T-cells improves the pCR rate and recurrence-free survival.
The inhibitory co-receptors or pathways, termed immune checkpoints, restrain T-cell functions in neoplastic disease as well as in normal physiology. One of the important inhibitory co-receptors is PD-1, which is induced on activated T-cells and downregulates functions of both CD4+ (“helper”) and CD8+ (“killer”) subsets. The investigators discovered B7-H1, a ligand of PD-1, and have demonstrated that B7-H1 is over-expressed in the majority of human cancers and plays an important role in immune evasion of cancer cells. In a phase 1 trial, antitumor activity of MDX-1106, an anti-PD-1 antibody, was observed in patients with a variety of advanced solid cancers, and B7-H1 was suggested as a potential pre-treatment biomarker for predicting response to treatment. The investigators hypothesize that modulation of B7-H1/PD-1 inhibitory pathway could significantly enhance efficacy of cancer immunotherapy by improving tumor microenvironment and protecting ongoing T-cell immunity. This project aims to advance preclinical and clinical research for understanding mechanisms of the PD-1/PD-1 ligand pathway and effects of perturbing B7-H1/PD-1 interactions.
The investigators have demonstrated the benefit of a humanized monoclonal antibody, ipilimumab, against the CTLA-4 in patients with metastatic melanoma. They have observed that this CTLA-4 blockade can induce immune-mediated destruction of the vasculature feeding tumors. In this project, the investigators have proposed to evaluate potential synergistic effects of ipilimumab and an anti-VEGF antibody, bevacizumab, when they are combined for treatment of patients with unresectable stage III or stage IV melanoma during a phase 1 trial. Specifically, the investigators would like to: determine the safety, tolerability, and dosing for the combination; determine the secondary endpoints (best overall response rate, time to progression, disease control rate, and the duration of response) for the combination using standard solid tumor response criteria and proposed immune-related response criteria; and carry out correlative studies to investigate the effects of ipilimumab combined with bevacizumab on tumor vasculature.
Although the immune system is capable of generating effective immune responses, immunotherapeutic interventions are modest at best. The goal of this P01 is to enhance the ability of the immune system to efficiently and effectively recognize and kill tumor cells by gene engineering approaches, testing the hypothesis that increasing the precursor frequency of high affinity T-cell receptor (TCR) T-cells, continuously generated by stably engineered bone marrow stem cells, will effect a potent antitumor protection. This will be studied in a project designed to understand the biology of the TCR-engineered T-cells, as well as projects to assess the differentiation of these cells from TCR-engineered human hematopoietic cells, embryonic stem cells, and induced pluripotenT-cells, in the context of the metastatic melanoma.
Hematopoietic stem cell transplantation (HCT) is curative therapy for a significant proportion of patients with hematologic malignancies; approximately 20,000 patients in the United States and 60,000 patients worldwide yearly undergo HCT therapy; however, patients often die from transplant-related complications or recurrent malignancies, or patients are not eligible because of advanced age, poor health, or inability to find a suitable donor. This P01, originally funded in 1968 to Dr. Donnell Thomas, winner of the Nobel Prize in Medicine, is designed to improve the safety of allogeneic transplant using a non-myeloblative preparative regimen, broaden the use of allogeneic transplant beyond 60 years of age, segregate effects of graft-versus-host disease from that of graft-versus-leukemia, assess the use of haplotype matching to increase the probability of donor selection, and optimize the timing of transplantation in the patients’ disease course.
This grant proposes to complete a phase 1 clinical trial for B-cell malignancies using a novel approach in which umbilical cord blood (UCB) T-cells are genetically modified with CD19-specific CARs to kill CD19 blasts by a unique virus vector-free (Sleeping Beauty) approach; the T-cells are expanded in a CAR-dependent manner on genetically modified K562 cells as artificial antigen-presenting cells; and the CAR-specific T-cells have universal potential for clinical use and will be banked, since T-cells from UCB are functionally naïve and thus expected that the endogenous T-cell receptor repertoires will have minimal potential for graft-versus-host disease (GVHD), which is extremely promising for treating of B-cell malignancies.
This P01 tests the hypothesis that natural killer (NK) cells are of general importance in allogeneic transplantation and that variable NK cell receptors influence clinical outcomes, based on projects that focus on developing killer cell immunoglobulin-like receptors (KIR) typing for clinical use in selecting donors with KIR, adoptive transfer of haploidentical stem cells with IL-15 to educate NK cells in vivo, and studies to assess the functions of B KIR haplotype in conferring a significant relapse-free survival to transplanted patients with acute myeloid leukemia (AML).
The overall hypothesis of this long-standing P01 is that through a better understanding of the cellular populations critical to transplantation, better treatment strategies for transplant for hematologic malignancies will be developed. For example, the investigators will, in one project, study cytokine-induced killer (CIK) cells as an effector cell in the graft-vs-leukemia (GVL) effect of allogeneic transplant, and, in another project, test these cells in the clinic post-transplant; examine the biology of the NK-T-cells and their role in protecting against GVHD while retaining GVT effects in certain regimens; examine the role of B cells and allogeneic antibodies in the development of chronic GVHD, as well as use immune-based strategies to treat various non-Hodgkin lymphomas in a post autologous transplant setting.
The goal of this P01 is to identify and characterize the genetic and cellular interactions between the allogeneic donor cells and the transplanted host that determine the repertoire and function of cells critical to formation of innate immune system, post-transplant, though projects designed to assess reconstitution of NK-cell populations and assess the acquisition of NK-cell self tolerance, the reconstitution of functional subsets of monocytes, reconstitution of dendritic cell compartments, and to develop approaches for ex vivo propagation or in vivo stimulation of donor T-cells that are reactive against antigens expressed on leukemia cells for purposes of adoptive immunotherapy to prevent recurrence of disease.
The Center for Blood and Marrow Transplant Research (CIBMTR) is a data resource which collects consecutive transplant outcomes from transplant centers throughout the world, and by so doing, permits and encourages research on outcomes in transplant that can’t be answered in randomized clinical trials. The database has information for more than 340,000 recipients and data is collected on essentially all of the allogeneic transplants done in the United States. Working committees (19) function in the CIBMTR to design observational research studies utilizing the CIBTMTR database, and the database also is used by investigators in the Blood and Marrow Clinical Trials Network (BMT CTN) to aid in the design of phase 2 and 3 clinical trials in transplantation which are undertaken by the network. A description of the BMT CTN, which is co-funded with the NHLBI, and its functions, is more fully outlined under “collaborations” on this website.
GVHD is a frequent, debilitating, and sometimes fatal condition that results from allogeneic hematopoietic stem cell transplantation (HSCT). While acute GVHD has been researched, investigations into the chronic form of the disease are lacking. This U54 is designed to provide a longitudinal observational study of immune-mediated disorders after HSCT, enrolling patients before onset of chronic GVHD (cGVHD), the biology and treatment of cutaneous sclerosis in a phase 2 clinical trial, as well as a pilot study of treatment of Bronchiolitis obliterans. As such, this study is part of the Rare Diseases Clinical Research Network (RDCRN). A parallel project, funded by an R01 (Improving Outcomes Assessment in cGVHD), assesses multiple measures of cGHVD activity as predictors of short-term and long-term outcomes of this disease.
The goal of this project is to improve the treatment options for GBM by the continuous improvement of herpes simplex virus (HSV) vectors for oncolytic viral therapy. Another goal is to develop serum microvesicles, commonly known as exosomes, as biomarkers for genetic and phenotypic properties of individual GBM tumors. A novel feature of this project involves the use of a nanotechnology-derived hand-held digital magnetic resonance (DMR) probe. The DMR will be used to characterize exosome number and antigenic profile in serum based on proteins critical to oncogenesis, using sera from GBM patients before and during treatment.
The Myeloproliferative disorders (MPD) comprise a family of lethal diseases that include Philadelphia chromosome-negative stem cell myeloproliferative neoplasms (MPN), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). This consortium of 26 academic centers in Europe and North America provides an international program for the study and treatment of this underserved disease group. The goal of the P01 is to develop a deeper understanding of the pathobiology of the MPDs and translate these findings into novel clinical trials. The P01 includes: studies of the genetic basis of clonal proliferation in PV, independent of the JAK2 V617 mutation, a mutation which is highly prevalent in this disease; studies of the dysregulation of the bone marrow microenvironment that cause abnormal trafficking of the CD34+ stem cells of primary myelofibrosis; several novel murine models of MPN; and, in the translation project, several phase 1/2 clinical trials for patients with PV and PMF, a stem cell transplant trial, and a large phase 2/3 trial to treat PV/ET, which will include an additional 17 clinical sites in Europe and the North America. A tissue bank core facility operates in the consortium as a central repository for MPN tissues to handle specimens at diagnosis and during the time-course of trials run in the network, as a unique resource for the MPN research community.
The importance of the bone marrow microenvironment in the pathogenesis of multiple myeloma (MM) forms the basis of this P01. The investigators will assess how the mechanisms whereby plasmacytoid dendritic cells (pDCs) mediate MM cell growth, survival, and drug resistance; assess the role of the Th17 cells and associated pro-inflammatory cytokines in the pathogenesis of MM; and utilize adaptive immunotherapy to overcome host immunosuppressive effects.
A major barrier impeding cure of cancer with current treatment strategies is the inability to effectively kill cancer stem cells. This P01 is designed to: more fully characterize the normal, pre-malignant and rare cancer stem cells in hematologic and solid malignancies for potential new treatment strategies, specifically characterizing the cancer stem cell in acute lymphoblastic leukemia; study the role of GPI-anchor deficiency in a clonal stem cell disorder, paroxysmal nocturnal hemoglobinuria; study the role of FLT3 (a tyrosine kinase) in leukemia stem cells from patients with AML; test microRNA targeting of normal and leukemia stem cell progenitor cells; and finally, using a unique gradient separation technique to isolate functionally homogenous adult bone marrow-derived stem cell populations; complete studies to determine common properties of adult and embryonic stem cells; and isolate epithelial stem cells from multiple tissues and compare these cells with bone-marrow derived stem cells.
The goal of this P01 is to investigate novel biologic approaches toward treatment of hematologic malignances. Two of the projects are specifically addressing targeting cancer stem cells (CSC): in one case by inducing differentiation of the multiple myeloma stem cell, as well targeting the CML stem cells in patients achieving remission to imatinib, to produce treatment-free remissions; in another project, focused on Hodgkin lymphoma cancer stem cell, to better characterize this CSC and their distinctive patterns of DNA methylation as well as plasma tumor markers, and to augment standard therapies with immunologic therapies, specifically a vaccine to elicit T-cell responses to EBV combined with rituximab, which targets the CSC, in combination with high dose cyclophosphamide.
Although various aspects of multiple myeloma (MM) pathobiology have been discovered, it is clear that genomic abnormalities remain the fundamental problem driving the malignant phenotype of this disease. Therefore, oncogenomic analysis, directed toward discovery of new pathways and targets for therapy, are necessary. In this P01, the investigators will first perform a clinical trial to determine whether high-dose chemotherapy and transplantation following induction with novel agent therapy improves outcome compared to novel therapy alone. A second project will characterize the genetic alterations in patients from this trial and determine correlation with outcome as well as characterize the spectrum of genetic lesions associated with progression of the disease from pre-neoplasia conditions to frank malignant multiple myeloma. A third project will define the role of homologous combination as a mechanism of genomic instability in MM. Finally, the genetic changes identified in these projects form the basis for a fourth project, in which, with a robust human MM model system, potential novel targets identified in the other projects will be validated in order to identify the next generation of targeted therapies in this disease.
This grant proposes to identify and characterize genetic variants that determine the effectiveness or toxicity of anti-cancer drugs. Specific aims of this project are: to populate the three-dimensional matrix of drug, gene and phenotype through multiple clinical and laboratory studies; to create tools of value to the Pharmacogenomics Research Network (PGRN) as well as other investigators in pharmacogenomics and the larger genomics community; to share findings through publication, deposition of data, and access to the Pharmacogenomics of Anticancer Agents Research Group (PAAR) databases; and to lead the development of a new PGRN Network Resource in support of research involving cell-based studies. The PGRN is co-funded with NIGMS (see also Collaborations on this website).
This pharmacogenomics project is to validate prognostic signatures in (estrogen receptor positive) ER+ breast cancer patients treated with aromatase inhibitors (AIs); to carry out mRNA gene expression profiling to discover and validate biomarkers for prediction of poor response to AI therapy and elevated relapse risk; and to analyze gene copy aberrations and mutations to determine the molecular mechanisms of resistance to endocrine therapy. The long-term goal is to generate a luminal breast cancer atlas that is annotated for clinical outcomes so that the treatment of ER+ breast cancer can be individually tailored with confidence and the emergence of new targeted treatments can be accelerated.