Grant Finder

LLS investigators are outstanding scientists at the forefront of leukemia, lymphoma and myeloma research at centers throughout the world. Search to see the many research projects that LLS is currently funding.

Grant: MCG 6559-18 | Special Grants:

Location:Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803

Year: 2018

Project Title: Therapeutic Development Of Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine In Mesothelin Expressing Childhood AML

Project Summary:

We propose to evaluate clinical and pre-clinical utility of mesothelin directed 
antibody-drug conjugate anetumab ravtansine in childhood AML. Clinical development and pre-clinical assessment of this agent’s efficacy will be conducted in parallel to facilitate timely transition of this agent to children with relapsed AML.

Grant: MCG 6558-18 | Special Grants:

Location:Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024

Year: 2018

Project Title: Therapeutic Development Of Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine In Mesothelin Expressing Childhood AML

Project Summary:

We propose to evaluate clinical and pre-clinical utility of mesothelin directed 
antibody-drug conjugate anetumab ravtansine in childhood AML. Clinical development and pre-clinical assessment of this agent’s efficacy will be conducted in parallel to facilitate timely transition of this agent to children with relapsed AML.

Grant: 7015-18 | Specialized Center of Research Program (SCOR):

Location:Walter & Eliza Hall Institute of Medical Research, Parkville 3050, Victoria

Year: 2018

Project Title: Directly Targeting The Cell Death Machinery To Treat Hematopoietic Malignancies

Project Summary:

Impaired cell death is now recognized as an important step toward the development of cancer, particularly leukemia, lymphoma, and multiple myeloma. Moreover, defects in cell death are also a major barrier to many currently used anti-cancer therapeutics. For the past 30 years, our team has focused on a form of programmed cell death called “apoptosis.” Apoptosis is a normal process in humans and animals and serves as one of the body’s safety mechanisms to assure that cells that have become damaged, for example due to virus infection, errors in their DNA, or trauma, will self-destruct to make way for healthy cells. When this process goes awry, damaged cells continue to survive and can become cancerous.

Apoptosis is controlled by proteins from the BCL-2 family. Some of these proteins, such as the BH3-only proteins BIM, BID, and PUMA, promote cell death by activating the two “effector” proteins, BAK and BAX, which rupture the membrane of the mitochondria, the energy-producing powerhouse of the cell. This, in turn, causes release of factors like SMAC/DIABLO and cytochrome c, which promote activation of caspases, enzymes that snip the cell up into its component parts for demolition and recycling. So-called pro-survival proteins,” particularly BCL-2, MCL-1, BCL-XL and BFL1/A1, prevent apoptosis by blocking the effect of the BH3-only proteins, and also by inhibiting BAX and BAK, making it more difficult for cells to die. In many cancers, the pro-survival proteins are abnormally over-abundant and the levels of the cell death inducing BH3-only proteins are abnormally low, allowing cancer cells to survive and continue to produce daughter cells.

Our research aims to develop drugs that mimic the effects of the apoptosis-inducing BH3-only proteins to block the pro-survival proteins BCL-2, MCL-1, BCL-XL and BFL1/A1 in cancer cells. By harnessing the cell’s own cell death machinery in this way, we believe that we can efficiently destroy cancer cells while still preserving the healthy cells in the body. This would decrease side-effects for patients and would make the treatment more tolerable.

A milestone in cancer research came in April, 2016 when the FDA approved ABT-199/venetoclax, which specifically antagonizes pro-survival BCL-2, for the treatment of refractory chronic lymphocytic leukemia (CLL). This BH3 mimetic was developed by Genentech and AbbVie in collaboration with members of our SCOR team and has paved the way for similar therapeutics to target other pro-survival proteins. Members of our team are currently collaborating with the French pharmaceutical company Servier on an inhibitor of MCL-1, which has recently entered clinical trials of acute myeloid leukemia. 

It is clear that the potential for BH3 mimetic therapy in hematopoietic malignancies is enormous, and we are superbly positioned to advance it. 

Our SCOR consists of five projects and four supporting Cores: 

Project 1, led by Andreas Strasser, will continue to work with Servier on refining MCL-1 inhibitors and on identifying other cellular pathways that might also be targeted to increase the efficacy of these MCL-1 inhibitors. In addition, this Project will commence the development of drugs that target the BFL1/A1 protein, another apoptosis inhibitor that is abnormally abundant in many T-cell lymphomas and leukemias. 

Projects 2 and 3 are our two clinical efforts. Project 2, led by Dr. David Huang and Dr. Andrew Roberts, will work on refining venetoclax (BCL-2 inhibitor) therapy, in particular identifying which patients will respond best to this treatment and which are more likely to be resistant. They will look at the mechanisms that lead to resistance and seek ways to overcome these by combining venetoclax with other established and novel therapies.

Project 3, led by Dr. Andrew Wei and Dr. John Silke, focuses on a different class of drugs, the so-called SMAC-mimetics, which promote apoptosis downstream of the BCL-2 family. They will also design clinical trials combining these SMAC-mimetic drugs with the BH3-mimetics (and with other more conventional therapies) to fight leukemia.

Projects 4 and 5 examine the structure of the different proteins involved in apoptosis and how they physically interact with each other. This is vital for the design of drugs that will target these proteins for therapeutic purposes. Project 4 is led by Dr. Peter Colman and will focus on how BAX is activated by the BH3-only proteins and how individual BAX proteins change their shape and join together to create holes in the mitochondrial membrane leading to cell death. Project 4 will also work with Project 1 on the structure and function of BFL1/A1 to help develop BH3 mimetic drugs to target this inhibitor of apoptosis. Project 5, led by Dr. Jerry Adams and Dr. Ruth Kluck, will collaborate with Project 4 on the structure of BAX and will also study its sister protein, BAK. This project will examine how BAX and BAK become activated. The overall goal of Projects 4 and 5 is to use structural biology to gain insight on how apoptosis may be therapeutically triggered by directly activating the apoptotic inducer proteins BAX and BAK.

Our four Cores will support the projects by providing expertise in genetics, screening, and medicinal chemistry, as well as through the provision of clinical samples and mouse models, allowing us to better translate our discoveries into the clinic.

Our team is arguably the world’s strongest center focused on the link between impaired cell death and cancer. BH3 mimetic drugs offer a validated new therapeutic approach that may well lead to cures for a wide range of blood cancers, and drugs that induce cell death in cancer are also showing promise in these diseases.

Our team is superbly placed to advance these therapies by our expertise on the protein families that control cell death and on the development and therapy of leukemia, lymphoma and multiple myeloma, by our long record of collaboration and high-profile discoveries, by our innovative approaches and unique resources, and by our close ties with both clinical and commercial partners which provide us with a clear pathway from laboratory discoveries to clinical cures.

Grant: MCL7000-18 | Mantle Cell Lymphoma Research Initiative (MCL-RI):

Location:Beckman Research Institute of the City of Hope, Duarte, California 91010-3000

Year: 2018

Project Title: Delivering Unique Immunotherapeutics For Treatment Of Mantle Cell Lymphoma

Project Summary:

City of Hope has a reputation for innovative translational research, and multiple researchers in the proposed application are prominent in the lymphoma field. The institutional commitment to translational science is evident in City of Hope’s investment in research support, regulatory affairs infrastructure, and campus clinical agent manufacturing facilities. Since patients with mantle cell lymphoma (MCL) have poor outcomes with standard therapies, our researchers have been developing MCL immunotherapies, which utilize the body’s immune defense mechanisms. Our projects are unified by a focus on targeting MCL cells using human antibodies or antibody fragments to specifically recognize molecules located on the surface of lymphoma tumor cells. In fact, 3 of the proposed agents to be tested in this grant were developed at City of Hope and will be manufactured here. 
The immunotherapies we propose target a range of MCL-associated molecules and employ novel mechanisms of action. Tumor target specificity is crucial to the safety and tolerability of any immunotherapy. To avoid severe side effects, the ideal target should be present only on MCL cells and not on normal cells. However even with perfect specificity, targeting a single molecule or cellular signaling pathway is frequently insufficient due to tumor escape mechanisms. Therefore we are exploring combining our antibody-based agents with commercial inhibitors of the B cell signaling pathways (BTK, PI3K, Akt) that allow lymphomas to grow and survive in an uncontrolled manner. We are also exploring combining agents between projects, in order to cut off tumor escape routes. 
Project 1: Development of a unique tumor-specific, antibody therapy against mantle cell lymphoma. Using a unique antibody discovery platform to target low-abundance, unique tumor cell markers, we have discovered an antibody fragment that binds specifically to human MCL cells. From this starting point, we engineered a modified antibody that binds highly specifically to MCL (MCL-Ab), with no binding to other subtypes of B-cell lymphomas, nor to normal blood cells or tonsil tissue. This MCL-Ab shows potent anti-tumor activity in mice with MCL. In Specific Aim (SA) 1, we will identify the MCL-Ab target molecule on the surface of MCL cells and confirm the antibody’s specificity for MCL (SA1). The MCL-Ab will then undergo optimization as a product for clinical use in humans as both a diagnostic test for confirming an MCL diagnosis (SA2) and as a potent, MCL-specific therapeutic agent (SA3). Clinical availability of an agent that is truly MCL-specific could be practice-changing in the treatment of this difficult disease.
Project 2: Combining CAR T cells with signaling modulators for treatment of relapsed mantle cell lymphoma. Chimeric antigen receptor (CAR) T cell therapy is a promising new immunotherapy that reprograms a patient’s own immune T cells. T cells are isolated from a patient’s blood and genetically modified with an antibody-derived CAR that targets a specific tumor molecule, and then re-administered to the patient, where the engineered immune cells will recognize and kill tumor cells. CAR T cell therapy is less effective for lymphoma than for leukemia, so we propose combining CAR T cells with 3 oral agents that modulate immune B and T cell signaling: the BTK inhibitor ibrutinib, an Akt inhibitor, and a PI3K inhibitor. In SA1 we propose a clinical trial of ibrutinib for relapsed MCL, followed by CAR T cells that target the CD19 molecule on leukemia and lymphoma cells. We will also test the combined use of CD19 CAR T cells with MCL signaling pathway inhibitors, Akt and PI3K, to improve T cell persistence and potency (SA2). Finally, we plan to modify the MCL-Ab from Project 1 for use as a CAR, with the advantage of improved specificity for MCL (SA3).
Project 3: Targeting oncogenic B cell receptor (BCR)-feedback control in refractory mantle cell lymphoma. Project 3 proposes to target the CD25 molecule that is exposed on the surface of both immune-inhibiting regulatory T cells (Tregs) and MCL cells, using a new CD25 antibody-drug conjugate (ADCT-301), in which the antibody component recognizes CD25 and delivers a potent poison directly to the target cell. In SA1, in a mouse strain with a human immune system, we will use the ADCT-301 to pre-deplete immune-suppressive Tregs and enhance the activity of Project 1’s MCL-Ab and Project 2’s CD19 CAR T cells. We have discovered that CD19 binding or PI3K/Akt inhibition can increase the amount of CD25 present on the MCL cell surface. In SA2, we will augment CD25 surface accumulation using Akt and PI3K inhibitors to maximize targeting by ADCT-301. In SA3, we will combine CD19 antibody or CD19 CAR T cells with ADCT-301 to enhance CD25 surface expression, and thus, ADCT-301 targeting. In funding year 4, we plan a clinical trial of ADCT-301 combined with inhibitor drugs or CD19 agents, depending on preclinical efficacy in SA2/3.
Core A: Pathology and Tissue Bank Core. Core A will provide tissue sample banking services, screen the MCL-Ab for specificity and diagnostic utility (Project 1), characterize tumor samples for the clinical trial (Project 2), and assess the immune status of mice (Project 3).
Core B: Translational Core. Core B will provide project management, clinical trial design, clinical protocol development, preparation of investigational new drug (IND) applications to the Food and Drug Administration (FDA), scientific writing, and regulatory support services.
Altogether, we believe that these projects will increase our understanding of the complexities of MCL and its interaction with human immune defenses. We are also taking multiple approaches to bolstering those immune defenses to more effectively resist MCL. This grant application includes 2 clinical trials of our own novel agents combined with existing MCL signaling inhibitors. These strategies represent potential breakthroughs in MCL treatment and prevention of tumor escape.

Grant: MCL7001-18 | Mantle Cell Lymphoma Research Initiative (MCL-RI):

Location:Joan & Sanford I. Weill Medical College of Cornell University, New York, New York 10022

Year: 2018

Project Title: Longitudinal Functional Genomics In Mantle Cell Lymphoma Therapy And Drug Resistance

Project Summary:

Despite recent therapeutic advances, mantle cell lymphoma (MCL) remains incurable due to its development of drug resistance. With each successive treatment failure comes a more rapidly proliferating disease and fewer treatment options. Our long-term goal is to develop superior therapies for MCL that are effective, well tolerated, durable, and can be individualized for patient treatment. The immediate objectives of our study are (1) to define the genomic basis and molecular mechanisms for drug resistance in MCL via clinical trials of targeted agents and (2) to develop strategies that overcome drug resistance. Our approach goes from the laboratory bench to the patient bedside and back, leveraging our unique blend of scientific and clinical expertise, state-of-the-art technology and reagents developed at Weill Cornell Medicine and Ohio State University.  
  
Before a healthy cell divides, it undergoes an orderly series of events that are governed by special regulatory proteins. In MCL cells, these proteins malfunction, leading to uncontrolled cell proliferation, which ultimately underlies drug resistance and disease progression. Our previous efforts to target one of these regulatory proteins in blood cancers paved the way for FDA approval of palbociclib, a novel drug for cancer treatment. In a separate effort to overcome drug resistance in MCL, we created a novel inhibitor of an enzyme that is dysregulated in many cancers, including MCL. Inhibiting this enzyme restores regulatory pathways and kills some resistant primary MCL cells. The planned project will build on these novel findings and employ three different approaches to develop new therapeutic strategies.  

Project 1: To develop rational treatment strategies for new and recurrent MCL (Peter Martin, Kami Maddocks, Jia Ruan, John Leonard). We aim to develop regimens that are well tolerated and suited to patient stratification. To accomplish this goal, we will conduct a multicenter phase II clinical trial (the PALIBR trial) to define subgroups most likely to benefit from a combination of palocicilib with another key drug, ibrutinib. Results from this study, along with those from Projects 2 and 3, should reveal the mechanisms of drug resistance. We will also explore whether additional strategies can overcome immune-mediated resistance to certain drug combinations. 

Project 2: To discover the genomic basis and mechanisms for drug resistance in MCL  (Selina Chen-Kiang, Lewis Cantley, Olivier Elemento). Results from our phase I PALIBR trial support our hypothesis that altering the cell cycle leads to reprogramming MCL for a deeper, more durable clinical response. By studying the MCL genomes of individual patients in the phase II PALIBR trial over time together with Project 1, we will identify the mutations associated with drug-resistance. 

Project 3: To target the epigenome in MCL  (Jihye Paik and Robert Baiocchi). Our preliminary evidence suggests that non-genomic chromosomal changes (alterations of the “epigenome”) in MCL promote MCL proliferation and survival. Targeting epigenomic activities using our novel inhibitor may therefore circumvent drug resistance and reveal new therapeutic targets. We will thus characterize epigenomic mechanisms in MCL cells, in collaboration with investigators from Projects 1 and 2.

  These innovative and timely projects will be supported by the Administrative Core and the extensive expertise of our Pathology Core (Giorgio Inghirami) and Genomics, Bioinformatics & Biostatistics Core (Olivier Elemento, Christopher Mason and Karla Ballman). We expect that the proposed study will shed new light on the genomic basis and mechanisms for drug resistance in MCL, discover novel resistance biomarkers and develop individualized therapies that overcome drug resistance in MCL – all of which have profound implications for the treatment of other blood cancers. 

Grant: MCG 6561-18 | Special Grants:

Location:The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19178-1457

Year: 2018

Project Title: Targeting CD38 In T-cell Acute Lymphoblastic Leukemia

Project Summary:

Acute lymphoblastic leukemia or ALL is a form of cancer of the white blood cells, characterized by the overproduction and accumulation of cancerous, immature white blood cells known as lymphoblasts. These lymphoblasts can arise from two different cell types known as T or B cells (designated as T-ALL or B-ALL). Both comprise the most common cancer among children and are the most frequent cause of death from cancer before 20 years of age.

T-ALL is a particularly aggressive cancer with a worse prognosis than B-ALL. Significant advances in the treatment of T-ALL have improved outcomes, but not all patients are cured and new treatments are needed. Currently, patients with T-ALL are treated with years of chemotherapy that has significant long-term and short-term side-effects.

One of the most promising modern therapeutic strategies for cancer treatment is immunotherapy. Immunotherapy involves empowering the immune system to kill cancer cells. The immune system is the part of the body that fights infections. One approach has included the use of proteins called monoclonal antibodies that specifically bind to a cancer-specific target expressed on the surface of cancer cells. This causes the immune system to attach and attack the cancer. Daratumumab is an antibody that recognizes a molecule known as CD38. CD38 is found on some cancer cells at very high amounts but is found at very low amounts on normal cells. This drug, daratumumab, has been shown to be very effective for patients with another type of blood cancer called multiple myeloma.

We have evidence that CD38 is expressed at high levels on a cancer cells from most patients with T-ALL. We also have evidence that daratumumab may be very effective against T-ALL cells when we use it in laboratory models of T-ALL.

We propose to test daratumumab in T-ALL. We want to confirm that CD38 is expressed in T-ALL cells both before and after giving patient chemotherapy. We also want to confirm that daratumumab is a good drug to fight T-ALL in the lab. If we confirm both of these are true, then we will open a clinical trial treating children with T-ALL with daratumumab. Our hope is daratumumab will be a safe and effective medicine for patients with T-ALL. We hope it will have fewer side effects than chemotherapy and will improve the chance for curing children with T-ALL.

Grant: 7016-18 | Specialized Center of Research Program (SCOR):

Location:The University of Texas MD Anderson Cancer Center, Houston, Texas 77210-4266

Year: 2018

Project Title: SCOR In High Risk Plasma Cell Dyscrasias

Project Summary:

Multiple myeloma is a cancer of plasma cells and already the second most commonly diagnosed blood-related tumor. Also, because there is an increase in the at-risk population with the aging of America, and a greater percentage of these patients appear to be developing this disease, new cases will grow by almost 60% from 2010 to 2030, ranking it third among all cancers in the rate of increase during this time. Myeloma remains incurable in the vast majority of patients, but the last 10-15 years have seen the development of many new drugs, including proteasome inhibitors, immunomodulatory agents, and, most recently, monoclonal antibodies. These drugs used alone, and especially in combination with each other, have improved patient outcomes, leading to an average survival of 10 years or more from the diagnosis of symptomatic myeloma, making this a success story in the war on cancer. However, patients with myeloma precursor states, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM), continue to progress to symptomatic myeloma, especially if they have higher risk features, through mechanisms that we do not fully understand. Frustratingly, no therapies are approved in this setting, watchful waiting without treatment remains the standard of care, and we still cannot predict for sure which patients will progress and which will not. Moreover, though survival has indeed improved overall, this has been largely in patients with standard risk disease, while those with high-risk symptomatic myeloma subtypes, which can be defined by molecular criteria, continue to have an average survival from diagnosis of only three years, and less than one year if they have relapsed and/or refractory disease. This is in part because our currently available drugs were targeted on features common to all myeloma patients and not developed with an understanding of the various high-risk subgroups, which represent unique types of myeloma. As a result, those with high-risk MGUS and SMM, as well as high-risk symptomatic myeloma, represent a population with a truly unmet and urgent medical need for the development of novel, targeted approaches to improve their outcomes.

Investigators at MD Anderson have been studying the molecular and clinical aspects of myeloma and its precursor diseases for many years. Based on those studies, and on the state of knowledge in the myeloma field as a whole, we became convinced that a better understanding of the molecular and immunologic mechanisms that contribute to the aggressive behavior of high-risk myeloma will uncover weaknesses in these cancers, which can be targeted with new small molecules and immune therapies to improve patient outcomes. Therefore, our specific aims are:

Specific Aim 1:  To study patients with the precursor states MGUS and SMM using advanced tools to understand the molecular and immune features of their disease so we can better predict who is at greatest risk of progression and develop an immunotherapy-based approach that can be personalized to each patient, which will delay and prevent progression to full blown myeloma, thereby avoiding the need for chemotherapy; and

Specific Aim 2:  To develop and study unique models of some of the most common high-risk myeloma subtypes, including those that involve translocation t(14;16), deletion (del(16q), del (17p)), and amplification (amp) 1q21, that will allow identification and testing of novel small molecule and immune-based therapies that will improve outcomes in these patients.

To accomplish our goals, we have assembled an experienced group of myeloma researchers who will work closely together on four projects focusing on high-risk plasma cell dyscrasias. Project 1, led by Drs. Elisabet Manasanch and Sattva Neelapu, is based on studies showing that progression of MGUS and SMM to symptomatic myeloma is enabled by a weakening of the patient’s immune system. They will analyze additional data from ongoing studies of patients with these precursor disease to fully understand the mechanisms involved, to better predict who will progress, and to develop novel immunotherapies that will strengthen the patient’s immune system and prevent progression. Project 2 investigators, led by Dr. Marcelo Aldaz, have found that abnormal function of the WW domain-containing oxidoreductase (WWOX) gene, which is seen in patients with t(14;16) and del(16q), causes an increase in the mutation rate of myeloma cells. They will study a new animal model of this abnormality to understand how WWOX loss contributes to the aggressive behavior of this myeloma subtype, which will help in developing new therapies specifically targeted for this abnormality. In Project 3, led by Drs. Robert Orlowski and Eric Davis, the investigators have developed unique models of del(17p) myeloma by knocking out the tumor suppressor TP53, which is supposed to protect us from developing cancer but can be lost in up to half of myelomas. They are using genomic techniques to identify what weaknesses are uncovered when this deletion occurs in myeloma cells and also how to attack these weaknesses. Finally, the leader of Project 4, Dr. Simona Colla, has been studying genes that are part of the 1q21 region, which is duplicated in a large proportion of patients with high-risk myeloma. She has identified Interleukin enhancer binding factor 2 (ILF2) as one of the key genes in this area, and will be doing additional studies to see how extra copies of this gene make myeloma cells less responsive to chemotherapy, and how this could be overcome.

Taken together, successful completion of these studies will support our goals of rapidly developing, and moving to the clinic, new “designer” treatments that could be personalized to the underlying myeloma and immune microenvironment in patients with high-risk disease, thereby improving their outcomes.

Grant: MCG-15875-18 | Special Grants:

Location:Joan & Sanford I. Weill Medical College of Cornell University, New York, New York 10022

Year: 2018

Project Title: SIRT3 As A Therapeutic Target For Therapy Eesistant B-cell Lymphomas

Project Summary:

Lymphomas are tumors of the immune system. Many of these tumors are
chemotherapy/immunotherapy resistant, but it is not known why this is, and we need a way to save these patients. We identified a protein called SIRT3 as a crucial driver of therapy resistant lymphomas. SIRT3 is uniquely localized to mitochondria, which are the source of energy and production of molecules needed for cells to build their various components. Our early results show that removing SIRT3 from lymphoma cells causes them to literally “die of starvation”. Without SIRT3, lymphoma cells cannot form tumors, grow or survive. However removing SIRT3 does not affect normal cells or the normal immune system. We launched an effort to design drugs that can penetrate mitochondria and specifically target SIRT3. Our SIRT3
inhibitors have powerful effects against lymphoma cells. Here, we will determine how SIRT3 induces chemotherapy resistance and how we can maximally reverse this effect. We will test whether our SIRT3 inhibitors make resistant lymphomas curable, which we expect will result in a entirely new concept in lymphoma therapy: preventing tumor cells from generating the molecular building blocks they need to protect themselves from chemotherapy and immunotherapy treatments. 

Grant: 7017-18 | Specialized Center of Research Program (SCOR):

Location:University of Miami, Atlanta, Georgia 30384-5803

Year: 2018

Project Title: Interventional Epigenetics In Myeloid Malignancies

Project Summary:

Cancers like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) arise due to a combination of genetic mutations and epigenetic abnormalities that sustain the abnormal behavior of cancer cells. The genetic material (DNA) of the cell can be considered a “hard drive” full of instructions that allow cells to grow, have unique functions, and ultimately live or die. Epigenetics, by analogy, is the “software” of the cell, allowing access to the information from the hard disk in a controlled manner. In myeloid cancers like MDS and AML, the genetic mutations often occur in genes that control the epigenetic regulation of gene expression; thus a single mutation can adversely impact the genetic and epigenetic control of cell behavior. While it is not possible to correct the genetic abnormalities in cancer cells, it is becoming increasingly possible to target and reverse the epigenetic abnormalities, and either kill the cancer cell or make it behave more normally. We have assembled a group of highly interactive scientists and physician researchers with expertise in MDS, AML, and epigenetics who are not only defining how these epigenetic abnormalities contribute to blood cancers but are focused on developing therapies that exploit the vulnerabilities that the genetic and epigenetic abnormalities create in cells. Our Center is focused on four research projects that explore different aspects of the epigenetic regulation of cell behavior: a project on histone methylation and its therapeutic targeting in AML (Drs. Ramin Shiekhattar, Arthur Zelent, and Ronan Swords), two projects on mouse modeling of critical epigenetic regulators and their therapeutic targeting (Drs. Feng-Chun Yang, Ross Levine, Omar Abdel-Wahab, and Mingjiang Xu), and a project on histone acetylation and its targeting in AML and MDS (Drs. Stephen Nimer, Phil Cole, and Maria Figueroa). To achieve the aims of the Center, we have enlisted the support of robust epigenomic and bioinformatics cores (led by Drs. Maria Figueroa, Steve Chen, and Sion Williams). As we delve into the fundamental nature of myeloid malignancies, we also aim to develop novel therapeutic strategies aimed at reprogramming the epigenetic abnormalities that underlie the myeloid malignancies.

Grant: MCG 6560-18 | Special Grants:

Location:The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19178-1457

Year: 2018

Project Title: Therapeutic Development Of Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine In Mesothelin Expressing Childhood AML

Project Summary:

We propose to evaluate clinical and pre-clinical utility of mesothelin directed 
antibody-drug conjugate anetumab ravtansine in childhood AML. Clinical development and pre-clinical assessment of this agent’s efficacy will be conducted in parallel to facilitate timely transition of this agent to children with relapsed AML.

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