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Harold Spielberg Research Fund

Simone Feurstein, MD

Pubmed Author Name: 
Simone Feurstein
Grant Year: 
2023
Original Research Center: 
University Hospital Heidelberg, Germany
Research Title: 
Autoimmunity and immunodeficiency in young adults with myelodysplastic syndrome
Summary: 

This research project aims to understand the biology and genetics of the disease myelodysplastic syndrome (MDS) in young patients. MDS is normally a disease of older persons (70+), and this study aims to determine the genetics and biology of MDS in patients diagnosed between the ages of 18 and 40 years old. MDS in young people is a distinct population with a lot of different genetic problems causing illness, most being related to the cell's repair of DNA and parts of the chromosomes. Autoimmune and inflammatory conditions are common in MDS patients and are associated with failures in the bone marrow - a part of the body responsible for making blood cells. However, how common, and how seriously these mutated genes affect patients is unknown. This study will look at the entire genetic profile of 122 patients with MDS. The first step will be to look at variants in genes that are known to predispose persons with those mutations to cancers. Then we will look at genes involved in problems of the immune system in young patients with MDS. This data will be compared to a group of patients who develop MDS when aged 70 or older to see a correlation between the mutations and how those mutations manifest for patients. Afterwards, variants will be assessed to look at the type of mutation present using a variety of techniques. The purpose of this study is to help us better understand the biology of this illness and the genetic changes that cause this illness in young persons. Currently, we use stem cell transplant to treat and/or cure MDS. Knowing more about these variants will help us better choose who can donate stem cells and how to best prepare the patient for that transplant. These data can also help us and the patients to find the safest and best way to make sure that the transplant is successful by tailoring our specific treatment after transplant, which includes medications that suppress the immune system. We currently have little knowledge of how these immune phenomena and MDS in young people are connected. This study will help us to understand if MDS in young persons is a distinct entity and whether it is correlated with inborn genetic mutations or acquired mutations in genes that affect the immune system.

First Year Report: 
Final Report: 
Current Position/Title: 
Physician Scientist
Current Institution: 
University Hospital Heidelberg, Germany

David Beck, MD, PhD

Pubmed Author Name: 
Beck DB
Grant Year: 
2022
Original Research Center: 
New York University Grossman School of Medicine
Research Title: 
Advanced genomic and molecular investigation of acquired bone marrow failure syndromes
Summary: 

Acquired bone marrow failure syndromes, such as myelodysplastic syndrome (MDS), are frequently caused by genetic mutations. Both the underlying mechanism and prognosis of MDS have been attributed to specific driver gene mutations, and genetic classification systems have led to improved clinical outcomes. Bone marrow failure, and MDS have been linked to autoimmune diseases although the clinical relevance of these associations has not been well defined. We identified an acquired mutation in the gene UBA1 that occurs in the earliest progenitors in the bone marrow, and leads to common inflammatory rheumatic and hematologic diseases such as rheumatoid arthritis and myelodysplastic syndrome. Patients with mutations in UBA1 have VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, with increased mortality from a variety of severe inflammatory and hematologic clinical signs, marked in large part by bone marrow failure that occurs late in life. Identification of UBA1 mutations as disease causing is paradigm shifting because it demonstrates the contribution of acquired mutations in common rheumatic diseases, highlights the role of ubiquitylation in inflammation, and reveals the importance of molecular diagnoses to improve clinical care in diseases with overlapping rheumatologic and bone marrow failure symptoms. Here we intend to expand upon these findings and identify and molecularly characterize additional novel, somatic, genetic drivers of acquired bone marrow syndromes, particularly involving overlapping autoimmune manifestations. We have already identified and sequenced a large number of patients with acquired bone marrow failure syndromes using exome and genome sequencing and have identified novel candidate driver mutations in UBA1. We propose here to expand upon these findings beyond UBA1 and perform more in-depth genetic analysis using long read genome sequencing to try to identify structural and non-coding variants that may contribute to VEXAS like phenotype. We will cross reference this data with our deep exome sequencing to both determine the sensitivity of the approach and confirm findings. Finally, we propose to molecularly characterize novel variants identified in UBA1 and those identified through long read sequencing to determine if these mutations are pathogenic. Together, our work will determine new genetic causes of acquired bone marrow failure missed on previous sequencing efforts, while better defining the cellular and molecular mechanisms underlying these diseases (what, where, and when). As a physician scientist, my overarching goal is to use these insights to improve care for patients with unexplained hematologic and inflammatory symptoms. Genetic reclassification, as has already been shown for VEXAS/UBA1 in a short period of time, will lead to improved prognosis and targeted care for patients going forward.

First Year Report: 
Final Report: 
Current Position/Title: 
Assistant Professor
Current Institution: 
New York University Grossman School of Medicine

Salima Benbarche, PhD

Pubmed Author Name: 
Salima Benbarche
Grant Year: 
2021
Original Research Center: 
Memorial Sloan Kettering Cancer Center
Research Title: 
Developing synthetic introns for targeting spliceosomal mutant MDS
Summary: 

We discovered a way to express a gene or protein of interest in cancer cells, but not healthy normal cells. Specifically, we created synthetic (not occurring in nature) introns that we can introduce into any gene of interest, such as a “killer gene,” such that the encoded protein is produced in cancer cells carrying a defined, cancer-causing mutation, but not produced in healthy normal cells that do not carry that specific mutation. These types of cancer-causing mutations are mainly identified in patients with myelodysplastic syndromes, a group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells. We believe that these synthetic introns will enable the development of new cancer therapeutics that are highly specific to cancer cells while sparing healthy cells. We aim to develop this technology to better understand and cure specific blood cancers.
 

Current Position/Title: 
Research Associate
Current Institution: 
Memorial Sloan Kettering Cancer Center

Audrey Lasry, PhD

Pubmed Author Name: 
Lasry A
Grant Year: 
2020
Original Research Center: 
New York University School of Medicine
Research Title: 
Single cell mapping of bone marrow microenvironment during MDS to AML transition
Summary: 

Myelodysplastic syndrome (MDS) is a pre-cancerous disease of the blood, which progresses to the more aggressive acute myeloid leukemia (AML) in approximately 30% of cases. MDS currently affects about 60,000 people in the US, and about 10,000 new cases are diagnosed each year. Life expectancy for MDS patients ranges from 5 months to 3 years, yet therapeutic options for MDS patients are limited.

In recent years, advances in understanding of the immune system have led to a major breakthrough in cancer therapy, with the development of immunotherapy drugs that target the immune system rather than the cancer cells. These drugs are effective in many types of cancer, and have revolutionized treatment for cancers that were often considered untreatable in the past. The effectiveness of immunotherapeutic drugs arises from their mode of action: instead of targeting the cancerous cells, they act by activating the immune system and driving it to target the tumor. Currently, established immunotherapies have yielded modest results in MDS/AML, and they are not offered to patients.

We will set out to map the composition and status of the immune system in different stages of MDS and AML, at high resolution, using advanced genomic technologies. We will then validate our findings in mice, and examine potential candidates for novel therapies. We are hoping to identify novel ways to activate the immune system in MDS, which will pave the way for the emergence of new therapies for this disease.

Current Position/Title: 
Postdoctoral Researcher
Current Institution: 
New York University School of Medicine

Sydney Lu, MD, PhD

Pubmed Author Name: 
Lu SX
Grant Year: 
2018
Original Research Center: 
Sloan-Kettering Institute for Cancer Research
Research Title: 
Therapeutic targeting of spliceosomal-mutant myelodysplastic syndromes with anti-cancer sulfonamides
Summary: 

Recurrent change-of-function mutations in RNA splicing factors are frequent in patients with myelodysplastic syndromes (MDS) and related myeloid neoplasms. Splicing factor mutations most typically occur as heterozygous mutations at recurrent ‘hotspots’ along the amino acid sequence and in a mutually exclusive manner with one another. Although much remains to be learned about how these mutations promote MDS development, recent results from our lab and others have demonstrated that cells expressing these mutations are preferentially sensitive to further alterations to the RNA splicing process.     

Exploiting the selective vulnerability of splicing factor mutated myeloid neoplasms to further splicing inhibition has led to clinical development of drugs targeting core splicing catalysis by inhibiting the function of the spliceosomal SF3b complex. However, the toxicity and efficacy in patients of direct SF3B complex inhibition is not yet known. Fortuitously, mRNA splicing is highly regulated process, requiring a large number of protein complexes and post-translational modifications in addition to protein:protein and protein:RNA interactions. This provides numerous additional potential opportunities to drug the splicing process. To this end, it has recently been shown that a class of anti-cancer sulfonamides selectively degrade the accessory splicing protein RBM39 to inhibit splicing. This class of compounds has previously been administered to cancer patients prior to the discovery of the mechanism of action and their safety profile is well established.

                Sulfonamides co-opt the endogenous cellular ubiquitin ligase machinery and the adapter protein DCAF15 to promote the proteosomal degradation of RBM39. Our preliminary data demonstrate that these compounds preferentially kill MDS and myeloid neoplastic cells harboring spliceosomal gene mutations and that RBM39 regulates splicing of cassette exons. Moreover, we have uncovered that there are important species-specific differences in sulfonamide efficacy, which potentially point deeper into the molecular mechanism of action of these compounds.

The goals of this proposal are now to (1) further study the preferential effects of sulfonamides in preclinical models of MDS based on the presence or absence of spliceosomal gene mutations, (2) clarify the precise residues of DCAF15 required for sulfonamide-induced RBM39 degradation, and (3) further understand the role of RBM39 on splicing and the effects of RBM39 versus SF3B1 inhibition on splicing.  Given the known safety profile of sulfonamides in patients, our proposal has immediate translational importance for patients with MDS.

 

First Year Report: 

We have shown that a class of novel anti-cancer drugs, called the “sulfonamides”, are safe and effective in targeting a protein in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) cells called RBM39. In our studies, the drug was able to inhibit MDS and AML growth, but left normal blood cell growth, development and function undisturbed. We also showed that MDS and AML cells which have RNA splicing factor mutations, a common class of mutations in these diseases, are especially sensitive to the sulfonamides. Given this we are planning to start a clinical trial studying the sulfonamides in relapsed or refractory myeloid cancers, including AML, MDS, myeloproliferative neoplasms, and related disorders.

AAMDSIF Harold Spielberg Research Fund

Shizue Spielberg and her husband, Harold, started funding MDS research through AA&MDSIF in 1998 after he was diagnosed with MDS.  In 1999, following his death, Mrs. Spielberg decided to honor him by establishing the Harold Spielberg MDS Research Fund. Her goal is for us to better understand how to treat and cure MDS.  This fund has been supporting research grants regularly thanks to the generosity of Mrs. Spielberg and her company.

Coleman Lindsley, MD, PhD

Pubmed Author Name: 
Lindsley RC
Grant Year: 
2017
Original Research Center: 
Dana Farber Cancer Institute
Research Title: 
Impact of telomere length and telomerase gene mutations on allogeneic stem cell transplantation outcomes in myelodysplastic syndromes
Summary: 

Myelodysplastic syndrome (MDS) is a diverse group of bone marrow diseases, unified by poor blood counts and a propensity for development of acute leukemia. MDS is most often diagnosed in older adults, arising as part of aging and without a toxic exposure or predisposing medical condition. In rare cases, however, MDS develops as a complication of an inherited bone marrow disease, such as dyskeratosis congenita, which causes a defect in telomere maintenance and have an increased risk of developing MDS and leukemia. Telomeres are caps that protects the ends of chromosomes from deterioration, and are important for preventing premature cellular aging. In preliminary studies in a large international cohort of MDS patients, we found that an unexpectedly high number of MDS patients have inherited abnormalities in genes important for telomere maintenance, that most of these patients were not known to have dyskeratosis congenita, and that their survival after bone marrow transplantation was poor, resulting from an elevated risk of transplant-related complications. Moreover, 3% of patients have rare inherited changes in telomerase genes that are of unknown clinical significance. Our results suggest that inherited variability in telomerase function is important for risk of MDS development, but that current methods for accurately identifying the patients with most risk are inadequate. Therefore, we propose to measure telomere length in the blood cells of MDS patients and correlate with clinical and genetic information. Based on this information, we will perform laboratory analysis of candidate mutations to determine their effect on telomerase function. To complete these studies, we already have samples from more than 1500 MDS patients, collected over 10 years from 130 different institutions, with complete genetic and clinical annotation. In the future, the results of this study may inform the prognosis and choice of treatment for MDS patients, and drive development of better therapies.

First Year Report: 

Myelodysplastic syndrome (MDS) is a diverse group of bone marrow diseases, unified by poor blood counts and a propensity for development of acute leukemia. MDS is most often diagnosed in older adults, arising as part of aging and without a toxic exposure or predisposing medical condition. In rare cases, however, MDS develops as a complication of an inherited bone marrow disease, such as dyskeratosis congenita, which causes a defect in telomere maintenance and have an increased risk of developing MDS and leukemia. Telomeres are caps that protects the ends of chromosomes from deterioration, and are important for preventing premature cellular aging.
In the first year of the award, we have measured the length of telomeres in the entire cohort of 1514 MDS patients across all ages and completed our genetic analysis of telomerase complex genes. We are currently correlating these results with clinical information to determine whether telomere length influences outcomes in MDS patients receiving allogeneic transplantation. Additionally, we have identified a number of patients that have rare inherited changes in telomerase genes that are of unknown clinical or biological significance. We are testing the impact of these rare changes on telomerase function in the laboratory in order to determine whether they may be involved in the process of MDS development in these patients.

Final Report: 

Myelodysplastic syndrome (MDS) is a diverse group of bone marrow diseases, unified by poor blood counts and a propensity for development of acute leukemia. MDS is most often diagnosed in older adults, arising as part of aging and without a toxic exposure or predisposing medical condition. In rare cases, however, MDS develops as a complication of an inherited bone marrow disease, such as dyskeratosis congenita, which causes a defect
in telomere maintenance and have an increased risk of developing MDS and leukemia. Telomeres are caps that protects the ends of chromosomes from deterioration, and are important for preventing premature cellular aging.
During the period of award, we measured the length of telomeres in the entire cohort of 1514 MDS patients across all ages and determined how telomere length influences outcomes in MDS patients receiving allogeneic transplantation. We found that shorter telomere length was associated with worse survival due to an increased risk of early toxicity, specifically among patients receiving intensive conditioning regimens. We also completed our genetic analysis of telomerase complex genes. We found that approximately 3% of MDS patients had mutations in these genes, and that mutations were associated with short telomere length, younger age of diagnosis, and worse survival due to increased
transplant-related toxicity. In the laboratory, we tested 20 different mutations, confirming that most caused inactivation of telomerase function.

Britta Will, PhD

Pubmed Author Name: 
Will B
Grant Year: 
2015
Original Research Center: 
Albert Einstein College of Medicine
Research Title: 
Therapeutic targeting of aberrant stem cells in MDS
Summary: 

Myelodysplastic syndromes (MDS) are the most common hematologic malignancies in the elderly, presenting as bone marrow failure and characterized by disorderly growth and differentiation of aberrant hematopoietic stem and progenitor cells. Bone marrow transplantation is currently the only curative option for MDS. Even though 5-azacitidine (5-aza) has resulted in clinical responses and improvements in overall survival, relapse and refractory disease continue to occur in some patients.

Recent findings show that cancer-initiating cells (CIC) can exist as pools of relatively quiescent cells that do not respond well to common cell-toxic agents and contribute to treatment failure. In fact, we and others have shown that karyotypically abnormal hematopoietic stem cells (HSCs) can survive during 5-aza induced remissions and expand before relapses. As a consequence, future treatments must be directed against those CIC-containing compartments, especially long-lived HSC populations, to develop a lasting cure for the disease.   

Our study will generate further evidence that the characterization of molecular alterations in aberrant HSCs will uncover potent new therapeutic options for future stem cell-directed therapies. Most importantly, our work will inspire further studies that monitor the successful eradication of aberrant and pre-leukemic HSCs during therapy. Ultimately, this will enable us to eradicate functionally altered HSCs suppressing normal blood production in other bone marrow failure syndromes, such as aplastic anemia, or leukemia.

First Year Report: 

Over the last year we have made substantial progress towards evaluating the use of antisense-mediated targeting of aberrant STAT3 expression and activation in leukemic (stem) cells from patients with MDS. Specifically, the comprehensive gene expression analysis of purified hematopoietic stem cells (HSCs) from 100 patients with MDS and MDS-to-AML has been initiated and is currently ongoing (AIM 1). We are collecting further patient material which is processed for global gene expression analysis by RNA-sequencing. We have further generated very exciting and strongly encouraging proof of concept data for using STAT3-ISIS-Rx / AZD9150, a therapeutic Generation 2.5 antisense oligonucleotide (ASO), in the therapeutic targeting of aberrant stem cells in MDS and AML (AIMs 2 & 3).

Specifically, our current data shows that AZD9150 specifically reduces STAT3 networks without compromising other STAT, family members which have been the main obstacle in targeting STAT3 using small molecule inhibitors in the past. Moreover, we found that STAT3 inhibition induced cell death and reduced the growth of leukemic cells, both ex vivo and upon transplantation into mice. We have now also data demonstrating that the AZD9150 is well incorporated into primary patient-derived hematopoietic cells which provides a critical proof of concept to utilize ASO-mediated interference as a novel therapeutic strategy in MDS. Our upcoming liens of experiments will evaluate in detail the efficacy of this novel therapeutic intervention using primary patient-derived stem cells. If we find successful targeting and impairment of aberrant HSCs by AZD9150, this strategy could be implemented in clinical practice in a very short period of time, as it is currently under investigation in clinical phase I trials for advanced lymphoma or solid tumors (NCT01839604 (completed), NCT02417753).

Final Report: 

Final Report:

Lifelong regeneration and maintenance of healthy blood formation (hematopoiesis) critically depends on the correct regulation of gene activation and silencing. We and others have reported aging-associated acquired genetic and epigenetic alterations, some of which have been linked to MDS pathobiology, in the past.

This study evaluated a new therapeutic approach of targeting of aberrant gene activation in immature blood cells to eradicate leukemic (stem) cells in patients with myelodysplastic syndrome (MDS). Owing to the generous support of AA & MDS International Foundation we could establish critical preclinical rationales for the use of a novel and highly specific inhibitor of signal transducer and activator of transcription-3 (STAT3), a signaling-induced gene-regulatory protein, for the treatment of MDS.

We carried out a comprehensive gene expression analysis of purified hematopoietic stem cells (HSCs) from patients with MDS and MDS-to-AML, and found that disease-initiating hematopoietic stem and progenitor cells harbor significant STAT3 over-expression. Importantly, abnormal STAT3 message levels also correlated with decreased overall survival and worsened clinical parameters, indicating functional relevance in MDS pathology (AIM 1).

We have further generated very exciting and strongly encouraging proof of concept data for using STAT3-ISIS-Rx / AZD9150, a therapeutic Generation 2.5 antisense oligonucleotide (ASO), for the targeting of aberrant stem cells in MDS and AML (AIM 2 & 3). Specifically, our collected data show that AZD9150 specifically impairs STAT3-dependent gene activation, sparing other STAT family members, which has been the main obstacle in targeting STAT3 using small molecule inhibitors in the past. Our data further demonstrate that AZD9150 is readily taken up into primary patient-derived hematopoietic cells, which provides a critical proof of concept to utilize ASO-mediated interference as a novel therapeutic strategy in MDS. Importantly, we found that ASO-mediated STAT3 inhibition selectively induced cell death and reduced the growth of leukemic cells ex vivo and upon transplantation into mice, while exerting no detectable molecular or functional changes in healthy immature blood cells. We are currently finalizing our study with a series of experiments evaluating in detail the efficacy of this novel therapeutic intervention for the successful targeting and impairment of aberrant HSCs, which we hope to complete and report by the end of this year. Together, our study provides a strong preclinical rationale for introducing AZD9150 as a new treatment option for patients with MDS. AZD9150 is currently under investigation in clinical phase I trials for advanced lymphoma or solid tumors (NCT01839604 (completed), NCT02417753) and could thus be implemented in the treatment of MDS in a timely fashion.

Archibald S. Perkins, MD, PhD

Pubmed Author Name: 
Perkins, AS
Lead Photo
Grant Year: 
2009
Original Research Center: 
University of Rochester
Research Title: 
Development of Targeted Therapies for 3q26-positive MDS
Current Position/Title: 
Professor - Department of Pathology and Laboratory Medicine (SMD)
Current Institution: 
University of Rochester

Dr. Perkins is an active participant in the clinical hematopathology service as well as a researcher exploring the genes that impact the development of leukemias and other human malignancies. His primary focus

Muneyoshi Futami, MD, PhD

Pubmed Author Name: 
Futami, M
Lead Photo
Grant Year: 
2010
Original Research Center: 
Northwestern University Feinberg School of Medicine and University of Tokyo
Research Title: 
Molecular basis for disordered myeloid growth in Monosomy 7
Final Report: 

Loss of chromosome 7 (“Monosomy 7”) occurs very frequently among adult and pediatric patients with myelodysplastic syndromes (MDS) or bone marrow failure syndromes that progress to myelodysplasia. Monosomy 7 carries with it a poor prognosis, even following a bone marrow transplant. Better understanding why monosomy 7 results in MDS would give rise to newer therapies, more effective and less toxic than bone marrow transplant. One important lead is that monosomy 7 cells express a defective receptor for the blood growth hormone G-CSF. G-CSF stimulates the production of normal whole blood cells. Even though monosomy 7 is common, it is difficult to culture monosomy 7 cells in order to study them. Dr. Futami developed two special cell lines that express the defective receptor. These cells display abnormal proliferation and defective maturation that characterizes MDS cells. He used these two cell lines to identify the biochemical changes that make the monosomy MDS cells different from normal blood cells, and found that defective receptor leads to unusual phosphorylation of Jak2. Dr. Futami and his colleagues expected that this abnormal Jak2 phosphorylation would be treated with novel agents. As expected, a Jak2 inhibitor BSK805 clearly inhibited abnormal growth of cells with defective receptor. He also found that defective receptor leads to abnormal gene expression of transcription factors which cause ineffective maturation of blood cells. These results will provide a clue to develop new types of therapies to correct this disease.

Current Position/Title: 
Adjunct Assistant Professor in Pediatrics
Current Institution: 
Northwestern University Feinberg School of Medicine