Dana-Farber Cancer Institute

Dana-Farber Cancer Institute

44 Binney Street

Boston, MA 2115

United States

SWI/SNF Complex and Glucocorticoid Resistance in Pediatric Acute Lymphoblastic Leukemia

Steroids are a highly effective component of therapy for acute lymphoblastic leukemia (ALL). However, patients whose leukemia does not respond to steroid therapy have high risk for relapse and poor prognosis. New understanding of and therapies for steroid resistance are critical to progress in ALL therapy. Cells respond to steroids via the glucocorticoid receptor (GR), which binds DNA and cooperates with the SWI/SNF complex to modify gene expression. The SWI/SNF complex modulates packaging of DNA, thereby controlling access of other proteins necessary for gene expression.

Selective inhibition of nuclear export as a novel therapeutic strategy in AML

Acute Myeloid Leukemia (AML)

Current treatments for children with acute myeloid leukemia (AML) often fail to induce long-term remissions and are also toxic to normal tissues, producing serious acute and delayed sequelae in a substantial fraction of patients. This proposal explores the therapeutic efficacy and the mechanism of action of novel CRM1 inhibitors, such as KPT-330, which appear to be highly selective anti-leukemic drugs. My preliminary results show that these novel CRM1 inhibitors induce rapid and selective cell death in cancer cells when compared to normal cells.

Identification and validation of new therapeutic targets in pediatric leukemia through an aneuploidy-based synthetic lethality screen

Acute Myeloid Leukemia (AML)

An abnormal number of chromosomes, or aneuploidy, is the most common cytogenetic abnormality in cancer. Aneuploidy is observed in 70% of hematologic malignancies and 95% of solid tumors. The ability to target cells based on their chromosome content, consequently, presents a unique and unexploited opportunity in cancer therapeutics. The work we propose in this renewal grant will significantly advance our goal of identifying methods to selectively target and kill aneuploid cancer cells.

Searching for genetic vulnerabilities in osteosarcoma through genome-wide RNAi screening

Osteosarcoma

An emerging concept in cancer drug discovery is that of genotype-specific drugs or drugs that only act in a cancer-specific genetic background. Osteosarcoma, or bone cancer, is characterized by the deletion or mutation of two major cancer-associated genes called p53 and pRb. We hypothesize that loss of p53 and pRb, in the human disease and in our mouse model of osteosarcoma, renders cancer cells particularly sensitive to inactivation of other genes or pathways that are less detrimental in non-cancerous cells.

Targeting the ETS Transcription Factor Rearrangement EWS/FLI in Ewing sarcoma

Ewing Sarcoma

There is an urgent unmet need for more efficacious therapies for childhood cancers. Due to market considerations, however, there is little incentive for commercial entities to develop drugs for pediatric malignancies. Moreover, many of the cancer-promoting, tumor-specific proteins in these pediatric cancers have been considered difficult to target ("undruggable") by traditional drug discovery approaches.

Discovery of New Targets and Pathways for T-ALL Therapy

Acute Lymphoblastic Leukemia (ALL)

For Thomas Look, MD, vice chair for research in the Department of Pediatric Oncology at Dana-Farber Cancer Institute, a Bridge Grant from the Alex’s Lemonade Stand Foundation was critical to his research into the genetic pathways drive T-cell acute lymphoblastic leukemia (T-ALL).

In vivo Analysis of Neuroblastoma Pathogenesis using Transgenic Zebrafish

Neuroblastoma

Neuroblastoma (NB) is an embryonic tumor of the nervous system accounting for approximately 15% of all childhood cancer deaths. High-risk neuroblastomas often worsen despite intensive chemotherapy and relapse is common and almost uniformly fatal. A major problem in being able to treat this childhood disease stems from the heterogeneity of the genetic abnormalities that underlie it, which result in a multitude of disease subtypes that make its treatment enormously difficult.

Using zebrafish to model the molecular origins of pediatric myeloid malignancies and acute myeloid leukemia

Acute Myeloid Leukemia (AML)

Myelodysplastic syndrome (MDS) is caused by the abnormal development of blood cells. Currently, the symptoms of MDS can be treated, but the disease itself remains incurable. About 50% of MDS-cases develop into deadly leukemia. The main reason that MDS is difficult to treat is that it is not a single disease, but consists of many subtypes with different symptoms and different underlying causes. To unravel MDS we need to exploit animal models, such as the zebrafish, that can realistically capture the complex disease and are accessible to experimental analysis in living animals.

Development of a Childhood Leukemia Translational Research Program

Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML)

Despite improvements in outcome over the last few decades, 15-20% of children with acute lymphoblastic leukemia and 40-50% with acute myelogenous leukemia ultimately succumb to their disease. Furthermore, current treatments result in many serious short- and long-lasting side effects. New and more effective therapies are urgently needed to increase cure rates and decrease treatment-related morbidity and mortality.

Identification of New Therapeutic Targets in Pediatric Acute Lymphoblastic Leukemia Through Mosaic Trisomy and Aneuploidy-Based Synthetic Lethality Screens

Acute Lymphoblastic Leukemia (ALL)

Leukemia is the most common type of cancer in children. Despite significant improvements in therapy over the past four decades, leukemia is still a leading cause of cancer-related death among children and young adults. Further improvements in leukemia therapy need to be built on a better understanding of the basic biology of cancer. A common feature of many types of cancer, including leukemia, is an abnormal number of chromosomes. An extra copy of chromosome 21, known as trisomy 21, is a hallmark of pediatric acute lymphoblastic leukemia (ALL).

Alex's Lemonade Stand Foundation for Childhood Cancer