B+ Research Grants

Children with acute myeloid leukemia (AML) having certain tumor proteins do not respond well to chemotherapy. These tumor proteins alter the way in which DNA is packaged in chromosomes and thereby turn on some tumor promoting genes while some tumor suppressing genes may be turned off. Fortunately, these marks can be easily removed and gene expression can be restored using specific drugs with lesser side effects than chemotherapy. We have generated mouse models using leukemic cells from such patients. These models faithfully replicate the human disease. We showed that combining two drugs which reverse these changes can completely cure mice transplanted with leukemic cells. The first goal of this proposal is to expand the study to test the efficacy of the drug combination to include more models. The second goal is to understand how these drugs work together to cure leukemia by using tools to detect the special marks and gene expression. The results obtained from this study will lay the foundation to allow the use of this drug combination in the clinic to treat children with AML.

Diffuse intrinsic pontine glioma, or DIPG, is an incurable brain cancer that mostly strikes young children. The median survival rate is less than one year after diagnosis. To date, there are no chemotherapeutic or targeted agents that have proven to be beneficial for treatment of these cancers. Dr. Becher leads one of very few laboratories around the world that focus exclusively on this type of deadly brain cancer. He is using a novel DIPG mouse model to study the function of proteins that drive tumor growth and to determine how novel anti-cancer drugs can inhibit tumor growth. His goal is to identify the most effective drugs against this type of brain cancer and then translate these findings by testing the drugs in clinical trials for children afflicted with this type of brain cancer. In this application, Dr. Becher is proposing to evaluate the anti-cancer activity of two novel cancer drugs alone and in combination in the newly developed improved DIPG mouse models.

Rhabdomyosarcoma (RMS) is a devastating pediatric sarcoma. There is still no effective treatment for children with relapsed or wide-spread disease. In contrast to adult cancers, RMS has fewer DNA mutations, suggesting that other molecular changes may be driving tumor growth and progression. We have identified 40 potential candidate genes that function to alter DNA structure and packaging in the cells without causing DNA mutations. Previous data suggest that these genes may play a role in RMS. Some of these genes may work together to exert biological effects. My proposed research will apply genome engineering technology to target each individual candidate gene and gene combinations in RMS cells to identify the ones that are essential for RMS tumor growth. New targets identified from the study will be the basis for novel therapy designs to improve survival of RMS patients with advanced disease.

Neuroblastoma is a common and deadly childhood cancer with an overall 5-year survival of less than 50% for high-risk tumors. Tumor initiating cells may drive therapeutic resistance and relapse which accounts for the majority of deaths in neuroblastoma. We have recently discovered a novel regulatory pathway involved in the cancerous properties of neuroblastoma tumor initiating cells. Our preliminary studies have further confirmed the therapeutic potential of using drugs to inhibit this pathway’s role in neuroblastoma cancer cells. In this project, we will determine the role of this pathway in the development of neuroblastoma and devise an approach to inhibit its cancerous activity with the long-term goal of improving neuroblastoma treatments for children diagnosed with this terrible disease.

Natural Killer (NK) cells are immune cells in our body which can kill cancer cells. Cancer cells often escape from NK cells mostly due to insufficient number and low activity of NK cells in cancer patients. Transforming Growth Factor beta is a protein produced by cancer cells which make NK cells less active. We will study the role played by this protein in suppressing NK cell activity in pediatric Acute Myeloid Leukemia patients. We will also use methods to neutralize Transforming Growth Factor beta to enhance NK cell activity and thus develop better treatment for pediatric Acute Myeloid Leukemia.

One of the reasons that curing cancer is so difficult is that tumors are made up of many different types of cells, each with its own behavior and drug susceptibility. Researchers are beginning to appreciate that a small population of tumor cells, called cancer stem cells, are more aggressive and able to survive chemotherapy. Our goal is to understand how cancer stem cells acquire the properties that enable them to persist and metastasize, and to discover new ways to treat cancer by targeting them. In addition to improving treatment efficacy, therapies that target specific molecular pathways are better tolerated by patients. We previously showed that neural progenitors – stem cells that give rise to the nervous system during development – depend on the function of a gene, called microRNA-302 (miR-302); without miR-302, the nervous system does not form properly resulting in death. Our preliminary work in a brain cancer model of glioma shows that miR-302, ordinarily non-active after birth, is turned on in glioma, the most common type of brain cancer. Because miR-302 is active in stem cells, we hypothesize that miR-302 marks the cancer stem cell population in glioma and other related cancers. In this project, we will use multiple cancer models and experimental techniques to test the function of miR-302 in cancer stem cells, specifically on the aggressiveness of brain-related cancers, and will dissect the molecular pathways that control cellular behavior.

Central nervous system (CNS) tumors comprise a diverse group of cancer types and are a leading cause of cancer-related death in children. In addition to surgery, radiation and chemotherapy are the mainstays of treatment and although tumors frequently respond initially, tumor recurrence and treatment resistance is common. Importantly, radiation and chemotherapy treatments also damage healthy developing tissues in children and can cause life-long and devastating toxicities. When effective, most anti-cancer therapies induce apoptosis (programmed cell death) in cancer cells. However, CNS tumors frequently increase their expression of key pro-survival proteins from the BCL-2 family (BCL-2, BCL-XL and MCL-1) to block this form of cell death and support the development of resistance. The recent development of novel medicines that block pro-survival protein function has created an unprecedented opportunity to enhance the chemosensitivity of cancer cells and have already been approved for use in other malignancies. We propose to use cutting-edge tools to measure dependence on pro-survival proteins within pediatric CNS cancer cells in order to determine which cancers are most sensitive to these new therapies. In addition, we will comprehensively define the most effective strategies for combining these new medicines with existing treatments to inhibit the development of therapy resistance and improve cure rates while also reducing toxicities.

Medulloblastoma is a brain tumor that primarily affects children and is the leading cause of cancer-related deaths in children. Currently, 30-40% of children with medulloblastoma die and therapies for treating medulloblastoma have not majorly changed since the 1980s. Recent research has shown that medulloblastoma actually represents many different types of tumors and potential factors driving medulloblastoma development have been proposed. However, these insights have not translated into improved patient outcomes because an efficient approach for validating these findings and for testing new therapies is lacking. We propose to address this critical need by developing an approach that will dramatically accelerate the identification of drivers of medulloblastoma and the testing of new therapies.

Chimeric Antigen Receptor (CAR) T cells, recently approved by the FDA, have revolutionized leukemia treatment. However, CAR T cell solid tumor therapy has been disappointing, because myriad inputs contribute to make solid tumors resistant to immune attack. Indeed, despite our very encouraging initial clinical results using IL13Ra2-targeted CAR T cells in glioblastoma multiforme, benefit is only temporary; CAR T cells vanish from patients within 7 days of administration, and rapidly lose the ability to kill brain tumor cells in culture. Improving CAR T cell persistence will vastly improve their efficacy in treating brain tumors.

Doing this requires us to understand and manipulate protein-level events in CAR T cells, as proteins are the ultimate effectors of cellular function. Identifying proteins responsible for T cell persistence will be critical to keeping CAR T cells from disappearing. The best way to do that is with protein-focused techniques like mass spectrometry and mass cytometry.

I pioneered a groundbreaking technique for using mass spectrometry on small numbers of cells, which has not been possible before. We will use this and other protein-focused techniques, as well as biological models of brain tumors and the immune system, to identify a unique protein signature corresponding to T cell survival and persistence. We hypothesize that these activated protein circuits can be leveraged to improve CAR T cell persistence and efficacy.

Metastatic disease, which is when the cancer has spread throughout the body, is responsible for about 90% of all cancer related deaths. For children afflicted with metastatic osteosarcoma, the most common bone tumor in the pediatric population, it often means a very aggressive cancer that is associated with an extremely poor outcome. Unfortunately one reason for this unacceptable outcome is due our lack of understanding the biology of the metastatic state and identifying better treatment options.
Recently our laboratory has created a new mouse model of metastatic osteosarcoma (OS) that mimics the human tumor development and progression. Using the tumors from this model, we have been able to analyze genes and determine pathways that are functioning abnormally, including the identification of key alterations within metastatic tumors in a key pathway in the cell known as the Wnt cascade.
Our proposal will continue to investigate the exact role of Wnt signaling during metastatic development, or evolution, through both innovative pre-clinical models as well as functional and therapeutic studies. Furthermore, using these models we will test a new therapeutic agent designed to target this pathway that one day can be brought to the clinical care of these patients. Therefore, by gaining a better understanding of the detailed role of Wnt signaling during metastatic development, we will elucidate novel molecular aberrations and further identification of novel therapies.