2018 Research Grants

 

Eleanor Chen
Institution:
University of Washington
Application Title: Virus-mediated gene therapy in rhabdomyosarcoma

Award: $50,000 (co-funded with Infinite Love)

Layman’s Summary:
Rhabdomyosarcoma (RMS) is a rare and devastating cancer of childhood. The two major types of RMS harbor distinct alterations in their DNA. Despite the promising discovery of major genes required to sustained RMS tumor growth, the challenge remains to find the best approach to target these genetic alterations in RMS tumors. My research will use novel genome editing technology to eliminate disease-defining genetic alterations in the tumor DNA of RMS and to test the efficacy of virus-mediated gene therapy approach to deliver gene targeting agents into RMS tumors. The goal of my research is to characterize the role of specific DNA alterations in RMS and to ultimately identify important therapeutic targets to improve survival of RMS patients.

 

Brian D. Crompton
Institution:
Dana-Farber Cancer Institute
Application Title:
Targeting kinase signaling in preclinical models of Ewing sarcoma

Award: $50,000 (co-funded with Rally Foundation)

Layman’s Summary:
Ewing sarcoma is the second most common bone cancer in children. Although cure rates in children with localized disease approach 75%, the treatment has significant toxicity. Moreover, for children with disseminated or relapsed Ewing sarcoma, outcomes are much worse. New and less toxic treatment approaches are needed for this disease. To address this challenge, we performed a screen of Ewing sarcoma tumor cells to identify candidate targets for the development of new treatment approaches. The protein focal adhesion kinase (FAK) was found to be highly active in Ewing sarcoma. In follow-up work we found that FAK inhibitors and aurora kinase inhibitors, another class of targeted therapies, have more potent anti-Ewing activity when used in combination than would be expected, suggesting that drugs targeting these pathways may be effectively combined for treatment of this disease. Both FAK inhibitors and Aurora kinase B inhibitors are classes of drugs that are now in clinical development for cancer patients. In this proposal, we now plan to demonstrate that other targeted agents and chemotherapeutics can be combined with AURKB inhibitors in Ewing sarcoma. We hope that this may lead to clinical trials testing the safety and efficacy of AURKB inhibitors alone or in combination with other agents for patients with Ewing sarcoma. In the current research proposal, we also plan to determine the mechanism by which the Ewing sarcoma is sensitized to treatment with Aurora kinase B inhibition. We believe that understanding these interactions could lead to the discovery of additional therapeutically targets for patients with this aggressive pediatric cancer.

 

Kathryn Lemberg
Institution:
Johns Hopkins University-School of Medicine
Application Title: Glutamine antagonist treatment of malignant peripheral nerve sheath tumor

Award: $50,000 (co-funded with Rally Foundation)

Layman’s Summary:
Malignant peripheral nerve sheath tumor (MPNST) is a type of cancer associated with nerves that occurs either in patients with neurofibromatosis type I or sporadically. Beyond radical surgery, there are no good treatments for these tumors. We found that MPNST cells do not survive when the amino acid glutamine is removed from the environment. Therefore a drug that blocks utilization of glutamine in tumor cells may be a useful therapeutic against MPNST. The drug 6-diazo-5-oxo-norleucine (DON) blocks glutamine metabolism and was previously tested as an anticancer agent in patients. Although DON showed promise, gastrointestinal (GI) side effects (nausea/vomiting, mouth sores, diarrhea) prevented its development as a medication. Our lab has developed modified versions of DON called DON prodrugs that release DON only when the prodrug is taken up and broken down by certain tissues. In animal models our best DON prodrug, JHU 395, shows better nervous system delivery of DON and less GI toxicity. We plan to use JHU 395 in MPNST cells to understand why MPNST cells are sensitive to blocking glutamine utilization. We will study how effective JHU 395 is in eliminating MPNST cells both alone and in combination with other drugs with activity against MPNST. In a mouse model of MPNST we will evaluate whether JHU 395 prevents tumor growth and prolongs survival. If successful, this study could move physicians towards testing inhibitors of glutamine metabolism in humans as treatments for MPNST.

 

Koichi Ogura
Institution:
Memorial Sloan Kettering Cancer Center (MSK)
Application Title:
Modeling, Characterizing, and Targeting STAG2-mutated Ewing Sarcoma

Award: $50,000 (co-funded with The Truth 365)

Layman’s Summary:
Ewing sarcoma (ES) is an aggressive bone cancer occurring in children and adolescents. Essentially ES contains the abnormal fusion of two genes, EWSR1-FLI1/ERG, that creates a protein believed to trigger ES development, but this abnormal protein has proven to be difficult or impossible to directly target with drugs. Therefore our work is focused on identifying other vulnerabilities in ESs that could be exploited for therapy. Aside from the EWSR1-FLI1/ERG fusion gene, these cancers contain very few other changes in their DNA. Among these are mutations that inactivate STAG2 gene. The STAG2 protein is involved in proper cell division, along with a related protein, STAG1, that can perform the same functions. Mutations that inactivate STAG2 are found in 25% of ESs and these are among the most aggressive cases, respond poorly to conventional therapies, and account for a large number of deaths due to ES. Clinically, this is a subgroup of ES that is in greatest need of new treatment options but how STAG2 loss makes ES more aggressive is not understood. Therefore this project aims to: 1) use the latest genome engineering techniques to make ES cell lines that differ only in the presence or absence of STAG2; we will use these cell line models to better characterize and understand how STAG2 affects ES cells; a better understanding may point the way to better therapies for this subset of ES; we will also use these cell line models to screen for drugs that may be specifically active in STAG2-mutated ES cells 2) use the latest therapeutic oligonucleotide approaches to target STAG1. This is because it has been found cancer cells lacking STAG2 become completely dependent on STAG1 for proper cell division. Therefore, inhibiting STAG1 may be an attractive therapeutic option in ESs in which STAG2 is already inactivated by mutation. We hope this work will lead to insights into the biology of ES and pave the way for rational targeted therapies for this highly lethal subtype of ES.

 

William Samsa
Institution:
Case Western Reserve University – School of Medicine
Application Title:
The crucial p53-dependent role of JAB1 in osteosarcoma pathogenesis

Award: $50,000 (co-funded with Rally Foundation)

Layman’s Summary:
Osteosarcoma (OS) is a highly malignant, most common primary bone cancer that predominantly affects the actively growing bones of adolescents. Metastatic OS ranks among the leading cause of childhood cancer-related deaths. Unfortunately, survival rates for OS have not improved in more than 30 years. Therefore, understanding OS pathogenesis is vital for developing better diagnostic methods and improving treatment outcomes. Our laboratory studies a recently discovered gene that is a potential oncogene and is highly overexpressed in OS. This gene has very recently emerged as a novel target for cancer treatment. In this proposed study, we will determine the role that this oncogene plays in causing OS formation in mice. We will genetically engineer mice that do not have this oncogene in bone cells, mate these mice with a mouse model of Li-Fraumeni Syndrome, and observe if spontaneous OS formation is reduced in these mice. We will also use an innovative, potent, highly selective, and orally available drug to inhibit this oncogene so we can determine if it will prevent tumor formation and growth. We will study normal human cells and human OS cells to determine the minimum concentration that inhibits OS growth. We will then use this information to test the drug’s ability to inhibit OS cell proliferation, growth, and migration using a combination of sophisticated molecular biology techniques. Thus, using live animals we will determine the role of a recently identified potential oncogene in the pathogenesis of osteosarcoma and characterize the efficacy of a novel drug to inhibit its formation and growth.

 

Ting Tao
Institution:
Dana-Farber Cancer Institute
Application Title: let-7-Independent Mechanisms of LIN28B in High-risk Neuroblastoma

Award: $50,000 (co-funded with Rally Foundation)

Layman’s Summary:
Neuroblastoma is an embryonal tumor that is often hard to treat successfully, accounting for ~15% of childhood cancer deaths. A gene named MYCN is amplified in approximately 20-25% of neuroblastomas and has been the most common genetic disorder that is associated with poor prognosis in neuroblastoma. Recent studies have identified LIN28B as one of the most frequently implicated predisposition genes and oncogenic drivers in neuroblastomas. Studies of the role of LIN28B in cancers and metabolic diseases so far have mainly focused on a pathway that depends on the ability of LIN28B to bind to the precursor of a microRNA called let-7 and prevent its maturation. To study the role of LIN28B in neuroblastoma tumorigenesis, I developed two stable transgenic zebrafish lines that overexpress human wild-type or mutant (loss of RNA-binding ability) LIN28B in the nervous system. My preliminary studies have shown that overexpression of either wild type or mutant LIN28B dramatically accelerates the onset and increases the penetrance of MYCN-induced neuroblastoma, and surprisingly that a protein called Akt is activated in either wild type or mutant LIN28B and MYCN expressing tumors. The tumors expressing mutant LIN28B and MYCN arise just as rapidly as those expressing wild-type LIN28B and MYCN and the let-7 microRNA family members are processed normally in these tumors. These results lead to my central hypothesis that high levels of expression of LIN28B promotes neuroblastoma initiation and progression through Akt activation via a let-7 independent pathway. My work in this project will not only elucidate the novel pathway, but also establish faithful in vivo models of these signaling cascades in zebrafish, as a first step toward the development and testing of small molecule inhibitors that can kill neuroblastoma cells at doses that are relatively non-toxic to normal tissues.

 

Alessandra Welker
Institution:
Massachusetts General Hospital (The General Hospital Corp.)
Application Title: A Role for Plexin A1 in Tumor Metastasis and Growth in Rhabdomyosarcoma

Award: $50,000 (co-funded with Infinite Love)

Layman’s Summary:
Relapse and metastasis are the major clinical problems facing patients with rhabdomyosarcoma (RMS), a devastating and common childhood cancer of the muscle. The two main subtypes of RMS, embryonal RMS (ERMS) and alveolar RMS (ARMS) differ in their clinical, biological and molecular characteristics and are also distinguished by differences in long-term prognosis. Sadly, greater than 50% of patients with relapsed or metastatic disease arising from either subtype of rhabdomyosarcoma will ultimately succumb to RMS. Treatment for RMS requires surgery to remove the tumor, chemotherapy, and radiation to kill rare cell types retained at the surgical site, with overall poor prognosis for patients with high-risk features including metastasis. Thus, there is great interest in uncovering new drug pathways that can suppress RMS tumor growth and metastasis. In the Langenau lab, we utilize powerful zebrafish, mouse and human RMS models to understand the mechanisms that drive tumor proliferation and metastasis. We have recently performed an unbiased screen to discover novel pathways of metastasis and tumorigenesis in RMS. PlexinA1, a gene that encodes a cellular receptor, came up as one of our top hits. By combining the power of our zebrafish, mouse and human models, my work will test new antibody drugs and small molecules that block PlexinA1 signaling. Importantly, PlexinA1 expression was found in the majority of patients from both subtypes of RMS, while levels are low in normal muscle. Together, my preliminary data indicates that PlexinA1 is an important regulator of RMS tumor growth, metastasis and tumor maintenance. My work will provide much needed pre-clinical data for moving these PlexinA1-inhibitory drugs into trials for relapsed and metastatic RMS.

 

April Weissmiller

Institution: Vanderbilt University Medical Center
Application Title: Probing MYC Recruitment to Chromatin in Pediatric Cancer A Role for Plexin A1 in Tumor Metastasis and Growth in Rhabdomyosarcoma

Award: $50,000 (co-funded with Rally Foundation)

Layman’s Summary:

Neuroblastoma (NB) is the most common tumor found in infants and almost all cases are diagnosed by age five. The mode of treatment for children that have NB is aggressive and invasive, and there is only a 50% survival rate for children classified as having high-risk disease. Despite efforts to identify strategies to treat NB, few new avenues have emerged. In this cancer the amount of a particular protein called N-MYC is increased. The more N-MYC a child has, the worse the diagnosis. The way that N-MYC works is that it physically associates with chromosomes and the result is that thousands of genes no longer behave normally, leading to changes that drive cancer progression.

This research project is centered on the discovery that for MYC to associate with chromosomes and cause tumorigenesis, it must form a direct connection with another protein called WDR5. The goal of this proposal is to see if the N-MYC/WDR5 interaction can be targeted in NB. We believe that if we can inhibit the N-MYC and WDR5 connection, then N-MYC cannot associate on chromosomes, and most of the changes that take place in a N-MYC amplified cancer will no longer happen. With the aid of our first year of funding from this fellowship, we are well on our way to testing this concept with experiments using cancer cells that have a lot of N-MYC and cells that we have introduced N-MYC or a version of N-MYC that cannot bind WDR5. So far our results show that there is a strong connection between N-MYC function and the N-MYC/WDR5 interaction in NB cells. Importantly, we are making great progress in the design of small molecule inhibitors that can target WDR5 and stop cancer cell growth. The goal of this proposal is to continue and complete the work that we initially proposed and are actively working on. We are hopeful that these studies will lead to one of the first targeted therapies that can prove successful in treating neuroblastoma and other pediatric cancers that have increases in N-MYC.