Sarcomas

Current Projects
Allison L. Didychuk, PhD

Kaposi's sarcoma herpesvirus (KSHV) is a human oncogenic virus and the causative agent of cancers including Kaposi’s sarcoma, primary effusion lymphoma, and Multicentric Castleman disease. The related human herpesvirus Epstein-Barr Virus (EBV) is even more prevalent than KSHV, and is linked to cancers including Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal carcinoma. Dr. Didychuk [The Rhee Family Breakthrough Scientist] is investigating the mechanisms by which KSHV co-opts the cellular host machinery to produce its own gene products in a manner distinct from other viruses and host cells. A molecular understanding of how herpesviruses hijack the late gene transcription machinery will reveal new therapeutic weaknesses in the viral lifecycle and allow for structure-guided design of novel anti-viral drug targets.

Project title: “Understanding the mechanism of genome packaging in oncogenic herpesviruses"
Institution: Yale University
Named Award: The Rhee Family Breakthrough Scientist
Award Program: Dale Frey Scientist
Cancer Type: Blood, Other Cancer, Sarcoma
Research Area: Virology
Xin Gu, PhD

Regulation of gene transcription is a major mechanism cells use to modify the levels of certain proteins in response to their environment. A specific class of genes called immediate-early genes (IEGs) responds rapidly to external stimuli to adjust downstream gene transcription programs before any new proteins are synthesized. Abnormal expression of IEGs has been implicated in multiple types of cancers, as well as in neurological syndromes like addiction. Despite extensive study, the regulation of IEGs remains poorly understood. Dr. Gu’s work focuses on revealing the molecular mechanisms of IEG expression in cells and establishing model systems to study the physiological and disease-related outcomes caused by misregulation of this process. Dr. Gu [National Mah Jongg League Fellow] received her PhD from MIT and her BSc from Peking University.

Project title: "Characterization of a novel pathway regulating the protein degradation of immediate-early genes"
Institution: Harvard Medical School
Named Award: National Mah Jongg League Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Michael E. Greenberg, PhD
Cancer Type: Gastric, Prostate, Sarcoma, All Cancers
Research Area: Cell Biology
Julia Su Zhou Li, PhD

Dr. Li’s research aims to uncover a missing link between repeated DNA sequences, genomic instability, and viruses. While abnormal expansion of “repeats” has been found at unstable genomic regions, known as fragile sites, that are implicated in cancer growth, the mechanisms and consequences of this genomic instability remain poorly understood. Dr. Li recently discovered a cluster of Epstein Barr Virus (EBV)-like repeat sequences in the genome that breaks when bound by abnormally high levels of EBV antigens. These findings illustrate how a chromosome can be broken in long-term EBV infection, which can threaten genome stability and trigger cancer development. Dr. Li aims to leverage this discovery to advance our understanding of how broken repeats threaten genome integrity for clinical screening of individuals susceptible to EBV-associated diseases, and for the prevention and treatment of disease in these individuals. This research could also lead to the discovery of other virus-like repeats and the potential biological function of these virus-like repeats in our genome.  

Project title: “Uncovering the link between repetitive DNA, genomic instability, and tumor viruses”
Institution: University of California, San Diego
Award Program: Dale Frey Scientist
Cancer Type: Blood, Other Cancer, Sarcoma
Research Area: Chromatin Biology
James J. Morrow, MD, PhD

Osteosarcoma is the most common bone tumor and primarily affects children and adolescents. Unfortunately, treatment approaches and outcomes for osteosarcoma patients have not significantly improved for 40 years. Dr. Morrow’s work is focused on understanding normal bone development and how this development goes awry, giving rise to osteosarcoma. He hopes this improved understanding will lead to new treatment approaches for pediatric osteosarcoma patients. Dr. Morrow received his MD and PhD from Case Western Reserve University School of Medicine, Cleveland and his BS from The Pennsylvania State University, State College.

Project title: "Application of single-cell approaches to investigate the developmental origin and early transformation steps of osteosarcoma"
Institution: Dana-Farber Cancer Institute
Award Program: St. Jude Fellow
Sponsor(s) / Mentor(s): Bradley E. Bernstein, MD, PhD
Cancer Type: Pediatric, Sarcoma
Research Area: Systems Biology
Benjamin A. Nacev, MD, PhD

Sarcomas are a family of tumors for which there are few targeted treatments and outcomes are poor once the cancer has metastasized. Many sarcomas harbor recurrent mutations in proteins, known as epigenetic regulators, that control which genes are expressed and when. Among the regulators most frequently impacted is ATRX, which condenses regions of DNA into tightly packaged chromatin that cannot be accessed for transcription, effectively “silencing” these genes. The effect of ATRX loss in sarcomas is poorly understood, however, and treatments that leverage ATRX deficiency are lacking. Using patient-derived sarcoma cell lines and tumor samples, Dr. Nacev aims to understand epigenetic dysregulation in ATRX-deficient sarcomas, to determine how this affects antitumor immunity, and to identify new therapeutic vulnerabilities.

Project title: "Understanding and targeting chromatin reorganization in ATRX deficient sarcomas"
Institution: University of Pittsburgh
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Jeremy N. Rich, MD
Cancer Type: Sarcoma
Research Area: Chromatin Biology
Esteban A. Orellana Vinueza, PhD

Dr. Orellana Vinueza is investigating whether changes that modify the shape, stability and function of transfer RNAs (tRNAs) play a role in the development of cancer. The tRNA molecules are involved in the process that translates messenger RNA into a protein. Dr. Orellana Vinueza focuses on a tRNA methyltransferase complex that malfunctions in glioblastoma and liposarcoma. He will assess how alterations in the activity of this enzyme affect global patterns of methylation in normal and human cancer cells. Methylation is the process that controls the timing and amount of proteins that are produced in cells. Understanding how this process breaks down may help decipher the mechanisms that drive cancer and guide the development of new treatments.

Project title: "tRNA dysregulation and cancer"
Institution: Geisel School of Medicine at Dartmouth
Award Program: Dale Frey Scientist
Cancer Type: Brain, Sarcoma
Research Area: RNA (RNA processing, miRNA and piRNA mechanisms, enzymatic RNAs, etc.)
Anand G. Patel, MD, PhD

Dr. Patel studies rhabdomyosarcoma (RMS), a fast-growing childhood cancer that can spread from muscles to other parts of the body. Dr. Patel has discovered that each RMS tumor consists of different subpopulations of cells that mimic different stages of early muscle development. He will characterize how chemotherapy or radiation therapy selects for specific subpopulations of resistant cancer cells that survive treatment within both patient tissue and in patient-derived models of cancer. Using this information, Dr. Patel aims to test whether directing therapy against resistant cell subpopulations improves treatment outcomes. Ultimately, the goal of this research is to uncover novel therapeutic targets and drugs for the treatment of pediatric RMS.

Project title: "Targeting the developmental architecture of rhabdomyosarcoma"
Institution: St. Jude Children's Research Hospital
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Michael A. Dyer, PhD
Cancer Type: Pediatric, Sarcoma
Research Area: Chemoresistance
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