Dr. Didychuk is investigating the mechanism by which the Kaposi’s sarcoma herpesvirus (KSHV) co-opts the cellular host machinery to produce its own gene products in a manner distinct from other viruses and host cells. This research should reveal insights into this unique mode of transcriptional control. KHSV is an oncogenic virus that causes various cancers including, Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease, in immunocompromised individuals.

Dr. Gadek focuses on the Sonic Hedgehog (Shh) signaling pathway, which can be altered in rhabdomyosarcoma (RMS) patients. RMS is the most common soft-tissue sarcoma in children, but survival rates and treatments for high-risk patients have not improved in three decades. Dr. Gadek will examine the timing of tumor development and the role of Shh signaling in tumor location and formation. This may lead to diagnostic markers and tools for identifying high-risk patients with altered Sonic Hedgehog signaling, which could improve treatment options and outcomes.

Ewing sarcoma is an aggressive bone tumor that occurs in children and young adults. Cure rates, particularly when disease has spread, are low with currently available treatments. Dr. Guenther aims to identify critical genes on which Ewing sarcoma cells are dependent for survival, with the goal of discovering weaknesses in these cancer cells that may be exploited to stop cancer growth. CITED2 is of particular interest as a Ewing sarcoma-specific dependency gene based on a genome-wide screen in hundreds of cancer cell lines. In some other cancers, CITED2 is described as important for helping cells repair damage and survive stress, such as when they are exposed to chemotherapy. She has found that CITED2 is present in higher levels in Ewing sarcoma cells than in other types of cancer, and when CITED2's function is turned off in Ewing sarcoma cells, they grow more slowly. She aims to first confirm that CITED2 is critical for Ewing sarcoma survival. She will also investigate what makes CITED2 important in cancer cells, including specific features of Ewing sarcoma cells that contribute to its high levels of activity.  Additionally, she wants to understand CITED2's function in Ewing sarcoma cells, including any role for CITED2 in the repair of damage to DNA after chemotherapy or stress. The goal of this work is to develop new directed cancer therapies for patients with this devastating disease. She hopes that these studies will have an additional impact on the treatment of other cancers where CITED2 has been shown to play a role, including acute myeloid leukemia.

Dr. Li focuses on how cells become cancerous when they have an abnormal number of chromosomes or broken parts of a chromosome. The centromere, which joins two arms of a chromosome, is essential for faithful chromosome segregation during cell division and genome stability. When chromosomes fail to be delivered correctly to each new cell, the abnormal chromosomes may form “neocentromeres” which have been discovered in developmental disorders and cancer. Dr. Li is developing tools to examine and manipulate these neocentromeres, which may lead to a better understanding of how cancer cells evolve and potentially novel anti-tumor strategies.

Dr. McCallum studies a compound, called alanosine, which exhibits anti-cancer activity against cells from sarcomas, mesothelioma, and pancreatic cancer. This compound is produced by a soil-dwelling bacterium. She seeks to elucidate how bacteria produce alanosine. Understanding the genes and enzymes that assemble this molecule will guide the discovery of additional novel chemotherapeutic agents that may be produced by bacteria.

Dr. Neggers is focusing on validating a new drug target for pancreatic cancer. Using large-scale genetic screening, Dr. Neggers discovered that a subset of cancers, including over 50% of pancreatic cancers, selectively require the VPS4A gene to proliferate and grow. When VPS4A is turned off, the cells stop dividing and die. He will study this vulnerability in clinically relevant patient-derived and mouse models of pancreatic cancer to understand how it functions. His research may help confirm whether this gene should be pursued as a significant drug target.

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.

Dr. Sheltzer studies how aneuploidy, or having too many or too few chromosomes in the cell, affects cancer development and treatment. Approximately 55% of breast cancers have an extra copy of one part (called the “q arm”) of chromosome 1. His lab is developing cutting-edge chromosome engineering technology to eliminate the extra copies of 1q from breast cancer cell lines and determine whether this prevents the cells from forming tumors. Additionally, they will test whether aneuploidy causes ovarian cancer cells to be sensitive to any chemotherapies, with the goal of identifying a drug that specifically kills cells with extra copies of chromosome 1q without affecting normal cells. These experiments could lead to highly effective “chromosome-specific” therapies based on aneuploidy.