Modern molecular characterization of tumors of the urinary bladder has illuminated cellular pathways that may be important for bladder cancer development. Dr. Arora is investigating the role played by a family of proteins called nuclear receptors in driving bladder cancer development and progression. These studies will provide insights into the fundamental basis of bladder cancer, while validating potential drug targets. Nuclear receptors are particularly attractive drug targets because they are highly amenable to modulation with drugs. He hopes to pave the way for the development of drugs to effectively target nuclear receptors in bladder cancer.

Neuroblastoma is a cancer of the nervous system that occurs in young children and is often lethal. An improved understanding of neuroblastoma tumorigenesis is urgently needed to catalyze development of innovative and effective therapies. Recent immunotherapy advances have provided optimism for the use of this treatment type in children with neuroblastoma. However, there is a desperate need for new molecules that can be safely and specifically targeted with immune-based therapeutic approaches. Recent work showed that a protein called glypican-2 (GPC2) is abundant on neuroblastoma cells, but not found on normal cells, and that GPC2 helps neuroblastomas grow aggressively. Thus, GPC2 may be an ideal cell surface molecule to target with immune-based therapies. Dr. Bosse seeks to validate GPC2 as a candidate for engineered targeted immune cells in high-risk neuroblastoma. This research will also define how GPC2 promotes cancer growth, thus providing additional critical knowledge for the therapeutic exploitation of an important tumor-sustaining pathway. Finally, this work will help establish a robust pipeline for the identification of novel tumor-specific molecules for immunotherapeutic targeting in pediatric cancer. This blueprint will allow for the rapid translation of prioritized molecules to a clinically available targeted immunotherapeutic, with an aim to make meaningful differences in the clinical care of children with high-risk pediatric malignancies.

Dr. Flynn aims to understand the interplay between cancer metabolism and RNA biology at the level of protein modifications, such as glycosylation. The use of metabolites to fuel cellular processes including cell division and protein synthesis are critical in both healthy tissue and cancer growth. This work will define glycosylation events that respond to and regulate the cancer state within RNA-based networks, thereby establishing new layers of regulation for future therapeutic targeting.

Christopher’s research centers on the earliest steps whereby normal cells transform into abnormal cells with the potential to become cancer. He will focus on better understanding the first steps of the process by which normal blood cells become lymphomas, cancers that are generally thought to arise from blood cells that have already committed to becoming lymphocytes, an important component of the immune system. He hypothesizes, however, that some lymphomas actually arise from earlier hematopoietic stem cells (HSCs). He will interrogate this hypothesis by studying a cohort of lymphoma patients who also have detectable genetic mutations in HSCs that are known to be associated with blood cancers – a condition known as clonal hematopoiesis of indeterminate potential, or CHIP – to determine whether the mutations in the HSCs were the earliest events in the development of the patients’ lymphomas. Having a better understanding of lymphomas’ cellular basis will hopefully allow new insights into their clinical behavior and therapeutic vulnerabilities.

Dr. Kory focuses on cancer cell metabolism. Cancer cells are characterized by rapid and uncontrolled cell growth. To sustain their accelerated growth, cancer cells rely on a constant supply of building blocks produced by specific metabolic pathways. One metabolic pathway, the mitochondrial one-carbon pathway, has recently been found to be especially important for the growth and survival of tumors and correlates with the survival of cancer patients. Inhibiting this pathway is a promising new strategy to treat cancer; however, its key components are still unknown. She aims to identify these components using a genetic screen applying the gene-editing CRISPR-Cas9 system to identify all genes required for its function in human cancer cells. She hopes to elucidate how cancer cells alter their metabolism to meet their high demands for building blocks and energy, which may also lead to the development of new drugs to treat cancers.

Immunotherapy is revolutionizing the clinical management of a variety of cancers. Unprecedented complete responses have been observed in hepatocellular carcinoma (HCC), a type of liver cancer that shows little response to conventional therapeutic approaches. Unfortunately, the clinical efficacy of nivolumab (Opdivo), a novel immune checkpoint inhibitor, is limited to less than 20% of HCC patients. Understanding the determinants of sensitivity and resistance to nivolumab and developing strategies that overcome resistance are therefore urgently needed to significantly improve the clinical management of HCC patients. Dr. Lujambio will combine the use of a novel mouse model of liver cancer and samples from HCC patients treated with nivolumab to identify genes that are involved in intrinsic and acquired resistance to this therapy. These findings will be critical to define biomarkers to select the HCC patients that are most likely to benefit from this immunotherapy. Moreover, a better understanding of the mechanisms of resistance to nivolumab will help design strategies to overcome resistance, providing novel therapeutic options for resistant patients.

Dr. Qu is using Small Cell Lung Cancer (SCLC), a highly metastatic and lethal subtype of lung cancer, as a model to gain a better understanding of brain metastasis. Brain metastases are the most common type of intracranial tumors; they cause morbidity and mortality in a large number of cancer patients worldwide. The lack of preclinical models for brain metastasis has hampered our ability to better understand how primary tumors spread to the brain and grow there. She will first develop in vivo transplant and ex vivo human "mini brain" cancer models to study SCLC metastatic growth in the brain microenvironment. Using these models, she will determine the molecular and cellular mechanisms of metastatic SCLC growth in the brain. This research will suggest new targets for inhibiting growth of SCLC and other cancers at distal metastatic sites in the brain, paving the way for novel treatment approaches for cancer patients.

Dr. Riscal aims to identify and characterize the molecular mechanisms by which a key enzyme involved in cellular metabolism, Fructose-1,6 bisphosphatase (FBP1), suppresses Hepatocellular Carcinoma (HCC) liver cancer initiation and progression. Recent findings comparing HCC tumors and adjacent normal tissues reveal that FBP1 is consistently underexpressed in HCC tumors, functioning as a tumor suppressor in this setting. Since liver cancer is the third most frequent cause of cancer deaths, his goal is to study more precisely how FBP1 opposes liver cancer progression and to help identify novel therapeutic targets for treating patients.

Dr. Roop seeks to advance HIV vaccine design efforts by studying the unique antibody response of infants infected with HIV. The 36 million people worldwide who are infected with HIV are at an increased risk for many forms of cancer. Infants who acquire HIV from their mothers rapidly develop broadly active antibodies that are capable of neutralizing a wide diversity of global HIV strains. An understanding of the developmental processes involved in eliciting this broad and potent response may reveal clues vital to vaccine design efforts. His research will develop a novel experimental protocol that will allow a detailed characterization of these infant antibodies, as well as reveal insights into the unique developmental processes by which they arise.  

Dr. Sabari studies how the three-dimensional architecture of the genome plays a critical role in gene control and is altered in cancer through non-coding mutations. While many well-defined protein-coding mutations have been identified in T cell acute lymphoblastic leukemia (T-ALL), ongoing whole-genome sequencing efforts of patient T-ALL samples are revealing an unexpected level of non-coding mutations within regulatory elements critical for genome architecture. Dr. Sabari is studying how these patient mutations alter the architecture of the genome, lead to alterations in gene control and subsequent development of T-ALL. He will perform comparative analyses of three-dimensional interaction networks in normal, transformed, and genetically engineered cell populations. These studies promise to reveal novel mechanisms of T-ALL initiation and maintenance.