Investigators

Summary

Dr. Falo is actively involved in a variety of research projects focused on the prevention and treatment of melanoma and skin cancers, and has research expertise in the areas of cutaneous drug delivery, radioprotection, immunobiology, vaccine design, antigen processing and presentation, dendritic cell biology, and molecular immunobiology and immunotherapy.

Summary

The research in the laboratory of Dr. Fernandez focuses on improving cancer treatment and patient outcomes through various areas:

1. Investigating drug-induced immunogenicity and liver injury.
2. Developing targeted agents for acute lymphoblastic leukemia.
3. Preventing capecitabine-induced hand-foot syndrome.
4. Studying the role of the NFAT transcription factor on immune cells.

The Fernandez lab aims to enhance treatment outcomes by understanding complex biological processes using pharmacogenomic approaches. Our work includes addressing the immunogenicity of protein-based therapeutics, studying drug-induced liver injury linked to chemotherapy, and personalizing treatments for acute lymphoblastic leukemias. Ultimately, our translational research strives to reveal underlying mechanisms, identify druggable targets, and bridge bench work with clinical practice.

Summary

The long-standing interests of our laboratory center on identifying specific mechanisms of human anti-tumor immunity and cancer immunosurveillance. We study T cell and antibody repertoire in cancer patients and in healthy individuals at risk for cancer and factors that influence that repertoire. We were the first to identify a human tumor antigen recognized by human T cells and antibodies, the epithelial mucin MUC1. We showed that tumors express an abnormal form of MUC1 that is recognized by the immune system as a foreign rather than a self-antigen. Studies in mice and primates showed that MUC1 was immunogenic and that anti-MUC1 immune responses can reject tumors. These studies supported multiple clinical trials of a MUC1 vaccine in patients with breast, colon, and pancreatic cancer. Most recently, we began testing a MUC1 vaccine for cancer prevention in individuals diagnosed with MUC1+ premalignant lesions. In addition to being a tumor antigen, MUC1 is an oncogene by virtue of promoting a highly inflammatory tumor microenvironment. We discovered that the tumor form of MUC1 activates NF-kB, binds p65 and translocates to the tumor cell nucleus where it binds to and activates promoters of inflammatory cytokines, such as IL-6 and TNF-a.  MUC1 has been associated with a more invasive cancer phenotype and we have recently deciphered the mechanism by showing that it forms complexes with CIN-85, also previously associated with cell motility and invasion.

While studying MUC1 and another tumor antigen that we discovered, cyclin B1, we made an important observation that many tumor associated antigens (TAA) described by their abnormal expression on cancer cells, are also abnormally expressed in other acute or chronic inflammatory conditions and are therefore more appropriately defined as disease associated antigens (DAA).  These include bacterial infections such as Mumps, viral infections such as chicken pox, and chronic inflammations such as inflammatory bowel disease (IBD). This observation helped us formulate and test a new hypothesis on cancer immunosurveillance. Working in collaboration with epidemiologists and creating appropriate mouse models, we showed that immunity to abnormal self-antigens, DAAs, is generated simultaneously with immunity to pathogens early in life in the course of febrile infections. Immune memory for DAAs contributes to effective immunosurveillance of other pathogen infections throughout life, as well as of cancer that expresses many of those same antigens. Lastly, we are pursuing an idea that the quantity and the quality of immune memory for DAAs is critical for maintaining general immune health. Using genomic and bioinformatics approaches, we are defining a gene expression signature that characterizes individuals with strong immunosurveillance ability versus those that lack that ability and designing DAA-based vaccines to promote immunosurveillance of cancer and other diseases.

Summary

Our research is directed toward developing fundamentally new transformations and highlighting their utility for complex molecule synthesis.

Summary

The overarching goal of my research is to understand the cellular mechanisms that lead to genome instability, focusing on regions of the genome especially vulnerable to harmful environmental exposures. I particularly focus on defining the roles of ADP-Ribose transferase enzymes (ARTs/PARPs) in orchestrating the maintenance of both telomere and centromere integrity when exposed to chronic oxidative stress, a leading cause of tumorigenesis. DNA-dependent PARPs are key components of the DNA damage response and as such, are primary targets in cancer therapies. However, little is known on how PARPs operate at telomeres and centromeres upon oxidative DNA damage induction and how PARP inhibitors affect non-diseased cells in cancer patients. My laboratory’s mission is to therefore develop a research program that will provide a deep mechanistic understanding of genotoxic stress-dependent cancer development and inform the rational design of cancer treatments which will ultimately reveal fruitful in a translational and clinical setting to provide therapeutic alternatives. Beside support from the UPMC Hillman Cancer Center start-up funds, my laboratory is currently funded by (i) an R00 (NCE; NIEHS) to investigate the roles of PARP1 and PARP2 in the repair of oxidative DNA damage and the resolution of G quadruplex structures at telomeres as well their role in regulating telomerase enzyme; and (ii) an MIRA R35 (NIGMS) that investigates the impact of oxidative stress on centromere integrity and cell viability as well the specific roles of PARP enzymes in preserving their integrity. Pending R01 grant proposes to investigate R-loop structures as novel substrates for PARP1 and focuses on uncovering PARP1 function in their resolution.

Summary

Bruce Freeman, PhD is a biochemist and pharmacologist who investigates eukaryotic cell production and actions of chemically-reactive inflammatory and signal transduction mediators (e.g., superoxide, nitric oxide, peroxynitrite, electrophilic lipids). He is presently the Irwin Fridovich Distinguished Professor and Chair of the Department of Pharmacology and Chemical Biology at the University of Pittsburgh School of Medicin. He, is a founding member of the Vascular Medicine Institute and a member of the University of Pittsburgh Cancer Institute. His laboratory team has made seminal discoveries related to the tissue production and target molecule reactions of reactive inflammatory mediators, which in turn reveals the fundamental process of redox reaction-regulated cell signaling. These insights have led to Dr. Freeman's identification and patenting of new drug strategies for treating metabolic diseases, fibrosis, cancer and acute/chronic inflammatory disorders. His team pioneered the concept that nitric oxide has cell signaling and pathogenic actions modulated by reactions with superoxide  (yielding the oxidizing and nitrating species peroxynitrite) and heme peroxidases (leading to biomolecule oxidation and nitration). His laboratory also discovered that metabolic and inflammatory reactions of unsaturated fatty acids yield electrophilic nitro and keto derivatives, products that manifest potent anti-inflammatory and tissue-protective signaling actions. The discovery of nitric oxide reactions with various oxidases and peroxidases has also revealed clinically-significant mechanisms of catalytic nitric oxide consumption that occur during inflammation and metabolic syndrome. His mass spectrometry-based observations of peroxynitrite, peroxidase and electrophilic fatty acid-induced post-translational protein modifications further underscore the significance of redox reactions in regulating cell and organ function. This work has led to numerous issued patents and ~300 peer-reviewed publications in high impact basic science and clinical journals. The Freeman team’s discoveries of the anti-inflammatory and metabolic actions of electrophilic nitroalkenes also led to the incorporation of Creegh Pharmaceuticals and the now clinical stage evaluation of CP-6 in subjects having obesity-related asthma.  Previously, Dr Freeman was Professor of Anesthesiology, Biochemistry and Molecular Genetics and Environmental Health Sciences at the University of Alabama at Birmingham. He was also Vice Chair for Research in the Department of Anesthesiology and Director of the UAB Center for Free Radical Biology. Prior to service at UAB, he trained at the University of California and Duke University, where he also served on the faculty. He has been the recipient of a number of honors, including being named a Fulbright Research Scholar and serving as an invited lecturer at Nobel Forums. He and his lab team have won more than $40 million in extramural funding to support their research activities. Dr. Freeman's academic leadership has also propelled students, fellows and faculty colleagues into prominent basic science, clinical investigator, legal, patent office and pharmaceutical industry positions.