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An NCI-designated Comprehensive Cancer Center, affiliated with the University of Pittsburgh School of Medicine
Research
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Dr. Valerian E. Kagan is one of the world’s recognized leaders and one of the most prominent authorities in the field of Free Radical Biology and Medicine. Internationally known for his profound interdisciplinary studies of oxidative stress, antioxidants, tissue, and cell acute and chronic injury, he has founded a new field of research “Oxidative Lipidomics” and demonstrated its research power in investigations of cell death mechanisms. Free radicals, lipid peroxidation and oxidative stress have been long associated with tissue and cell damage through yet not well characterized specific mechanisms. The incompleteness of this knowledge is a stumbling block in discovery, development and effective implementation of antioxidant preventive and therapeutic strategies. The research performed by Dr. Kagan is a breakthrough in the field as it uncovers specific pathways through which enzymes of oxidative metabolism participate in the production of specific oxygenated lipid molecules that act as signals triggering cell death program as well as mechanisms involved in clearance of damaged or dead cells. Understanding these key signaling pathways is of prime importance for obtaining new insights into mechanisms of radiation injury, inflammation, and immune responses. Based on the discoveries of Dr. Kagan’s lab mechanism-based approaches to creation of novel generations of preventive, protective and mitigating small molecule drugs have been developed that are being tested in a number of conditions.
As Director of the Solid Tumor Cell Therapy Program at UPMC Hillman Cancer Center, I oversee both clinical and research studies aimed at developing effective T cell-based immunotherapies for advanced cancer. We employ an integrated translational approach based upon preclinical in vitroexperimentation, in vivo murine models, and informative human clinical trials. The analysis of clinical results feeds further basic experimentation in an iterative process aimed at elucidating important immunologic principles for the successful treatment of human cancers.
My lab’s cancer research, based on our NCI R01, is to determine if radioprotectants instilled in the urinary bladder prior to irradiation of pelvic or prostate tumors can protect against radiation cystitis without dampening treatment efficacy. We utilize a mouse model of prostate cancer using orthotopic injections of TRAMPC-1 cells, to which mitochondrial targeted free-radical scavengers are instilled into the bladder using novel infrared guidance method; assuring the instillate enters the bladder and not the prostate. Fractionated irradiation is used following a single drug installation to determine the duration of bladder protection; important as multiple instillations can lead to urinary tract infections. As some irradiated tumor cells can become senescent, reestablishing tumorigenicity at a later time, we are also investigating the use of senolytic drugs post radiation therapy. A potential cause of cell senescence is inhibition of mitophagy where damaged mitochondria cannot be cleared from cells for degradation in lysosomes. Nitric oxide (NO•) plays a crucial role in both mitochondrial signaling and cell senescence. We hypothesize that restoring NO•-dependent pathways and increasing cGMP/PKG levels may be beneficial in clearing senescent cells and preventing tumor recurrence and development of treatment resistance. This one (irradiation) – two (senotherapeutics) punch approach offers the potential to eradicate greater numbers of tumor cells and clear any remaining senescent ones, thus treating tumors and reducing risk of their recurrence.
My lab is currently pursuing several projects:
1. The role of TIM-3 in CD8+ T cells
This project currently involves the study of - TIM-3, a novel protein of the T cell immunoglobulin and mucin domain family in regulation of CD8+ T cell function during viral infection (using LCMV as a model system) and responses to syngeneic tumors. We are also interested in elucidating signaling pathways downstream of TIM-3.
2. The role of TIM-3 in regulatory T cells (Treg)
Work from our lab and others has shown that expression of TIM-3 is associated with acquisition of a more potent "effector" Treg (eTreg) phenotype. We are studying how this phenotype contributes to the effects of Treg on immune responses to viral infection and tumors, using both mouse models and correlative studies in humans.
3. Regulation of T cell and mast cell activation by PIK3IP1/TrIP, a novel regulator of PI3K
Dr. Kane's lab has found that a novel transmembrane protein known as PIK3IP1 (PI3K-interacting protein 1) or TrIP (transmembrane inhibitor of PI3K) is expressed in both T cells and mast cells. This protein appears to restrict early activation of both cell types. The lab is currently characterizing mice with inducible deletion of TrIP to better understand how this protein functions in vivo, especially in the context of syngeneic tumors.
As an assistant director of outcomes research, my mission is to assess the value(s) of various treatments and clinical outcomes for cancer care via these tasks below:
1. Establish the infrastructure by collaborating with multi departments for outcomes analyses for cancer treatments.
2. Perform Cost effectiveness analyses and health economics in cancer treatments.
3. Assess various treatment and planning techniques that increase quality and outcomes in cancer care.
4. Serve as NRG oncology physics subcommittee for national clinical trials.
Dr. Kinchington’ s research program focuses on the biology of the human alpha-herpesvirus Varicella Zoster Virus (VZV) and its interaction with human neurons and skin using novel model systems. VZV causes Chickenpox upon primary infection, but then remains with the Host for life in a latent state in sensory neurons. When the Virus reactivates, it causes Herpes Zoster, or Shingles, a painful and debilitating disease that causes significant human morbidity and long-term consequences. Chief among those is the development of long-term, intractable and debilitating chronic pain called post-herpetic neuralgia, or PHN. Zoster also causes many eye diseases that affect vision and even cause blindness, including stromal and retinal disease, ocular inflammation, ophthalmoplegia and total loss of corneal sensation.
Our research addresses two aspects of VZV. The first uses human cultured neurons to understand axonal transport of viruses in neurons, the maintenance of the latent state and reactivation from it. We aim to identify the role of a set of RNAs made during latency termed VLT (For VZV latency Transcript). Human neurons are derived in vitro from human stem cells or progenitors, and we established them as a solid experimental model in which VZV reactivation could be reliably achieved. A second VZV project is to identify the molecular determinants of the attenuation of the widely live attenuated VZV vaccine used to prevent chickenpox. While quite safe in most people, the vaccine is not perfect and sometimes causes a rash or even full-blown chickenpox. It can also go latent and give rise to Zoster. We are evaluating how some of the 200+ changes in the vaccine (compared to its parent) contribute to attenuation, but placing them into wild type virus, and then assessing attenuation in several validated human skin models, as well as in human neuron systems. Together, we may be able to develop an improved vaccine candidate that does not cause skin disease or reactivate to cause zoster.
Dr. Kirkwood’s research focuses upon melanoma immunobiology, therapy and prevention. His translational studies established the first effective adjuvant therapy of melanoma, and identified the immunological basis of this therapy, and are now probing the role of molecularly targeted agents (BRAF, MEK, and PI3Kdelta/gamma inhibitors) that may improve upon the efficacy of anti-PD1 immunotherapy, both in advanced melanoma and in the adjuvant operable high-risk melanoma settings. He has advanced the multimodal therapy of melanoma with surgery, stereotactic radiotherapy, and molecular antitumor agents, displacing chemotherapy in the management of melanoma. He is now pioneering novel clinical trial designs to assess the myriad potential combinations of recently-approved molecular and immunological therapies that are anticipated to be the focus of translational clinical research trials in melanoma for the next decade.
His laboratory is engaged in the molecular and immunohistological analysis of tissues obtained from local institutional, regional, national, and international trials of new therapy. Tumor tissues from patients participating in new modalities and combination therapies, neoadjuvant trials, and prevention interventions are probed using current immunopathological and molecular assessments of signaling pathways, and immune responses to melanoma. Dr. Kirkwood initiated the Biospecimen Repository of the Melanoma and Skin Cancer Program (1996-present, 7,000+ specimens) funded initially through his Specialized Program of Research Excellence 2008-2019, and more recently an endowment that have been promoted research by investigators within and outside the University of Pittsburgh, the Regional Melanoma Translational Research Consortium, the National Clinical Trials Network and the International Melanoma Working Group.
We are currently studying FR901464, a natural product that regulates cancer-related genes by novel mechanisms. This compound inhibits cancer proliferation at concentrations as low as 1 nM. To study FR901464, we completed a chemical total synthesis of this natural product. Combination of this powerful, stereocontrolled chemical synthesis and cell biology will provide insights into the molecular mechanisms of FR901464. More recently, we have developed an exceptionally active FR901464 analog (meayamycin) that inhibits tumor growth at 10 pM (analogouus to one pack of sugar (5 grams) in 400 Olympic swimming pools).
How do different organs and tissues arise? What are the genetic and epigenetic mechanisms that drive this development? To address these questions, we design statistical methods and algorithms and apply them to large-scale, genome-wide data. Ultimately, our goal is to generate, test, and confirm hypotheses that are relevant to human health. Current projects include methods for biology at single cell resolution, disease-specific variant prioritization through non-coding regulator loci, and embryonic development of the heart and eye.
