Program Members

Summary

My laboratory is focused on developing novel clinical models of glioma and identifying druggable targets to facilitate early phase clinical trials.

Gliomas are intensely heterogenous tumors that not only contain numerous cell types, but also demonstrate the ability to transition between different phenotypic states. This complexity has made developing model systems that recapitulate human tumor biology both difficult and essential. Traditionally, models of gliomas are 2-dimensional cell lines and only represent certain subtypes of the highest-grade glioma, glioblastoma. This is because the unique biology of lower grade gliomas has prevented them from being studied either outside of the lab or in animals. We have created ex-vivo culture systems that allow us to investigate critical aspects of the tumor microenvironment, immune response, and discover targets for therapy. Our laboratory has previously shown the ability to establish lower grade glioma organoids in vitro, maintain those cultures for extended periods of time, hibernate, and then reanimate tumor tissue without loss of either genetic or phenotypic fidelity. Our work also includes extensive and sophisticated live-cell imaging analysis that allows for longitudinal, non-invasive assessment of organoid response to treatment.
Our organoid model systems, in addition to glioma stem cell and mouse models, allow us to perform highly sophisticated assessments of drug response across platforms, and identify rare but critical druggable targets in gliomas. These analyses include complex metabolic tracing and immune cell response assessment. Despite the fundamental principles of genomics, immunology, and cellular cancer biology that underlie our work, our group focuses on projects that have high potential for immediate clinical translation.

Summary

Dr. Altschuler's laboratory studies mechanisms of signal transduction by the second messenger cAMP in cell proliferation. cAMP-dependent protein kinase (PKA) and Exchange protein activated by cAMP (Epac) represent the main effectors of cAMP action. Both pathways converge at the level of the small GTPase Rap1b, via its Epac-mediated activation and PKA-mediated phosphorylation. The role of Rap1 activation (Epac) and phosphorylation (PKA) coordinating the early rate-limiting events in cAMP-dependent cell proliferation are studied using a multidisciplinary approach including molecular and cellular biology techniques in vitro, as well as in vivo validation using transgenic/knock in technologies in endocrine tumor models.

Summary

Dr. Barry is interested in breast and gynecologic cancer research specifically related to preoperative and salvage radiation therapies. Dr. Barry is a board-certified radiation oncologist and a Clinical Assistant Professor of Radiation Oncology at UPMC Hillman Cancer Center at UPMC Magee-Womens Hospital.

Summary

Research in my laboratory is focused on cytochrome P450 enzymes (P450), their role in human health and disease, and their potential as drug targets. While most studies focus on steroidogenic P450 enzymes as drug targets for prostate and breast cancer treatment, my goal is to evaluate the potential of targeting fatty acid metabolizing P450 enzymes for cancer therapy. I am particularly interested in the CYP4F enzyme family of fatty acid -hydroxylases which, according to our findings, are upregulated in several cancer type. CYP4F enzymes are involved in the metabolism of arachidonic acid to the potent lipid mediator 20-hydroxyeicosatetraenois acid (20-HETE). While 20-HETE regulates the blood pressure in healthy individuals, it also promotes cell proliferation and migration and tumor angiogenesis in cancer. An unselective inhibition of 20-HETE producing CYP4 enzymes leads to a significant decrease of lung tumor size in mouse models. However, the clinical exploitation of these enzymes has not been realized yet due to high protein sequence similarities, the absence of isoform specific inhibitors, and a substantial lack of structural and functional information. Our long term goal is to establish CYP4F enzymes as novel potential drug targets for cancer therapeutics. Recent efforts in my lab were focused on the isoform CYP4F11 in lung cancer. My team has shown for the first time that a transient CYP4F11 knockdown in lung cancer cell lines leads to decreased cell proliferation and migration which is associated with decreased 20-HETE production. We also generated recombinant human CYP4F11 protein to conduct in-depth biochemical studies to probe enzyme function and to solve structures of CYP4F11 using X-ray protein crystallography. We aim to examine other CYP4F isoforms in various cancer types, unravel their cellular function in addition to 20-HETE production, and solve protein structures for the directed design of selective drugs.

Summary

Dr. Brufsky's research interests include novel clinical therapeutics for breast cancer, bone-breast cancer interactions and therapeutics, molecular biology of metastatic breast cancer, and novel management strategies for metastatic breast cancer. Dr. Brufsky manages approximately 30 clinical trials investigating various aspects of breast cancer etiology and treatment. His main clinical interests are in breast cancer medical oncology with a particular interest in metastatic breast cancer.

Summary

Dr. Bukowinski is an assistant professor of pediatrics at the University of Pittsburgh School of Medicine.  He cares for patients with a variety of oncologic diagnoses covering the spectrum of solid tumors, leukemia, and neuro-oncology. He serves as the UPMC Children's Hospital of Pittsburgh site Primary Investigator for the Pediatric Early Phase Clinical Trials Network (PEP-CTN) for clinical trials for the Children’s Oncology Group.

Summary

My research is focused on clinical and translational studies of soft tissue and bone sarcomas. Currently, I am investigating an immunotherapy utilizing an anti-PD1 inhibitor for patients with advanced sarcomas. In the future, I plan to further study novel immunotherapeutic approaches for advanced sarcomas, particularly with combinatorial strategies.

Summary

Yu-Chiao (Chris) Chiu, PhD, is an Assistant Professor of Medicine in the Division of Hematology/Oncology at the University of Pittsburgh. Dr. Chiu’s research interests include bioinformatics, machine learning, cancer genomics, and pharmacogenomics. The goal of his laboratory is to systematically model genomics and pharmacogenomics to better understand cancer biology and improve cancer therapy. His laboratory has been funded by NIH/NCI (K99/R00 Pathway to Independence Award), NIH/OD (R03 and Administrative Supplement), UPMC Hillman Cancer Center Developmental Pilot Program, Pittsburgh Liver Research Center Pilot and Feasibility Grant, Leukemia Research Foundation, and Fund for Innovation in Cancer Informatics. To date, Dr. Chiu has published more than 100 journal articles and conference articles/abstracts. His research is well-recognized by the broad cancer and bioinformatics communities, including recent publications in Science Advances (highlighted by @NCIgenomics as the #1 favorite paper of 2021), BMC Medical Genomics (selected as Springer Nature Research Highlights in Genetics of 2019), and Bioinformatics Advances. Dr. Chiu’s membership in the Cancer Therapeutics Program of the UPMC Hillman Cancer Center expands the impact of his research by teaming up with clinical, translational, and basic cancer scientists – to bridge cutting-edge computational algorithms to unmet needs in precision oncology.

Summary

The Deiters Lab works in the areas of Chemical Biology and Synthetic Biology, with the goal of developing novel approaches toward a better understanding of human health and disease. This includes 1) the discovery of small organic molecules that inhibit or activate specific biological pathways. Our discovered microRNA inhibitors have therapeutic implications in cancer and viral infections. 2) We are developing methods for specific covalent modification of proteins and cell surfaces with applications in inhibition of protein function and immunotherapy. 3) We are genetically re-wiring the circuitry of cells in order to give new functions to proteins and organisms. Our approach is based on the expansion of the genetic code with synthetic, unnatural amino acids. 4) Light is a unique control element that enables the regulation of biological processes with high spatial and temporal resolution. We are engineering light-responsive nucleic acids and proteins and are applying them to the optical control of cell signaling, gene editing, and protein degradation.

Summary

Dr. Dorritie was previously involved in laboratory research focused on the development of novel therapeutic agents for acute myeloid leukemia. More recently, she has shifted her focus to early phase clinical trials in hematologic malignancies, specifically immune therapies for lymphoma and multiple myeloma. She is a member of the Cancer Therapeutics Team.  She has played a key role in the development of the chimeric antigen receptor (CAR) T-cell and bispecific antibody programs at UPMC and serves as lead or co-investigator on several clinical clinical trials.

Summary

My research is directed towards the development of new therapies for primary and secondary brain tumors using targeted drugs, inhibitors of angiogenesis, and immunotherapies. I am also interested in the identification of molecular markers of prognosis in patients with malignant glioma and other primary brain tumors.

Summary

My clinical and research interests are in the study of improved diagnostics and treatments for patients afflicted with pancreatic cancer. Specifically, in collaboration with researchers at UPMC Hillman Cancer Center and at the University of Pittsburgh, I am active in the following research projects: 1) using surgical drain fluid to perform liquid biopsy for improved staging of patients with PDAC; 2) gamma-delta TIL therapy for patients with metastatic PDAC; 3) radiomics for improved pre-operative staging and risk-stratification for patients with PDAC; 4) novel drug delivery systems for improved regional therapy in patients with metastatic GI malignancies.

Summary

My primary research interests are investigating the effects of external beam radiation therapy on immune status and developing novel radiation therapy techniques for gastrointestinal cancers. Currently, I am working on developing methods for calculating radiation dosimetry to the immune system during external beam radiation therapy and employing these methods to develop new
strategies to reduce immune system dose and mitigate the risk of radiation-induced lymphopenia, which has been shown to be a negative prognostic factor in multiple solid tumors including  pancreatic cancer.

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

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

Summary

As a clinician investigator, I am interested in the development of novel, biologically-informed therapies for relapsed/refractory high grade lymphoma. In particular, my clinical research is focused on understanding the molecular genomic profile of each tumor in order to match it to cognate therapeutic agents, an approach that provides a foundation for precision medicine trials that create individualized treatment regimens for each patient. As part of this effort, I would like to align my research with the investigators in the Precision Medicine Institute and the Center for Immunotherapy. Additionally, I’m interested in investigating the biological underpinnings of virally-mediated malignancies including EBV-driven Hodgkin lymphoma and HIV associated cancers. To that effect, I have studied the effects of checkpoint blockade (CPB) in HIV-associated Kaposi’s sarcoma. This study was the first report to demonstrate the high efficacy and tolerability of CPB in this disease space and was subsequently recognized in an AACR press release. The development of novel agents and new effective combinations based on improved understanding of tumorigenesis has been the main goal of my academic career.

Summary

Dr. Geyer’s research interests include the design, implementation, and analyses of phase III clinical trials in early breast cancer that evaluate new therapeutics and diagnostics with potential for changing existing standards of care. More broadly, his focuses include immunology and immunotherapy, cancer therapeutics, biology and virology, and genome stability. Dr. Geyer has co-authored more than 100 peer-reviewed publications and served as co-chair of steering committees for practice-changing international phase III studies such as the KATHERINE and OlympiA trials.

Summary

My research as a neurosurgeon-scientist has focused on the translation of new therapies and intraoperative visualization of glioblastoma (GBM). I direct the Brain Tumor Nanotechnology Laboratory in the Hillman Cancer Center studying the use of magnetic iron-oxide nanoparticles (MIONPs) for the targeted imaging and magnetic hyperthermia therapy (MHT) of GBM after convection-enhanced delivery (CED). This collaborative and translational NIH- funded research involves Johns Hopkins University and Penn State University developing a new treatment for GBM. My research is also focused on the study of fluorescence-guided surgery (FGS) and photodynamic therapy (PDT) of GBM. My team was the first to use Gleolan (5-ALA) and perform FGS on a GBM patient in the US in 2011. We also led the FDA effort for approval of 5-ALA (Gleolan) in the US in June 2017.

Summary

Dr. Ikeda’s research interests focus on furthering the understanding of the various cellular mechanisms that regulate urinary bladder contractile and storage functions, as well as determining the consequences of neurogenic injury, chemical cystitis and ionizing radiation exposure to the lower urinary tract to elucidate novel therapeutic agents. Dr. Ikeda is currently investigating the senotherapeutic actions of soluble guanylate cyclase activators on radiation-induced cell senescence in the urinary bladder and orthotopic prostate tumors. This project is supported by the Hillman developmental pilot award and has since been expanded to a multi-PI R01 submission (R01CA285362) submitted with Dr. Anthony Kanai. 

Summary

1) Acute myeloid leukemia (AML) in older patients: My research focuses on developing strategies to improve treatment outcomes for older patients with AML. I oversee clinical trials that are focused in older AML. 2) Chronic graft-versus host disease (GVHD): Another focus is in the study of chronic GVHD and long-term follow-up of allogeneic stem cell transplant patients. I run our chronic GVHD and transplant survivorship clinic, and oversee clinical trials in acute and chronic GVHD.

Summary

Dr. Johnston has over two decades of drug discovery experience in the pharmaceutical, biotechnology and academic sectors. Since joining the University of Pittsburgh Department of Pharmacology & Chemical Biology in 2005 to help design and build the infrastructure for a high-throughput drug discovery screening center at the Drug Discovery Institute, Dr. Johnston has led 21 screening campaigns, and reconfigured the NCI 60 cell line assays for cancer drug combination screening. In 2011, Dr. Johnston joined the Department of Pharmaceutical Sciences in the School of Pharmacy to establish chemical biology laboratories, where he has continued to conduct his research in high-throughput and high-content screening (HTS/HCS) assay development and implementation, and to establish drug discovery collaborations throughout the scientific community. His research has focused on pursuing chemical biology approaches to identify small molecules with the potential to be developed into new therapies for prostate cancer, melanoma and head and neck cancer.

Summary

I am PhD investigator and medical physicist with expertise in radiopharmaceutical dosimetry and modelling as well as PET- and SPECT-imaged based dosimetry. During my PhD studies, I developed small scale/micro dosimetry models for the thyroid gland to calculate the radiation absorbed doses when treated or exposed to α-particle or Auger-electron emitting radiohalogens (e.g., Astatine and Iodine isotopes). My post-doctoral work and research as a faculty at Johns Hopkins University focused on pre-clinical and clinical projects regarding image quantification and dosimetry of radiopharmaceutical therapy and diagnostics. I have worked extensively on pre-clinical studies using α-particle emitting radiopharmaceuticals for treatment against metastatic breast, prostate and melanoma cancers. This includes ex vivo imaging and quantification of organs/tissues of interest with the iQID-camera system, helping to determine the microscale distribution and activity concentrations of the α-particle emitting radiopharmaceutical within normal organs/tissues and tumors. I incorporate these iQID-camera images with dosimetric models to more accurately calculate and translate estimated radiation absorbed doses from pre-clinical models to the clinic. My research focuses are to develop improved analysis for dosimetry of targeted radiotherapeutics by incorporating and developing non-invasive imaging techniques (i.e. PET- and SPECT-imaging), microscale dosimetry models based on iQID-cameraimages, and more extensive evaluation of short and long-term toxicity of targeted α-particle therapy (TAT), particularly those with complex decay pathways.

Summary

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.

Summary

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.

Summary

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).

Summary

My broad areas of expertise include human hematopoietic and leukemia stem cell biology. My research is focused on (1) understanding miRNA control of the molecular and signaling pathways that direct the cellular fate of normal and malignant human hematopoietic stem and progenitor cells and (2) elucidating the developmental, cellular and molecular origins of adult and pediatric leukemia. My research is guided by multi-omic analysis of primary patient samples/tissues and utilizes functional genomics in combination with xenotransplantation into immune deficient mice.

Summary

Dr. Li has broad knowledge in medicine, biology, and drug and gene delivery and has established a strong research program centered at the interface of biology and biotechnology. 
His lab has developed several novel delivery systems that are aimed to solve major issues in his fields through improved understanding of the fundamental aspects of drug formulations and comprehensive structure-activity relationship (SAR) study. His group proposed the concept of “new amphiphilic surfactants with interfacial drug-interactive motif”, which has helped to solve the problem of formulating many “hard-to-formulate” drugs (Molecular Pharmaceutics, 2013; Biomaterials, 2015). Another breakthrough from Dr. Li’s group is the development of ultrasmall nanocarriers for improved cancer treatment (Theranostics, 2020; Biomaterials, 2021, Materials Today, 2023). Dr. Li’s group has discovered that covalent coupling of nucleosides-based drugs (such as gemcitabine, azacitidine, cytarabine, decitabine, and others) into an amphiphilic polymeric carrier led to a drastic reduction in sizes from ~150 to ~15 nm. This system is highly effective in codelivery of various front-line water-soluble and water-insoluble drugs. Due to its ultrasmall size, this technology holds promise in overcoming the challenge of ineffective tumor accumulation and penetration seen in cancer patients. More recently, his group has developed another new delivery system that is highly efficient in tumor accumulation through targeting CD44 on tumor endothelial cells (ECs) (Nature Nanotechnology, 2023). This system is suitable for delivery of small molecules or nucleic acids alone or codelivery of both types of therapeutics.

In addition to the development of improved delivery systems, Dr. Li’s group has sought to uncover new mechanisms involved in resistance to chemotherapy and/or immunotherapy. His lab has recently identified glutamate metabotropic receptor 4 (GRM4) as a novel negative regulator in antitumor immunity in multiple tumor models (Science Advances, 2021). More recently, Dr. Li’s group has identified Xkr8 as a novel gene that is critically involved in chemotherapy-induced immune suppression and cancer relapse, suggesting a new combination therapy via targeting Xkr8 (Nature Nanotechnology, 2023). 

Summary

Dr. McAuliffe focuses on the surgical treatment of all breast diseases, with special interest and research emphasis on invasive lobular breast cancer, de-implementing low-value breast surgical care, pre-invasive neoplasms such as DCIS and LCIS, premenopausal and elderly breast cancer, breast conservation therapy, locally advanced breast cancer and axillary management. She collaborates with the Breast Disease Research Repository for breast biospecimens and leads several breast surgery clinical trials.

Summary

I am a physician scientist in radiation oncology with a focus on identifying targetable mechanisms of pancreatic cancer resistance in the laboratory, and dose escalated hypofractionated radiation therapy in the clinic. Over the course of my education and training, I have developed the expertise and skills to pursue my primary goal of identifying and solving research problems whose solutions can bring increased quantity and quality of life to my patients. I have a broad range of medical and scientific experience, and have been the most fulfilled when answering questions that could have a clear impact on the lives of patients I have met over the course of my career.
My primary long term research interests lie in the study of therapeutic resistance in cancer, and the discovery of targetable mechanisms by which response to cancer therapies can be enhanced. My postdoctoral and now current laboratory focus is on the interplay of stromal signaling with therapeutic resistance and metastasis in pancreatic cancer, and how the tumor microenvironment changes in response to radiation therapy. These interactions can dramatically affect the response radiation therapy and targeting them has the potential to substantially alter clinical outcomes. My lab utilizes orthotopic and metastatic mouse models to study the cellular and intracellular mechanisms of radiation sensitivity and resistance, and the ensuing immune and tumor microenvironment response, with the goal of discovering new therapeutic targets to synergize with current treatment modalities. We are currently studying the role of alpha and gamma secretases in modulating paracrine stromal signaling, and the effect of inhibition of these protein complexes on tumor response to radiation therapy. We are also investigating the impact dysregulated lipid metabolism on the suppressive pancreatic cancer immune microenvironment. My goal is to develop novel combination therapies to be brought back to the clinic, improving responses to therapy and overall clinical outcomes. 
Recent and Ongoing Projects: The role of ADAM10 in driving fibrosis and therapeutic resistance in pancreatic ductal adenocarcinoma: My postdoctoral research in the lab of Sana Karam, and the primary current focus of my lab is studying mechanisms of stromal crosstalk, fibrosis and immune infiltration in the PDAC tumor microenvironment. We identified through TCGA analysis that low expression of both EphrinB2 and ADAM10 confers an excellent prognosis, but overexpression of either leads to poor clinical outcomes. Through RNA sequencing analysis of PDAC tumors prior to treatment with neoadjuvant SBRT we found that high expression of ADAM10 and EphrinB2 was a poor prognostic sign in this cohort. We also found in orthotopic mouse tumors that ADAM10 expression was upregulated following RT. We hypothesized that induction of ADAM10 in response to cytotoxic therapies can lead to activation of the EphB4/EphrinB2 complex resulting in increased fibrosis, then driving aggressive tumor biology and resistance to cytotoxic therapies. We found that EphrinB2 cleavage produces a detectable biomarker of radiation induced fibrosis in patient plasma samples after treatment with SBRT. We also found that pharmacologic inhibition of ADAM10 abrogates radiation induced fibrosis in mouse tumors and enhances tumor killing by RT. By knocking out ADAM10 in tumor cells we dramatically altered the tumor proteome following RT, blocking induction of fibrotic matrisome protein expression, and leading to substantial increase in the efficacy of RT in orthotopic and metastatic models. My lab continues to study the impact of ADAM10 on tumor fibrosis, EMT and metastasis through its downstream targets, with the goal of developing therapeutic strategies targeting these pathways. This work was funded by grants from the RSNA and Cancer League of Colorado, and resulted in a first author publication in Cancer Research. 
Tumor fibrosis and immunosuppression through tumor cell activation of fibroblast notch signaling:
We are currently investigating multiple mechanisms of tumor-stromal crosstalk and how manipulation of these interactions can alter tumor sensitivity to radiation and cytotoxic therapies, as well as facilitate a more permissive tumor microenvironment to allow for anti-tumor immune responses. Stromal activation and fibrosis contributes heavily to immune suppression in PDAC by preventing immune cell infiltration and promoting suppressive polarization of macrophages, lymphocytes and MDSCs. Another key downstream target of ADAM10 cleavage involved in fibrosis and EMT is the Notch pathway. Notch is key mediator of cell surface signaling, and requires cleavage by ADAM10 and the gamma secretase complex to translocate to the nucleus and activate transcription. Notch is involved in many aspects of development and is dysregulated in KRAS driven malignancies like PDAC, impacting tumor cell survival, migration, invasion as well as stromal activation and immune cell polarization. 
We have found that blocking Notch cleavage through gamma secretase inhibition can dramatically sensitize syngeneic orthotopic tumors in vivo to radiation therapy, though this effect is much less significant in vitro. We have also found that PDAC tumor cells can activate notch signaling in fibroblasts in vitro, which is abrogated by gamma secretase inhibition. We are currently investigating the effects of genetic and pharmacologic manipulation of notch processing on tumor cells, fibroblast and immune cells within the tumor microenvironment. We hypothesize that tumor cells promote mesenchymal notch signaling, leading to fibrosis and immunosuppression within the tumor microenvironment. We are testing whether the clinically available gamma secretase inhibitor nirogacestat can enhance tumor response to radiotherapy and immunotherapy by blocking myofibroblast activation and stromal fibrosis. This project has been funded by the RSNA Research Scholar Grant, and is currently funded by ACS Clinician Scientist Development Grant CSDG-22-119-01-ET (2023-2027). This work was selected for an oral presentation at the 2023 ASTRO conference and a manuscript is in preparation. 
Tumor cell orchestration of TME immunosuppression through lipogenesis and recruitment of ApoE:
Our other main focus is the role of tumor cell orchestration of immunosuppression through metabolic manipulation of the tumor microenvironment. We are investigating mechanisms by which PDAC tumor cell lipogenesis promotes macrophage infiltration and suppressive polarization, preventing activation of an antitumor immune response. We found that one of the most overexpressed proteins in the microenvironment of mouse and human PDAC tumors is the lipoprotein ApoE. ApoE is a crucial protector against atherosclerosis as well as Alzheimer’s disease. ApoE is a key mediator of cholesterol metabolism, present in a variety of lipoprotein particles. Knockout or mutation of ApoE can lead to accelerated atherosclerosis as well as development of B-amyloid plaques. ApoE secretion in atherosclerotic plaques promotes M2 macrophage polarization, preventing an autoimmune response, promoting plaque regression and fibrosis. 
PDAC tumor cells have large alterations in their lipid metabolism, overexpressing the enzymes mediating lipogenesis, greatly upregulating fatty acid synthesis downstream of glycolysis. RT has been shown to oxidize lipid particles, as well as elevate lipid levels in normal tissues for weeks following exposure. By mass spectrometry analysis, we found that ApoE expression in the PDAC TME is increased by high dose RT in a manner dependent on ADAM10. We have also found that neoadjuvant SBRT leads to an upregulation in ApoE in patient tumor samples, in addition to a downregulation of the LDL receptor, which binds ApoE containing lipid particles. 
We hypothesize that de novo tumor lipid synthesis serves to recruit macrophages, which secrete ApoE to incorporate these excess lipids into lipoprotein particles, promoting M2 macrophage polarization, immunosuppression, and fibrosis. We further hypothesize that RT enhances this lipid synthesis, recruiting ApoE expressing macrophages, resulting in the late treatment effects of fibrosis and immunosuppression. This could represent a novel and targetable mechanism by which through lipogenesis PDAC co-opts physiologic atheroprotective immunosuppression to foster a cold immune microenvironment. Targeting tumor lipogenesis in conjunction with tumor-directed RT has potential to enhance the immunostimulatory effects of RT while mitigating its immunosuppressive and pro-fibrotic effects. We are currently further testing these hypotheses to examine the impact of modulating lipogenesis and ApoE expression on response to radiation as well as immunotherapy.

Summary

I am an assistant professor of radiology and the co-director of the preclinical in vivo imaging facility (IVIF) at UPMC Hillman Cancer Center. I have expertise in molecular imaging (PET, SPECT, optical), organic synthesis, peptide synthesis, conjugation and radiochemistry, targeted radiotherapy (α and β), and animal model of cancer. My research focus is on the development of novel radiopharmaceuticals for molecular imaging and targeted radiotherapy therapy. As the co-director of the IVIF I help investigators incorporate pre-clinical imaging to enhance their research through the IVIF as well as develop novel targeted. In addition, the IVIF provides laboratory support for clinical trials investigating radiopharmaceuticals at UPMC.

Summary

I am a clinical scientist in the department of Radiation Oncology whose academic career is focused on the rational use of radiation therapy in the context of multidisciplinary cancer therapeutics, specifically focusing on the role of radiation therapy with immunotherapy. I have active collaborations with Drs. Jason Luke and Riyue Bao in the TIIL lab to leverage complex datasets to identify optimal patients for whom radiation therapy might be most beneficial. I am committed to an investigative career at UPMC HCC and foresee an important role as a primary investigator in biomarker driven clinical trials as well as a collaborator with medical and surgical oncology to provide quality radiation oncology input and support for multimodality trials.

Summary

Glioblastomas are highly invasive primary tumors with poor prognosis despite current therapies. Individual targeted therapies have failed to offer long-term survival benefits, although combinations of rationally selected inhibitors may have significant therapeutic applicability for these tumors. Studies by our group and others have also shown aberrant, constitutive activation of NF-kB and Akt as common features of malignant gliomas, supporting their functional role in contributing to apoptosis resistance and refractory growth despite cytotoxic chemotherapy, irradiation, and molecularly targeted therapies. This activation may in part reflect deletions of NF-kB inhibitor-alpha, a common alteration in malignant gliomas, dysregulated stimulation by cell surface tyrosine kinases, such as EGFR and PDGFR-alpha, which are amplified in molecular subsets of malignant gliomas, and mutations in PTEN and other molecular targets that drive Akt and NF-kB activation. Thus, new therapeutic approaches are urgently needed. We have demonstrated that inhibition of NF-kB, Akt, and Bcl-2 may constitute a promising strategy to enhance the efficacy of conventional therapies, such as irradiation and cytotoxic chemotherapy, and potentiate the activity of agents targeted against growth signaling mediators.

Summary

Dr. Saeed’s research efforts are focused on immune modulatory approaches in patients with gastric & esophageal cancer, colon cancer and hepatocellular carcinoma as well as chemoprevention/ immunoprevention in the high-risk GI population. She has published more than 150 peer reviewed papers, posters and book chapters, and have led more than 40 clinical trials, focused on various immune modulatory regimens including but not limited to immune checkpoint inhibitor combinations with chemotherapy, other checkpoint inhibitors, antibody drug conjugates, bi-specific T cell engagers (BiTE), angiogenesis inhibitors, as well as immunotherapy combinations with regional approaches like stereotactic radiosurgery and intensity-modulated radiation therapy. She currently lead several investigator-initiated trials focused on novel targeted immunotherapy combinations including the ongoing phase I/II CAMILLA multicohort study looking at Cabozantinib plus Durvalumab with or without Tremelimumab in GI malignancies. Results from phase I/II part of the CAMILLA led to the development of the currently ongoing global pivotal trial, STELLAR 303, in patients with previously treated microsatellite stable colorectal cancer. She is also the study chair for a soon to open SWOG/intergroup NCI national trial (S2303) testing a novel chemo-immunotherapy regimen in patients with advanced gastric & esophageal adenocarcinoma. 

Summary

I am a clinical investigator who designs clinical trials in the space of colorectal cancer for drug development. My clinical research interests are targeted therapeutics and immunotherapy. I also collaborate with translational scientists to conduct correlative sciences. My translational research interests include understanding resistance mechanisms to immunotherapy, biomarkers analysis for immune response and investigating mechanisms of resistance to targeted therapy.

Summary

My research interests center on applying a Quantitative Systems Pharmacology (QSP) approach that integrates experimental and computational analyses to understand disease and drug mechanisms, which will lead to developing more effective therapeutic strategies.

Summary

My research has focused predominantly in the pathobiology of lung cancer and how the tumor microenvironment affects the natural biology and response to treatment. Working in collaboration with colleagues from the department of medical oncology we have discovered multiple possible biomarkers for disease management. In the future, I would like to integrate digital pathology analysis platforms into these studies. Specific topics of current investigation include: 1) Small cell lung carcinoma subtypes and genomics; 2) Morphologic features of lung cancer and its stroma, impact on natural biology; 3) Grading of Neuroendocrine Tumors; 4) Senescence in lung carcinoma immune response. In addition, in my role as the co-director of TARPS and as a member of TPIL, I hope to facilitate team based science, especially with regard to tissue based investigations.

Summary

I am an Assistant Professor of Health Informatics in the Department of Health Information Management within the School of Health and Rehabilitation Sciences at the University of Pittsburgh, with a secondary appointment at the Intelligent Systems Program (ISP). I am also leading our efforts at the Pitt HexAI Research Laboratory. I am also affiliated with the Center for AI Innovation in Medical Imaging (CAIIMI). Starting from August 2022, I am honored to serve our community as the Vice Chair of IEEE Computer Society at Pittsburgh. I have a deep passion for AI-Powered healthcare informatics and health data science with better patient diagnosis, prognosis, and treatment using largescale
multiple clinical data sources and advanced computational algorithms.
I am currently collaborating with Dr. Kurt Weiss on a research project entitled "Using Artificial Intelligence to Predict Response to Therapy in Adult and Pediatric Sarcomas", awarded by Pitt's Clinical and Translational Science Institute (CTSI). The main goal of the project is to develop, train, test, and validate deep learning medical image analysis algorithms and computer vision methods to predict response to therapy in sarcoma, localizing and characterizing CT and MRI findings in predicting response to the therapy.

Summary

My research has been rooted in developing and applying new technologies involving “high content” imaging methods to biomedical challenges. We have been applying quantitative systems pharmacology (QSP) to multiple disease areas including liver diseases and solid tumor cancers.  My interests include integrating QSP with patient microphysiology systems (MPS) to generate pathophysiological experimental and computational models to create a powerful paradigm in drug discovery and development. The latter has led to developing patient digital twins and patient biomimetic twins for liver diseases together with creating the BioSystics-Analytics Platform to manage, analyze, share and computationally model patient and biomimetic twin data. We spun-off BioSystics that merged with Nortis, Inc. to form NUMA Biosciences, a precision medicine company. In addition, our development of next generation spatial biology analytics for highly multiplexed fluorescence image data from patients led to the formation of PredxBio to address patient heterogeneity in drug discovery and development.

Summary

Dr. Taylor’s research interests include targeted and novel treatments of gynecologic cancer, correlated biomarker development for defining personalized cancer therapy, and screening and early detection of gynecologic cancers, particularly in individuals with hereditary predisposition to cancer. Her collaborations extend to colleagues within the Women’s Cancer Research Group at the University of Pittsburgh School of Nursing. As an interdisciplinary team of researchers, their focus is on overlapping research interests regarding patients’ quality of life, health services research, and patient-reported outcomes. This work is crucial to addressing all aspects of cancer care, which extends beyond cancer directed therapies.

Summary

Dr. Tyagi’s research interests include application of intravesical drug delivery techniques and urinary biomarkers to advance the diagnosis and care of bladder cancer, prostate cancer, benign prostatic hyperplasia and interstitial cystitis/painful bladder syndrome.

Summary

Dr. Liza C. Villaruz is an Associate Professor of Medicine at the University of Pittsburgh and UPMC Hillman Cancer Center and Co-Leader of the Immunotherapy and Drug Development Center at Hillman. She is a clinical and translational investigator in lung cancer with a focus on early drug development. She has active involvement in current clinical trials and a strong track record of successful development of institutional clinical trials with the National Cancer Institute and with industry partners.

Summary

My major research interests center around the discovery of small molecules with phenotypic assays in clinically relevant cellular and whole organism models. It is becoming increasingly clear that better models of the in vivo milieu are needed to improve the discovery of new drug candidates. Zebrafish, C. elegans, and Drosophila in particular provide unique opportunities to discover novel potential therapeutics using functional assays in a living animal as a complement to cellular and tissue model approaches. Together with members in the Departments of Neurology and Developmental Biology, I have established methodology for zebrafish chemical screening, generated automated image analysis tools for quantification of reporter gene expression, and automated neurobehavioral assays in multiwell plate formats. Currently, active zebrafish discovery projects include kidney and heart regeneration, angiogenesis and vascular malformations, early safety assessment, and neurodegenerative diseases. Cancer-related research efforts include the discovery of small molecule modulators of mitogen-activated protein kinase phosphatases (MKPs), PUMA, profilin-1, and estrogen receptor alpha as treatments for metastatic breast and colon cancer.

Summary

The Wipf group develops tools of synthetic organic chemistry in the search for innovative new therapies and therapeutics. We identify original synthetic methods, strategies and molecular mechanisms, and we apply them in medicinal chemistry and chemical biology, total synthesis, and natural products chemistry. We select target molecules on the basis of their unique architectures and biological activities, as well as for showcasing our synthetic methods. We employ insights from flow and photochemistry, material science and nanoparticle research to improve synthetic access and modify the properties of our target compounds. Most significantly, we are committed to collaborative drug discovery and development in diverse therapeutic areas, including oncology, neurodegeneration, fibrosis, neuromuscular diseases, inflammation, and immunology.

Summary

Norman Wolmark, MD, has spent decades conducting groundbreaking research and early clinical trials in the treatment of breast and bowel cancers.  Many of his early studies were conducted at the University of Pittsburgh alongside the late Dr. Bernard Fisher. Dr. Wolmark serves as Chairman of the NSABP Foundation and as Group Chair and Contact Principal Investigator of the NCI-funded NRG Oncology research organization, which combined the legacy National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG). Dr. Wolmark is a member of a number of professional associations and organizations, including the American Society of Clinical Oncology, the American Association of Cancer Research, and the American Surgical Association. He has authored more than 400 scientific publications and has served on the editorial boards of publications such as the Journal of Clinical Oncology, the Journal of Surgical Oncology, and Clinical Breast Cancer, as well as having served as a reviewer for journals such as the Annals of Internal Medicine, Breast Cancer Research and Treatment, Cancer Research, and the New England Journal of Medicine. Dr. Wolmark lectures internationally and has been recognized for his invaluable contributions to practice-changing research. 

Summary

The research focus of Dr. Xie's laboratory is nuclear receptor-mediated transcriptional regulation of genes that encode drug metabolizing enzymes and drug transporters. In addition to metabolizing drugs, the same enzyme and transporter systems are responsible for the homeostasis of endogenous chemicals. Therefore, besides drug metabolism and disposition, this regulation has broad implications in many human diseases, including liver diseases (fatty liver, liver fibrosis, liver cancer, and autoimmune hepatitis), endocrine disorders, metabolic syndrome, and cancers. Dr. Xie’s research is conducted using a combination of molecular biology and genetically engineered mice that include tissue and cell type-specific transgenic, knockout and humanized mice.

Summary

About one-third of the patients treated for prostate cancer opts for surgical removal of their tumors, with the remaining undergoing external beam radiation therapy (EBRT) or brachytherapy, along with androgen deprivation therapy (ADT; e.g., Leuprolide). While irradiation destroys the majority of cancerous cells, surviving ones can become senescent and resistant to treatment with increased risk of tumor reemergence. We have preliminary data that cinaciguat, a soluble guanilate cyclase (sGC) activator, decreases Bcl-2/BAX to enhance clearance and prevent reemergence of TRAMP-C1 orthotopic tumors in irradiated mouse prostates and in culture. Cinaciguat is a heme mimetic that promotes the formation of a heterodimer capable of catalyzing the formation of cGMP. Moreover, as cinaciguat acts only on heme-free sGC which accumulates in cells experiencing high levels of oxidative/nitrosative stress, such as following EBRT, it acts locally at the tumor site without systemic side effects in normal tissue where reduced sGC-Fe2+ is responsive only to nitric oxide (NO•). We are investigating the benefits of cinaciguat in: i) decreasing the detrimental effect of sGCα1 overexpression through enhanced dimerization of sGC; ii) increases cGMP levels via heme-free sGC to decrease Bcl-2 levels and promote apoptotic clearance of senescence cells (senolytic effect) and decrease NF-κβ-mediated cytokine release to dampen the SASP (senomorphic effect); iii) acting at the tumor site to limit systemic side effects; iv) obviating the need for ADT. We are using fractionated EBRT and the androgen-sensitive, luciferase-expressing, orthotopic TRAMP-C1 prostate cancer mouse model and cultured cells to characterize the therapeutic actions of cinaciguat.

Summary

The main research focuses of my lab are:
1. establishing new immunocompetent mouse models for lung cancer and utilizing them to study the therapeutic efficacy and mechanisms of novel combination of targeted therapy with immunotherapy
2. identifying new therapeutic vulnerabilities to overcome drug resistance in lung cancer
3. characterizing the organ-specific tumor immune contexture to develop immunotherapeutic strategies.
4. targeted degradation of KRAS mutants using in vivo PROTAC system. 

Summary

Amer H. Zureikat, MD, is chief of the Division of Gastrointestinal (GI) Surgical Oncology at UPMC Hillman Cancer Center, co-director of the UPMC Hillman Cancer Center Pancreatic Cancer Program, and associate professor of surgery at the University of Pittsburgh School of Medicine. Dr. Zureikat specializes in cancers and diseases of the pancreas, stomach, liver, and duodenum, and practices state-of-the-art robotic surgery.