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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. 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.
Dr. Beumer is a tenured Professor of Pharmaceutical Sciences with a secondary appointment in the School of Medicine at the University of Pittsburgh, and holds the distinction of Diplomate of the American Board of Toxicology (DABT). He is intimately involved in the design, execution, supervision, and data analysis of PK and metabolic studies covering the entire spectrum of preclinical vitro-vivo, clinical phase 1, 2, 3, and post-marketing studies, with funding in each phase. Dr. Beumer is PI on one of only 3 NCI N02 Preclinical Pharmacology Contracts, mPI of one of the two U24 PK consortia supporting the NCI ETCTN efforts, and he is mPI of one of only 8 clinical ETCTN UM1 Grants, funding the Pittsburgh Cancer Consortium. He directs the Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) of the UPMC Hillman Cancer Center (HCC), traditionally also the PK core of the NSABP-RTOG-GOG (NRG) and ALLIANCE. He has served as co-chair of the NCI Investigational Drug Steering Committee (IDSC), is co-chair of the IDSC Pharmacology Task Force, and is a founding member of the “TDM in oncology” committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT).
Dr. Beumer has over 190 peer-reviewed publications, and has presented at national and international venues. He is also the Editor-in-Chief (U.S.) of the journal Cancer Chemotherapy and Pharmacology, and was awarded the 2021 Michaele Christian Oncology Drug Development Award and Lectureship by the National Cancer Institute Cancer Therapy Evaluation Program.
Dr. Beumer’s interests are the development of anticancer agents partnering with both NCI and pharmaceutical partners, focusing on early trials that aim to study the pharmacology (PK/PD) of these novel agents (first-in man, mass balance, organ dysfunction, etc). His laboratory is able to support clinical trials with pharmacokinetic analyses by LC-MS/MS up to 14C analysis in a variety of samples from mass balance studies.
The research in the laboratory of Dr. Fernandez focuses on improving cancer treatment and patient outcomes through various areas:
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.
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).
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.
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.
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.
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.
