Clinical & Pre-Clinical Pharmacology

Dr. Baker’s cancer-relevant research interests broadly cover translational and clinical pharmacology of anti-cancer agents. Recently, her laboratory has focused on the preclinical development of anti-cancer agents for the treatment of acute myeloid leukemia (AML), with an emphasis on tyrosine kinase inhibitor (TKI) drug combinations. Dr. Baker’s research interests include developmental therapeutics for AML, clinical pharmacology of tyrosine kinase inhibitors, variability in anti-cancer drug disposition and investigational anti-cancer drug development.

My current research focuses on determining how targeted and cytotoxic chemotherapy impact the brain and how drug transporters contribute to these effects. Consistent with this research, I am interested in the translational pharmacology of anticancer therapeutics, especially the characterization of preclinical and clinical pharmacokinetics and pharmacodynamics.

Our research team members are engaged in pre-clinical target identification for pharmacologic treatment of neurodegenerative and psychiatric disorders. We use in vivo and in vitro high-resolution fluorescence microscopy and high-content analysis of live neurons to reveal complex interactions between signaling pathways that regulate cell survival/function and circadian clock signaling. This work is designed to identify new avenues of chronotherapeutic target development for CNS disorders. Current work focuses on two related themes: (1) Alzheimer’s Disease and desynchronization of cortico-limbic circadian rhythms and (2) MAPK signaling: gates, oscillators and circadian timing.

The overall goal of Dr. Hu’s research is to evaluate the contribution of uptake transporters, in particular OCT and the OATP1B-type transporters, in the disposition and toxicity of anticancer drugs, with particular emphasis on peripheral neurotoxicity. Her laboratory utilizes multi-level approaches including in vitro, in vivo models, aims to understand the underlying mechanisms that drive the extensive inter-individual pharmacokinetic variability, drug transporter regulation, antitumor efficacy, and drug-drug interaction in response to drug therapy in cancer patients. Another area of research interest is to design of preclinical and clinical studies to evaluate pharmaceutical agents as modulators of side effects associated with tubulin poisons, such as paclitaxel and vincristine.

The overarching goal of the Kroetz laboratory is to understand the molecular basis of interindividual variability in drug response and toxicity. Genomic association studies are used to identify genes and pathways involved in common toxicities associated with cancer therapy, including taxane-induced peripheral neuropathy and bevacizumab-induced hypertension. Functional genomic studies are then used to define the role of these genes and pathways in the dose-limiting toxicities. A second area of research is on the role of ABC transporters in drug resistance and physiologic function. Ongoing efforts include cryo-EM studies of MRP4 and investigation of MRP4 in resistance to immunotherapy.

Our laboratory is focused on identifying therapeutic targets for kidney diseases. Acute kidney injury and renal cell carcinoma are the two major areas of interest. Our recent work has identified several protein kinases and membrane transporters as therapeutic targets for renal disorders. We utilize high throughput screening assays and functional genomics to identify molecular targets for renal diseases, followed by validation in in vivo animal models. The overall goal of these studies is to identify new therapeutic strategies to treat acute kidney injury and renal cell carcinoma, diseases for which no effective therapies are currently available.

Dr. Phelps’ lab is involved in both pre-clinical and clinical development of numerous small molecule anti-cancer and immuno-modulatory agents under development. Their work aims to understand the mechanisms involved in the absorption, distribution, metabolism, and excretion (i.e. pharmacokinetics, PK) of these agents, and how both the PK and pharmacodynamic (PD) effects of these agents are altered by genetic differences (polymorphisms) among individuals (i.e. pharmacogenetics, PG).

Dr. Sparreboom's research studies the contribution of solute carriers to chemotherapy-induced toxicity profiles, identifies chemical inhibitors of critical transporters, translates the findings to clinical trials in collaboration with scientists and oncologists, and ultimately improves the long-term outcome of patients with cancer by modulating the therapeutic window of widely-used chemotherapeutics. His research is currently focused on the development of transport modulators that could be used in conjunction with platinum-based drugs and tyrosine-kinase inhibitors, with emphasis on the development of innovative preclinical model systems.