Research

Zhou Lab

Overview

The central hypothesis we have been actively exploring is that the failure of a treatment is attributable to pharmacokinetic and/or pharmacodynamic failures, such as inadequate drug concentrations at the site of action or activation of alternative signaling pathways. The rationale behind this hypothesis is based on our previously and recently published studies in the area of experimental cancer therapy. In addition to the cancer treatment related studies, we have been actively working on collaborative projects in which we utilize our drug analysis skills and pharmacokinetic animal study techniques to characterize systemic pharmacokinetics and biodistribution of nanomedicine and biologic drugs in mouse models.

Chronic treatment with certain MKIs in NSCLC may activate cancer associated fibroblasts (CAFs), which could in turn reduce drug penetration into the tumor and render NSCLC cells less responsive to long-term MKI therapy. Our ongoing study is concerned with the quantitative assessment of the impact of activated CAFs on the distribution of MKI using subcutaneous and orthotopic murine models of human NSCLC and the identification of the key molecular factor that regulates the activation of CAFs in MKI-treated NSCLC xenografts.
Given that the activation of “bypass signaling” appears to be an inevitable consequence of cancer treatment with all existing small molecule targeted therapeutic agents and it takes extremely long time for small molecule therapeutic agents to be approved by the FDA, we are prompted to test a different treatment approach that have the potential to target any gene of interest. In this project, we aimed to test the intratumoral gene knockdown efficiency of the focal adhesion kinase (FAK)-targeting siRNA that is delivered to the lung tumor using a peptidic nanoparticle platform. Results of this study will provide the framework to develop RNA interference-based therapies to silence genes involved in the pathogenesis of lung cancer.
Although deregulation of cellular metabolism is long believed to play a key role in tumorigenesis, targeting cancer metabolism for therapeutic purposes remains challenging. Since our preliminary data showed that deletion of Tat-interacting protein 30 (TIP30) in A549 human lung adenocarcinoma cells resulted in the upregulation of genes involved in suppressing mitochondrial metabolism, we hypothesize that activation of TIP30 increases mitochondrial metabolism, production of ROS and oxidative stress, eventually leading to tumor growth arrest. The aim of this ongoing project is to examine the association between TIP30 expression levels and mitochondrial metabolisms in tumors and tumorigenic potential and to explore the mechanism underlying the effect of TIP30 on cellular metabolic pathways.
Combination therapy is considered a better strategy over monotherapy to target different mechanisms of blood pressure control. However, there is limited clinical data available to guide the selection of combination regimens in part due to the fact that clinical testing of new drug combinations is prohibitively expensive. As a result, the initial choice of drugs and dosing schedules is largely empirical, and whether the various degrees of improved therapeutic outcome with combination therapy are due to additive, synergistic or antagonistic effects remains undefined. We proposed to develop an isobolographic analysis-based approach to determine the nature and degree of interactions between two antihypertensive drugs used in combination. This approach has the potential to examine the impact of age on the patterns of synergistic or antagonistic interactions between two antihypertensive agents across doses, thereby assisting in the rational selection of promising drug combinations for further clinical development and providing clues for the investigation of underlying mechanisms.

Selected Publications

Zhou Q, Lv H, Mazloom AR, Xu H, Ma'ayan A, Gallo JM (2012). Activation of Alternate Pro-Survival Pathways Accounts for Acquired Sunitinib Resistance in U87MG Glioma Xenografts. J Pharmacol Exp Ther. 343:509-19. [Impact Factor: 3.891]

Ballesta A, Zhou Q, Zhang X, Lv H, Gallo JM. (2014). Multiscale design of cell-type-specific pharmacokinetic/pharmacodynamic models for personalized medicine: application to temozolomide in brain tumors. CPT Pharmacometrics Syst Pharmacol. 3:e112. [Impact Factor: N/A]

Zhou Q, Whelan G, Zhou SF, Lane ML, Vesely DL. (2014) Subcutaneous pharmacokinetics of the cardiac hormone vessel dilator. Clin Exp Pharmacol Physiol. 41:565-70. [Impact Factor: 2.01]

Zhou Q, Bennett LL, Zhou S. (2016) Multifaceted ability of naturally occurring polyphenols against metastatic cancer. Clin Exp Pharmacol Physiol. 43(4):394-409. [Impact Factor: 2.01]

Zhou Q, Guo X, Choksi R (2017) Activation of Focal Adhesion Kinase and Src Mediates Acquired Sorafenib Resistance in A549 Human Lung Adenocarcinoma Xenografts. J Pharmacol Exp Ther. 363(3):428-443. [Impact Factor: 3.867]

Ashraf Ul Kabir, Tae-Jin Lee, Hua Pan, Jeffrey Berry, Karen Krchma, Jun Wu, Fang Liu, Hee-Kyoung Kang, Kristina Hinman, Lihua Yang, Samantha Hamilton, Qingyu Zhou, Deborah V. Novack, Robert Mecham, Samuel Wickline, Mark Miller, Kyunghee Choi. (2018) Requisite endothelial reactivation and effective siRNA nanoparticle targeting of Etv2/Er71 in tumor angiogenesis. JCI Insight. 3(8). [Impact Factor: 6.014]

Zhou Q, Pan H, Li J. Molecular Insights Into Potential Contributions of Natural Polyphenols to Lung Cancer Treatment. Cancers (Basel). 2019 Oct 15;11(10):1565. [Impact factor: 6.162].

Wilson AJ, Zhou Q, Vargas I, Palekar R, Grabau R, Pan H, Wickline SA. Formulation and Characterization of Antithrombin Perfluorocarbon Nanoparticles. Methods Mol Biol. 2020;2118:111-120. [Impact factor: 10.71].

Li M, Li J, Guo X, Pan H, Zhou Q. Absence of HTATIP2 Expression in A549 Lung Adenocarcinoma Cells Promotes Tumor Plasticity in Response to Hypoxic Stress. . Cancers (Basel). 2020 June 11; 12(6), 1538. Feature Paper. [Impact factor 6.162].

Taneja College of Pharmacy

Taneja College of Pharmacy

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Zhou Lab

Research

Overview

Selected Publications