Page 25 - Annual Report 2020
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                      vascular biology and angiogenesis research,
which is applicable to finding new treatments
for cardiovascular disease and stroke as well as cancer. The third member of our team is a visiting scientist named Zhu Zhu, who has contributed
her molecular biology skills to a variety of our impactful cancer and vascular biology studies. We have recently revealed a molecular pathway that regulates angiogenesis, which sheds light on the etiology of diseases associated with dysregulation of vascular signaling networks (Journal of Biological Chemistry, 2019). We have identified biological processes that contribute to UV-induced skin damage, serving as a basis for new treatments for severe sunburn (BioRxiv, 2020). We are focused on making basic science discoveries that have strong promise to translate to the clinic. Our ultimate
goal is to improve the health and quality of life of individuals locally, nationally, and beyond.
Discovering new mechanisms of small
cell lung cancer progression
Small cell lung cancer is particularly deadly because tumor refractory growth typically
occurs within about one year of chemotherapy, which underscores the importance of identifying therapeutically targetable molecular drivers of acquired resistance. We have recently discovered that a dopamine-regulated phosphoprotein called DARPP-32 drives small cell lung cancer growth (British Journal of Cancer, 2020). Using a multitude of models, we have shown that DARPP-32 and
its splice variant t-DARPP promote
lung tumor growth through increased
proliferation, Akt/Erk-mediated survival
and anti-apoptotic signaling. We have
revealed that small cell lung cancer
patient-derived specimens exhibit
aberrantly high DARPP-32 and t-DARPP protein expression relative to normal lung, in which DARPP-32 isoforms are virtually undetectable by immunostaining. The cancer-specific expression profile of DARPP-32 isoforms lends itself well to safe targeting and minimal toxicity to nonmalignant tissue. DARPP-32 isoforms represent potential therapeutic targets.
Combating non-small cell lung cancer resistance to targeted therapy
Many non-small cell lung cancer patients are diagnosed with advanced disease and tested for specific tumor-causing mutations, including those that frequently occur in a gene called EGFR (i.e. epidermal growth factor receptor). EGFR mutation positive advanced stage lung cancer patients benefit from treatment with drugs designed to inhibit EGFR signaling. Unfortunately, most patients develop resistance to these drugs within 12-18 months and rapid cancer progression recurs.
To address this problem, we have identified new biomarkers that can likely predict drug resistance susceptibility of individual lung cancer patients.
We have discovered that a protein called DARPP-32 promotes resistance to drugs that target EGFR.
We are currently conducting research to develop DARPP-32 as a marker
of resistance as well as test new therapeutic approaches to improve the treatment of EGFR mutation positive lung cancer.
Figure 2: Vascular system (green) of a larval zebrafish used as a disease model.
Role and therapeutic control of vascular permeability in cardiovascular disease and cancer
Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular permeability is induced by a protein called VEGF (i.e. vascular endothelial growth factor). Given the prominent role of VEGF in promoting pathologies associated with cancer, heart disease, and stroke, inhibiting vascular permeability mediated by VEGF and inflammation is an important therapeutic pursuit. We hypothesize that VEGF and other permeability inducing factors mediate vascular permeability through a protein called STAT3,
and thus, targeting the STAT3 signaling cascade represents a promising strategy to reduce pathological effects of permeability during cancer and cardiovascular disease. We are currently using
a variety of in vitro and in vivo models to understand the molecular basis of STAT3-regulated permeability.
                                                              Figure 1: Lung cancer cells showing the nucleus (blue) and 2 receptors (EGFR: green, ERBB3: red).
                                  Other professional activities:
Funding:
The Elsa U. Pardee Foundation Grant
Grant-in-Aid Award, Office of the Vice President of
Research, University of Minnesota
Editorial Board:
Nature Partner Journals: Precision Oncology
Grant Review:
National Institutes of Health, National Cancer Institute U.S. Dept. of Veterans Affairs, Mental Health
& Behavioral Sciences
American Cancer Society, Institutional Research Grants Pennsylvania Department of Health
Florida Department of Health
National Cancer Institute
                       THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 25
           
























































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